---

Table of contents  :  Signalling ways extra-individual signaling : pheromones intra-individual signaling cellular receptor and mobile ligand synaptic signaling paracrine signaling autocrine signaling endocrine signaling both receptor and ligand on plasma membrane : juxtacrine signaling intracrine signaling Cell membrane transport Signal transduction pathways (STP) receptors membrane receptors ionotropic receptors (5x) metabotropic / G protein-coupled receptors (GPCRs) catalytic receptors receptors tyrosine kinase tyrosine kinase-coupled receptors receptors tyrosine phosphatase receptors serine / threonine kinase receptors guanylate cyclase receptors coupled to intracellular adapters Nuclear receptors Non-receptor solute carriers (SLC) (12x) Non-receptor ion channels voltage-dependent ion channels (4x) Metabolisms of chemical elements Iron metabolism Intracellular STP enzymes Cross-talking among STPs Scaffolds in STPs Enzymes in STP Transcription factors in STPs

---

SIGNALLING WAYS

• extra-individual signalling
• ultrasound in animal communication :
• echolocation and the pursuit of prey by bats (Chiroptera)
• in rodents of the Muridae family it may indicate distress in infants or a sexual or predatory encounter in adults
• ultrasonic alarm calls (twin advantages of being highly directional and inaudible to key predators) : in the wild by a rodent of the Sciuridae family, Richardson's ground squirrel (Spermophilus richardsonii), warns conspecifics of impending danger^ref
• odortypes : genetically determined body odors that distinguish one mouse from another. They are released into the extracellular space, reached the bodily fluids, and passed to other animals
• those specified by H-2, the MHC of the mouse, are the best known odortypes, highly expressed in urine. Trained mice in a Y-maze olfactometer are able to discriminate nearly identical inbred mice that differ genetically only at the MHC (MHC congenic mice), while they cannot distinguish genetically identical inbred mice. Mice that are unable to express their genomic class I MHC genes because they lack b₂-microglobulin are distinguishable by scent from otherwise identical mice which possess an intact b₂-m gene. This odortype disparity appears at 9-12 days of gestational age, the period in which the MHC is first detectable in fetal cells of normal mice^ref. Odorants comprising prerenal odortypes are already present in blood, albeit in masked form^ref. Because MHC molecules and the peptides that bind them are quite unique for each individual, these peptides are good candidates for sensed genetic individuality within species via olfactory recognition : peptides that bind MHC class I molecules activate neurons in the sensory epithelium of the vomeronasal organ (VNO), the secondary olfactory system, of mice^ref. Anyway mice lacking a VNO can discriminate MHC-determined odortypes, so the VNO is not necessary for learning to discriminate between MHC odortypes^ref. Odortypes are involved in :
• reproductive behavior :
• mating selection, thereby favoring outbreeding and heterozygosity : mice do a lot of sniffing of the face and the urogenital region
• maintenance of early pregnancy (embryonic implantation) : at 9-12 days of gestation, odortypes specified by paternal (non-maternal) MHC haplotypes become apparent in maternal urine^ref, thus the odortypes of pregnant women are a compound of maternal and fetal odortypes^ref. If during a critical period of pregnancy, the female is exposed to another male, or to the smell of that male, she loses the pregnancy (Bruce effect). When pregnant mice are exposed to urine samples containing different MHC peptides, only those peptides corresponding to unfamiliar males triggered pregnancy loss. Although the "peptide hypothesis" provides a solid explanation for intraspecific communication, it does not rule out other explanations, such as those that propose that fragments of the MHC molecules, or the MHC molecules themselves, act as communication signals, or that bacteria living on the skin influence the body odor and deliver a message : any of those hypothesis has been disproved, but the peptides are sufficient to induce an olfactory memory of an individual
• newborn mice already express their MHC odortype (which is detectable at 9 days of gestational age : the urines of H-2-dissimilar infant mice, even at 1 day of age, are distinguished in the Y-maze)^ref
• mothers to recognize and preferentially retrieve syngeneic (genetically identical) pups from other pups differing only for MHC. Reciprocally, we report the ability of pups to recognize their familial environment, regardless of whether they had been nursed by their biological mothers or by foster mothers. Early learning experiences of the MHC environment are apparently a key element in survival, assuring maternal protection and promoting outbreeding^ref.
A prime experimental method of identifying H-2 odortypes is the specially designed Y-maze in which mice are trained, by water deprivation and reward, to distinguish odors conducted to the arms of the maze from H-2-dissimilar mice or their urines. Urine would seem to be a unique source of H-2 odortypes. If H-2 odortypes represent mostly compound odors composed by H-2 genetic variation in the urinary output of odorous metabolites, as distinct from simple odors that depend on chemical differences of single odorants, then the kidney, which is not responsible for H-2 odortype specificity, may nevertheless impart a unique character to urinary odortypes by virtue of differential excretion/resorption processing of various constituent odorous metabolites. In that case, various organs and tissues, among which the hematopoietic/lymphoid system is known to contribute to H-2 odortype specificity, may exhibit tissue-specific varieties of H-2 odortypes, their products having not yet been subjected to renal processing. Discrimination of H-2 odortypes is not appreciably affected or impaired by the usual concurrent segregation within the genome as a whole^ref. Y-maze behavioral testing of urine fractions from anion exchange chromatography indicates that volatile acids are necessary and sufficient to convey MHC odortype information. Diethyl ether extracts, which are expected to contain the more volatile, less polar organic acids, are also discriminable in the Y-maze olfactometer. No compounds unique to urine of either genotype have been detected, but compounds appear to occur in characteristic ratios in most of the samples of each type. Nonparametric statistical analysis of the gas chromatographic data showed that 8 of the peaks occurred in significantly different relative concentrations in the congenic samples. 1 of the peaks was shown to represent phenylacetic acid, which has implications for the mechanism of the MHC specification of odortype. Hence the MHC-determined urinary odor is composed of a mixture of volatile carboxylic acids occurring in relative concentrations that are characteristic of the odortype^ref. The major urinary proteins (MUPs) are proteins secreted by the liver and filtered by the kidneys into the urine of adult male mice and rats, the MUPs of rats being also referred to as a_2U-globulins. The MUP family also comprises closely related proteins excreted by exocrine glands of rodents, independently of their sex. The MUP family is an expression of a multi-gene family. There is complex hormonal and tissue-specific regulation of MUP gene expression. The multi-gene family and its outflow are characterized by a polymorphism which extends over species, strains, sexes, and individuals. There is evidence of evolutionary conservation of the genes and their outflow within the species and evidence of change between species. MUPs share the 8-stranded b-barrel structure lining a hydrophobic pocket, common to lipocalins. There is also a high degree of structural conservation between mouse and rat MUPs. MUPs bind small natural odorant molecules in the hydrophobic pocket with medium affinity in the 10⁴-10⁵ M^-1 range, and are excreted in the field, with bound odorants. The odorants are then released slowly in air giving a long lasting olfactory trace to the spot. MUPs seem to play complex roles in chemosensory signalling among rodents, functioning as odorant carriers as well as proteins that prime endocrine reactions in female conspecifics. Aphrodisin is a lipocalin, found in hamster vaginal discharge, which stimulates male copulatory behaviour. Aphrodisin does not seem to bind odorants and no polymorphism has been shown. Both MUPs and aphrodisin stimulate the vomeronasal organ of conspecifics^ref.
• other odortypes originate from unidentified loci in the rest of the genome, including both sex chromosomes^ref
• pheromone : a substance secreted to the outside of the body by an individual and perceived (as by smell) by a second individual of the same unicellular or multicellular species, releasing a specific reaction of behavior in the percipient. Chemical structures :
• alcohols
• esters
• carbonyls
• ethers
• epoxides
• hydrocarbons
Specificity is given by stereoisomerism or relative concentrations.
Examples of biological effects :
• Bruce effect : the blocking of pregnancy in a newly impregnated female mouse by a pheromone (the odor of a strange male).
• Whitten effect : initiation and synchronization of the estrous cycles and reduction of the frequency of reproductive abnormalities in female mice by the odor (pheromone) of a male mouse placed among them; when more than four female mice are placed together in a cage their estrous cycles become very erratic.
Putative pheromones in humans include:
• estrogen-like steroid estra-1,3,5(10),16-tetraen-3-ol (EST) (found in female urine) EST did not significantly affect physiological arousal in women or men
• testosterone derivative D^4,16-androstadien-3-one / androstadienone (AND) (an androgen derivative that is the most prevalent androstene in human male sweat, male axillary hair, male axillary skin surface, and blood plasma (2.05 +/- 0.74 pmol/ml^ref)) is able to simulate the human female vomeronasal organ in picogram (pg) quantities, resulting in changes in autonomic activity. When 100 pg of androstadienone were injected directly to the vomeronasal organ a significant reduction of nervousness, tension and other negative feeling states was observed. Concordant changes were observed in autonomic physiology^ref. It activates the anterior part of the inferior lateral prefrontal cortex (PFC) and the posterior part of the superior temporal cortex (STP), regions identified as cortical fields underlying other than olfactory functions, including various aspects of social cognition and attention^ref. It increased physiological arousal in women but decreased it in men^ref, and yields effects on women's mood; the feeling of being focused. The mood effects were not dependent on menstrual cycle phase^ref. The absolute detection threshold for androstadienone was determined to be 211 micro M using the method of constant stimuli. Sensitivity distribution for androstadienone, but not for the reference odor phenylethyl alcohol, was bimodal, with a smaller group of individuals with a high sensitivity to androstadienone (supersmellers). A lack of correlation between thresholds for androstadienone and phenylethyl alcohol further suggested that the bimodality for androstadienone was not due to individuals with a high general olfactory sensitivity, precluding the possibility that the bimodal sensitivity distribution for androstadienone would depend on individual differences in trigeminal activation. In line with an earlier observation, there was a statistical tendency for women to be more sensitive to androstadienone than men^ref. Male subjects exhibited higher androstadienone sensitivity in the pre/peri-pubertal group as compared to the post-pubertal group. This difference was not observed in female subjects. Correspondingly, a negative correlation between age and androstadienone sensitivity was found for male subjects, but not for female subjects. In contrast to this sex-specific change of the androstadienone odor threshold, verbal skills and odor identification abilities increased with age in all subjects regardless of their sex. In conclusion, the present observations confirm previous research on sex-differentiated effects of aging during puberty on sensitivity towards odorous steroids. While the underlying causes are unknown, it may be hypothesized that the decreased sensitivity could result from the increased endogenous levels of androstadienone in male subjects. Future studies should include both steroid and non-steroid odorants to further explore these age-related changes^ref. Only high concentrations of AND (0.00625 M) increased positive mood and decreased negative mood in women compared to men, and had sympathetic-like effects in women, and parasympathetic-like effects in men^ref
These potential human chemosignals were not consciously discernible in a strong-odor carrier (clove oil and propylene glycol). In a double-blind, within-subject, repeated-measures experiment with 65 subjects, we demonstrated that both steroids produced sustained changes in digit skin temperature and palmar skin conductance (an indicator of sympathetic nervous system tone) within 6 min of exposure^ref while the subjects were completing psychological questionnaires or reading. These effects, however, did not follow the sex-stereotyped pattern predicted by a sex attractant function. Both androstadienone and estratetraenol raised the skin temperature of men's hands and lowered it in women. Likewise, each steroid increased skin conductance, with a significantly greater effect on women than men. Women's responses were observed only in the sessions run by the male tester, an effect that may or may not be solely attributable to tester sex. Men's responses, in contrast, were not affected by this difference in socioexperimental condition. Similarly, women experienced an immediate increase in positive mood only in the presence of the male tester, while men's responses were unaffected by this socioexperimental context. One source of this sex difference may be the fact that the majority of women were in the late follicular phase of their menstrual cycle. Although it is premature to classify these steroids as pheromones, our data suggest that they function as chemosignals that modulate autonomic nervous system tone as well as psychological state^ref.
During the neutral context, none of the compounds affected mood or autonomic nervous system function. However, compound effects were significantly increased within arousing contexts. During the sexually arousing context, both compounds increased sexual arousal. During the sad context, AND maintained positive mood in women and increased negative mood in men. Memory for events during the sad context was impaired by AND in women but not in men. Finally, effects of AND on physiology were observed during the sexually arousing context whereby AND increased skin temperature in both sexes but reduced abdominal respiration rate in men only. These results suggest that sex-steroidal compounds modulate mood, memory and autonomic nervous system responses and increase their significance within specific behavioral contexts. These findings lend support to a specific role for these compounds in chemical communication between humans^ref.
Women are most likely to cheat on their long-term partner when they are at their most fertile, and they tend to choose genetically superior men for their fling. That's the claim of a study by Czech researchers, which found that the smell of a socially dominant male is most exciting to women in stable relationships, especially on days when they are ovulating. 48 men were asked to complete a questionnaire, rating statements such as "I am the life of the party", in order to score the volunteers' social dominance. The researchers also asked them to wear cotton pads under their arms to collect sweat. A group of 65 women then smelled the pads and rated the sexiness and masculinity of the scent. Women in the middle week of their menstrual cycle, the point at which fertility is at its peak, tended to prefer the smell of the men who scored highest on the dominance quiz. This preference was not shown by women at other points in their cycle. What's more, the effect was only significant for women in long-term relationships. Both menstrual phase and relationship status can have an effect on which men women tend to prefer. The results support a theory of mixed mating strategies, which argues that women should want different things from different men at different times. Females are expected to pair up with the males most likely to invest in parental care, but any affair is likely to be conducted with successful males who, although they may not be good dads, provide good genes. Other studies have shown that women are more likely to get involved in extra-pair affairs during their fertile period : in such cases more socially dominant males would be preferred. The idea is difficult to assess, because male quality is difficult to judge. Other researchers have used measures such as the 'ruggedness' of a man's face, or the symmetry of his features. A high dominance score is a reflection of high mating quality. Such individuals are more likely to reach high social status. And this may reflect high genetic quality. Perhaps the most controversial part of the study is the claim that women find the smell of sweaty cotton pads enticing. Some raters found particular body odours sexy; others simply found them 'not repellent'. But laboratory conditions are rather unnatural, and the smells would be judged more positively in more relevant, that is, intimate, conditions^ref.
Web resources : Pherobase by chemical ecologist Ashraf El-Sayed of the New Zealand-based company HortResearch
• cellular receptor and mobile ligand (if the receptor is moved (receptor shedding) => retrocrine signalling)
• synaptic signalling (wiring transmission) : a synapse is a stable adhesive junction between 2 cells across which information is relayed

Kinds of synapses :
• chemical synapse : the usual type of synapse seen in vertebrates, in which the impulse is carried by a neurotransmitter. Several key criteria are generally recognized as important in synaptic assembly :
• cells remain individuals : there are points of contiguity but not continuity between cells across which information is transferred. Implicit in this notion is that there must be surfaces of separation, in essence, membrane surfaces parallel each other with a fluid-filled cleft in between
• adhesion : in the initial stages of synapse formation there are recognition events through which one surface recognizes another. If the "fit" is right, the pre- and postsynaptic surfaces are locked together by putative and bona fide adhesion molecules; the latter set in nonsynaptic cell systems have been unequivocally shown to function in cell:cell adhesion
• stability : the adhesive clamp provides stability and aligns the "active zones" and postsynpatic elements in relation to one another. Certain adhesion molecules, such as N-cadherin, may also change conformation and, therefore, adhesivity in response to synaptic activity and modulate further synaptic responses. The polarity of the cytoskeleton may also influence stability as the organization of the cytoskeleton may change to further stabilize the synapse.
• directed (vectorial) secretion : on the presynaptic side, a secretory apparatus is assembled that is activated by appropriate signaling events. On the postsynaptic side, a receptor surface is put in place containing molecular machinery that transduces signals into relevant intracellular signals. The presynaptic and postsynaptic surfaces of separation partition certain functions in the lateral plane of the membranes, such that complex microdomains are formed around a central "active zone" for secretory communication. The configuration of these microdomains may change in response to synaptic activity
Localizations :
• immunological synapse
• neuronal synapse / synapsis : the site of functional apposition between neurons, at which an impulse is transmitted from one neuron to another, usually by a chemical neurotransmitter (e.g., acetylcholine, norepinephrine, etc.) released by the axon terminal of the excited (presynaptic) cell. The neurotransmitter diffuses across the synaptic cleft to bind with receptors on the postsynaptic cell membrane, and thereby effects electrical changes in the postsynaptic cell which result in depolarization (excitation) or hyperpolarization (inhibition)
• axoaxonic synapse : one between the axon of one neuron and the axon of another neuron.
• axodendritic synapse : one between the axon of one neuron and dendrites of another.
• axodendrosomatic synapse : one between the axon of one neuron and the dendrites and body (soma) of another, as in motoneurons.
• axosomatic synapse : one between the axon of one neuron and the body (soma) of another.
• dendrodendritic synapse : a rare type of synapse involving transmission from a dendrite of one cell to a dendrite of another.
• loop synapse : one having a relatively long area of contact of fiber membranes; seen in many invertebrates.
• synaptic glomerulus : a glomerulus formed by the coming together of a number of end-feet around a central dendrite, all enclosed by a layer of neuroglial cells; found in the sensory nuclei of the thalamus, in the olfactory bulbs, and in a few other locations in the brain
• nonencapsulated nerve glomerulus : type of free nerve ending in the connective tissue of various organs, with the terminal branches of the nerve forming spherical or elongated structures resembling glomeruli.
• corpusculum nervosum terminale / terminal nerve corpuscle / end bulb / encapsulated nerve ending : a sensory nerve ending characterized by a fibrous capsule of varying thickness that is continuous with the endoneurium
• bouton de passage / bouton en passant : a button-like swelling on an axon at an en passant synapse (synaptic contact between non-terminal parts of axons; seen in coelenterates and among certain special cells in the CNS of vertebrates)
• bouton terminal / boutons terminaux / terminal button / synaptic bouton / end-foot / synaptic knob : a button-like terminal enlargement of an axon that ends in relation to another neuron at a synapse
• synaptosome : any of the membrane-bound sacs that break away from axon terminals at a synapse after brain tissue has been homogenized in sugar solution; it contains synaptic vessels and mitochondria.
Synaptogenesis : both axonal and dendritic filopodia actively partecipate in synapse formation, with highly dynamic interactions at contact sites of advancing axon growth cones and dendritic filopodia. Transport packets containing preassembled synaptic vesicle components begin to accumulate at presynaptic sites immediately after axons and dendritic filopodia establish initial contact. Presynaptic components are assembled very rapidly, within 1 to 2 hours of initial contact between neurons. Presynaptic differentiation is characterized by the appearance of varicosities containing accumulations of synaptic vesicles at the presynaptic side as well as by the onset of activity-evoked vesicle-recycling. Presynaptic differentiation precedes postsynaptic differentiation in developing hippocampal neurons but the contrary occurs in cultured hippocampal neurons, while it occurs simultaneously in cultured cortical neurons. Highly motile dendritic filopodia are progressivelty replaced by developing spines or protospine, which then mature into spines, tiny protrusions at which most synaptic contacts are made. Ultrastructurally identified synapses are localized throughout the axon arbor : in more mature arbors, however, ultrastructurally identified synapses are preferentially localized to distal end branches. 80% of new branches originate at axon arbor sites rich in synaptic clusters. Consequently, synapse formation and stabilization may be required for new branch extension. The formation and stabilization of new synapses may, therefore, trigger the developmental, activity-dependent increase in axon arbor complexity. During development, more synapses are established than ultimately will be retained. Therefore, the elimination of excess synaptic inputs is a critical step in synaptic circuit maturation. Synapse elimination is a competitive process that involves interactions between pre- and postsynaptic partners. The dynamics of synapse formation and of synapse elimination may be much more rapid in the CNS than at the NMJ, where synapse elimination has been well characterized. At the vertebrate NMJ, a single muscle cell is initially innervated by multiple motor axons. The transition from multiple innervation to innervation by a single motor axon occurs gradually as some terminal branches retract from each muscle fiber before others, a process requring about 24 hours for withdrawal of the presynaptic terminal. Motor axons lose branches asynchronously and without spatial bias, suggesting that local interactions at each NMJ regulate synapse elimination. Synapse elimination at the NMJ is an activity-dependent process, where weakening of synaptic function is thought to precede synapse dismantling of about 1.5 hours : presynaptic disassembly precedes disassembly of the postsynaptic apparatus upon synapse destabilization. Rapid synapse disassembly precedes branch elimination. Neural activity may play permissive rather than instructive roles : activity is not required for initial aspects of synaptogenesis. The neural synapse in the CNS has been proposed to be derived from the classic adherens junction of epithelia in that it uses cadherins and their binding partner to sustain adhesive struts across the cleft.
Synapses also occur at sites of apposition between nerve endings and effector organs, e.g. :
• neuromuscular junction (NMJ) : agrin is a proteoglycan released by growth cones of motor neurons on the muscle fiber surface where it binds to MuSK inducing clustering of N AChR. AChR clustering at the postsynaptic site is thought to be an activity-independent triggering event in neuromuscular synpase differentiation, because AChR clustering can occur at nerve-muscle contact sites in the presence of pharmacological activity blockers, as well as uninnervated muscle fibers. Further, AChRs aggregate in muscle fibers of mice lacking all motor neuron innervation, in patterns that closely resemble those of innervated muscles. AChR clustering is however, dependent on MuSK expression by the postsynaptic muscle fiber. Thus, initial phases of postsynaptic differentiation can occur in the absence of nerve. Such activity independent differentiation and patterning of signals within the muscle cell may serve to restrict synaptic innervation to the center of the muscle fiber and to selectively promote axonal innervation at specific sites. Though some aspects of postsynaptic differentiation may occur independently of the presynaptic motor neuron, selective stabilization of AChR at synaptic sites requires neural-derived agrin, a process that is required for the activity dependent maturation and stabilization of neuromuscular synapses. At the mature NMJ, pre- and postsynaptic membranes are separated by a synaptic cleft containing extracellular proteins that form the basal lamina. Synaptic vesicles are clustered at the presynaptic release site, transmitter receptors are clustered in junctional folds at the postsynaptic membrane, and glial processes surround the nerve terminal.
Neurotransmitters are stored in synaptic vesicles and are released after synaptic vesicle fusion at the active zone (an event that is triggered by an action potential followed by a rapid influx of calcium into the presynaptic terminal). Neurotransmitter receptors and accessory molecules accumulate in the postsynaptic membrane directly opposite to the active zone in a postsynaptic membrane specialization known as the postsynaptic density (PSD).
• amino acids (mM/g)
• excitatory

name	producing cell(s)	receptor(s)
L-Glu	cerebral cortex projections  subthalamic nucleus (STN)  ventroanterior and ventrolateral nuclei of the thalamus	NMDA AMPA kainate mGluRI 1 mGluRII 2 mGluRII 3 mGluRIII 4 mGluRI 5 mGluRIII 6 mGluRIII 7 mGluRIII 8
L-Asp

• inhibitory

name	producing cell(s)	receptor(s)
L-Gly		Gly receptor
g-aminobutyrric acid (GABA)	substantia nigra pars reticulata (SNpr), cerebellum (Purkinje's neurons), striatum, lateral globus pallidus (LGP), hippocampus, spinal cord	GABAA GABAB GABAC
taurine (a sulphur containing amino acid, is the most abundant intracellular amino acid in humans; conditionally essential amino acid for preterm neonate; in healthy individuals the diet is the usual source of taurine; although in the presence of vitamin B6 it is also synthesised from Met and Cys)		GABAA NMDAR (antagonist)  Gly receptor

D-serine synthesis and release by astrocytes as an endogenous ligand for the "glycine" site of NMDAR defy the concept that a neurotransmitter must be synthesized by neurons
• amines nmol/g
• esters

name	producing cell(s)	receptor(s)
acetylcholine (ACh)	PNS :  lower motoneuron preganglionic and postganglionic neurons of parasympathetic system preganglionic neurons of orthosympathetic system CNS  cortical afferences intracortical interneurons hippocampus	N M1 M2 M3 M4 M5

• biogenic monoamines
• catecholamines :

name	producing cell(s)	receptor(s)
noradrenaline / norepinephrine (NE)	PNS : postganglionic neurons of orthosympathetic system  CNS : brainstem nuclei  locus coeruleus (midbrain) lateral tegmental nucleus / nucleus tractus solitarii	...
dopamine (DA) / prolactin inhibiting factor (PIF)	Sommering's substantia nigra pars compacta (SNpc; area 9; => striatum),  mesolimbic tract neurons (area 10; => nucleus accumbens)  nigrocortical tract neurons (area 10; => cortex)  hypothalamopituitary tract neurons	D1 D2 D3 D4 D5

• indoleamines :

name	producing cell(s)	receptor(s)
5-hydroxytriptamine (5-HT) / serotonin / enteramine Plasma free Trp levels increase after meals containing large quantities of FFA, which can displace Trp from plasma proteins : anyway 5-HT release from neurons is regulated by limiting entry into secretory vesicles and intraneuronal 5-HT degradation.	raphe nuclei, EC cells in Langerhans' islets, fundus and pylorus of stomach, jejunum, ileum, and colon	5-HT1A 5-HT1B 5-HT1C / 2C 5-HT1D 5-HT1E 5-HT1F 5-HT2A / 2 / D 5-HT2B / 2F 5-HT3 / M 5-HT4 5-HT5A 5-HT5B 5-HT6 5-HT7

 

name	producing cell(s)	receptor(s)
histamine / b-aminoethylimidazole	mast cells, basophils, ECL cells in fundus of stomach, neurons, stomach mucosa,  rapidly growing tissues	H1 H2 H3 H4

• proteins : endozepine / diazepam binding inhibitor (DBI) / acyl coenzyme A binding protein (ACBP) / GABA receptor modulator binds to GABA_A and stimulates steroidogenesis in adrenocortical and Leydig cells
• endozepine-2
• endozepine-4
• endocannabinoids / amides and esters of long-chain polyunsaturated fatty acids (lcPUFA)

The activity of these compounds at their specific receptors is limited by cellular uptake through anandamide membrane transporter (AMT) (inhibited by N-(4-hydroxyphenyl)-arachidonoylamide (AM-404) or by VDM11), followed by intracellular degradation by endocannabinoid hydrolases (fatty acid amide hydrolase (FAAH), monoglyceride lipase (MGL), ...).

	name	producing cell(s)	receptor(s)
acylethanolamides (AEs)ref	palmitylethanolamide (PEA)	astrocytes	CB2
	anandamide (arachidonylethanolamide (AEA)) arachidonic acid + PtE =>  + PA	immature dendritic cells, neurons, astrocytes	CB1
	homo-g-linolenylethanolamide (HEA)	astrocytes	CB1
	docosatetraenylethanolamide (DEA)	astrocytes	CB1
	oleylethanolamide (OEA)	small intestine, astrocytes	PPAR-aref
	myristylethanolamide
	palmitelaidylethanolamide
	palmitoleylethanolamide
N-palmitoylethanolamine (PalEtn)		immature dendritic cells, neurons
2-arachidonoylglycerol amide (2-AG)		immature dendritic cells, neurons	CB2
oleamide / sleep-inducing factor

• other

morphine has been discovered for decades in trace amounts in animal organs and fluids such as toad skin, cow brain, and human heart and urine, as well as in invertebrates such as mussels. The most widely accepted explanation was such morphine was of environmental origin, since it also occurs in hay, lettuce, and milk. In the plant kingdom, a pair of oxygen atoms is incorporated into each morphine molecule during the transformation of 2 molecules of L-tyrosine into a pair of dopamine molecules. Neuroblastoma cells raised in a 18O–enriched atmosphere generated morphine with a molecular weight 4 mass units higher than morphine produced in cells grown in a regular 16O atmosphere, which indicated the presence of 2 atoms of 18O per morphine molecule. Pancreas cells grown in an 18O atmosphere also yielded isotope-labeled reticuline and norlaudanosoline, which are morphine precursors. The researchers also supplied carbon-13–labeled morphine precursor L-tyramine to neuroblastoma cells. The resulting morphine was 6 mass units heavier than normal, corresponding to the incorporation of one molecule of 13C–labeled tyramine. Ion chromatograms showed the tyramine exclusively labeled the cyclohexane ring of morphine, a pattern that exactly follows that of the poppy plant. In the poppy, S-reticuline is converted to R-reticuline, which in turn is transformed into morphine with R configuration at carbon atom C-9ref. The reticuline discovered in the human cell lines was S-reticuline, and when neuroblastoma cells were supplied with 13C–labeled S-reticuline, the resultant morphine was also R configured. This suggests human cells carry out the same stereochemistry conversion as in plants : morphine is present in human cells at a nanomolar rangeref. This biosynthetic pathway probably existed before animals and plants diverged. Morphine is a product of the dopamine pathway, which in turn is central to the brain's reward and motivation circuitry. Addictive behavior, social attachment behavior, and pain mechanisms are examples of reward and motivation functions that endogenous morphine may impact.

neuroblastoma cells and pancreatic carcinoma cells

m3

• neurosteroids : steroid locally produced (n-pmol/g) in brain ex novo or through metabolism of precursors that reach the brain through blood; they affect neuronal and brain functions through genomic and nongenomic mechanisms, depending on their molecular structure^ref
• 5a-dihydroprogesterone (DHPROG)
• 3a-hydroxylated,5a-reduced metabolites (3a-hydroxypregnanes) of ...
• progesterone (PROG) (3a-hydroxy,5a-pregnan-20one/3a,5a-THP) (agonists of PR)
• deoxycorticosterone (3a,21-dihydroxy,5a-pregnan-20one/3a,5a-THDOC)
• pregnanolone (PREG) (3a-hydroxy-5b-pregnan-20-one)
• allopregnanolone (Allo / AP) (3a-hydroxy-5a-pregn-20-one)
... are positive allosteric modulators of GABA action at GABA_A receptors^ref. In rodents, a reduction of their endogenous brain concentrations rapidly lowers the potency of GABA in eliciting GABA_A receptor-mediated inhibitory postsynaptic currents. This effect is related to anxiety-like behavior, increased aggression, and a reduced sensitivity to the loss of righting reflex induced by GABA_A receptor agonist or positive modulators. Conversely, enhancement of 3a,5a-THP or 3a,5a-THDOC brain content results in anxiolysis, sedation/hypnosis, anticonvulsant, and anesthetic action. Different classes of psychotropic drugs--i.e., antidepressants, selected atypical antipsychotics, ethanol, GABA--increase neurosteroid concentrations in brain, and these increases may be relevant to their pharmacological actions. Drug-induced increases of neurosteroids in rodent brain are often associated with elevation of their plasma content, such that alterations of plasma steroid concentrations are assumed to reflect parallel changes in brain. Nevertheless, brain neurosteroid concentrations are uneven across various regions, and the dose-dependence of their response to a pharmacological challenge shows brain-regional differences as well. These observations are consistent with the present knowledge on the distribution of steroidogenic enzymes in brain--they show not only a brain region, but also a cell-specific expression that may spatially and temporally determine the local concentrations of specific neurosteroids
• 3b-hydroxypregnanes :
• epalons, a shortened form of epiallopregnanolone (3b-hydroxy-5a-pregn-20-one; EpiAP), an endogenous metabolite of progesterone with potent actions at the GRC, despite initial reports assumed that it had no effect^{ref1, ref2}
• epipregnanolone (Epipreg, 3b-hydroxy-5b-pregnan-20-one) has no action at GRC^ref
The 5b-pregnanes ... :
• 5b-pregnan-3a-ol-20-one (epipregnanolone)
• 5b-pregnan-3a,21-diol-20-one (5b-tetrahydrodeoxycorticosterone)
... are both less potent than their corresponding 5a derivatives. A 3a hydroxyl group is essential for neuromodulatory activity in the expressed receptors, as demonstrated by the observation that 5a-pregnan-3b-ol-20-one (allopregnanolone) and 4-pregnen-3, 20-dione (progesterone) are both inactive
• DHEA and its ester sulfate metabolite, DHEAS, are steroids mainly secreted by the adrenal cortex, but also within the brain where they are considered as neurosteroids. No receptor was identified for DHEA (other than s₁ OR) or DHEAS. Their putative effects are mediated by their conversion into active sexual streroids, estradiol and testosterone, but their role is not clarified^ref.
• electrical synapse / ephapse : a point of lateral contact (other than a synapse) between nerve fibers, across which impulses are conducted directly through the nerve membranes from one fiber to the other; it is common in invertebrates but in vertebrates it has been found at only a few CNS sites
• gap junction / nexus : a type of intercellular junction comprising a narrowed portion (about 3 nm) of the intercellular space that contains channels or pores (about 2 nm) composed of hexagonal arrays of membrane-spanning connexin subunits around a central lumen (connexon) through which pass ions (current) and small molecules such as most sugars, amino acids, other molecules that modulate synaptic function (nucleotides, vitamins, hormones, and cyclic AMP). In electrically excitable tissues, these gap junctions serve to transmit electrical impulses and synchronize electrical activity via ionic currents and are known as electrotonic synapses; they are present in such tissues as myocardial tissue and the central nervous system.
• paracrine signalling
• pH
• thiol donors (reducing agents). Click here for ROS detection.
• N-acetyl-L-cysteine (NAC) (Mucomyst^®, Mucosil^®)
• dimethylthiourea
• quercetin
• autacoids or local messengers :
• gasotransmitters : endogenously produced gaseous transmitters. They cannot be stored in vesicles; rather, exquisitely regulated biosynthetic enzymes are activated when signaling is initiated. Gas sensors such as heme, guanylyl cyclase, and the heme-containing transcription factor CooA are sufficiently precise to distinguish diatomic gases^ref. Most gasotransmitter sensors share a modular design : a sensory module that contains a heme cofactor reminiscent of myoglobin where the gas binds (most proteins lack the functionality to bind O₂, CO, and NO with their amino acid side chains, and so they co-opt a heme cofactor) and a transmitter module that amplifies the gas-binding signal (kinase, nucleotide cyclases, phosphodiesterases). Cells often use gases to signal their positions : positioning is clearly important in embryonic development, tumor formation, and symbiotic as well as pathogenic relationships
• oxygen (O₂) : including an O₂-sensing phosphodiesterase that controls biofilm formation by the bacterium Acetobacter xylinum
• nitric oxide (NO^.) / endothelial-derived relaxant factor / endothelium-derived relaxing factor (EDRF) (see also organic nitrates, nitrites and several other compounds that are able of denitration to release NO^.) is a byproduct of arginine degradation by nitric oxide (NO) synthase (NOS). Insects, marine sponges, plants, and bacteria all use NO as a signaling molecule. In plants, NO modulates leaf expansion and root growth, and it also seems to protect plants from environmental and infection stresses^ref. NO dilates the vasculature, controlling regional blood flow and pressure. Macrophages, neutrophils, and leukocytes use NO to fight viruses, bacteria, and parasites. In the CNS, NO contributes to memory, pain, and appetite. NO has been linked to aggressive behavior
• carbon monoxide (CO) (see also CO donors / carbon monoxide-releasing molecules (CO-RMs)) is a by-product of heme degradation by heme oxygenase (HO). CO is relatively stable, so it does not conform to the classical definition of a transmitter as degrading rapidly : the mechanisms by which the CO-generated signal is attenuated, and by which CO is cleared from the site of action remain unanswered. CO is required for ejaculation and anal sphincter function^ref
• hydrogen sulfide (H₂S) (see also toxicity) is produced by cystathionine ß-synthase (CBS) from L-cysteine. H₂S activates K_ATP channels and/or adenylate cyclase => hyperpolarize cell membranes, relax smooth muscle cells, or decrease neuronal excitability^{ref1, ref2}
• relax vascular smooth muscle cells decreasing blood pressure
• in the CNS, it modulates synaptic activity in the brain, regulates the activity of glia and protects neurons from oxidative stress. H₂S also enhances responses mediated by NMDAR, including the induction of hippocampal long-term potentiation (LTP) and brain development. Calcium entry through glutamate receptors activates CBS via calcium/calmodulin

Mark Roth, a biochemist at the Fred Hutchinson Cancer Research Center, Seattle, and his colleagues tried exposing mice to air laced with relatively low concentrations of the gas: within minutes, the mice seemed to fall unconscious. Their core body temperature dropped by some 20ºC, and their breathing slowed from about 120 breaths a minute to fewer than 10^ref. When re-exposed to clean air after 6 hours, the mice bounced back without any evident side-effects. This indicates that it's possible to decrease metabolic rate on demand. By shutting down metabolism, the body's need for oxygen diminishes, which could revolutionize treatment for a host of human ills. In conditions such as stroke, cardiac arrest and other traumas, healing can be limited by the amount of oxygen that can be supplied to damaged tissues. This could be helped by reducing the body's overall need for oxygen. Decreasing total oxygen demand during that period of time is of interest. And inducing a state of suspended animation would buy doctors more time to address the trauma. The gas may also help with cancer treatments. Radiotherapy works best when the target cells are well supplied with oxygen, but it can be detrimental to healthy cells. Inducing hibernation reduces oxygen demand in healthy cells and so should help to protect them. A lot of work needs to be done to determine how to use the treatment, when to use it, and what kind of benefits you get. To that end, Roth and colleagues are working to induce a state resembling suspended animation in larger animals.
• ammonia is a vasoconstrictor, possibly by acting through intracellular alkalinization
• sulfur dioxide (SO₂) and nitrous oxide (N₂O), both produced by bacterial metabolism, may be a vasodepressor and NMDA antagonist, respectively
HO and NOS are both oxidative enzymes using NADPH as an electron donor. Both involve constitutive and inducible biosynthetic enzymes :
• constitutive forms of the enzyme are differentially activated
• calcium entry stimulates NOS by binding to calmodulin


nNOS is localized to NMDAR by the PDZ-domain adaptor protein PSD95. Calcium entry activates nNOS by a calcium/ calmodulin-dependent mechanism. NO can diffuse to neighboring cells to activate soluble guanylyl cyclase or to nitrosylate cysteine residues on target proteins. Nitrosylation inhibits NMDA receptors providing a negative feedback loop. C-terminal PDZ domain ligand of nNOS (CAPON) competes with PSD95 / DLG4 for nNOS to facilitate the nitrosylation and subsequent activation of Dexras1.
• calcium entry in neurons through voltage gated Ca²⁺ channels (VGCC) or release from intracellular stores activate PKC. Through phosphor-ylation, PKC activates casein kinase 2 (CK2) a₁a^'b which in turn phosphorylates and activates HO₂ on the endoplasmic-reticulum (ER) membranes. HO₂ cleaves heme to generate CO, iron, and biliverdin in a reaction dependent on cytochrome P450 reductase (CPR). CO can then activate soluble guanilylyl cyclase (sGC) and Ca²-activated K⁺ channels (K_Ca).


• functions of the inducible forms are virtual opposites :
• macrophage-inducible NOS generates NO to kill other cells
• HO₁ generates bilirubin to exert antioxidant cytoprotective effects and also provides cytoprotection by facilitating iron extrusion from cells. HO₁ also reduces several hallmarks of inflammation including edema, leukocyte migration, and production of pro-inflammatory cytokines. HO-1 seems to interact with COX pathways^ref, which are responsible for producing pro-inflammatory prostaglandins. For this reason researchers at the University of Pittsburgh are investigating whether measuring gases in exhaled breath offers a diagnostic marker of inflammation. The neuronal form of HO, HO₂, is also cytoprotective. Normally, neural NO in the brain seems to exert some sort of behavioral inhibition. However, excess release of NO in response to glutamate's NMDAR activation leads to stroke damage. On the other hand, massive neuronal firing during a stroke presumably activates HO₂, leading to neuroprotective actions of bilirubin. Loss of this neuroprotection after HO inhibition by mutant forms of amyloid precursor protein may mediate neurotoxicity in familial Alzheimer's disease.
NO and CO both appear to be neurotransmitters in the brain and peripheral autonomic nervous system.
Both NO and (weakly) CO stimulate soluble guanilylyl cyclase (sGC) to form cGMP^ref, which finally relaxes smooth muscle cells via PKG type I and II, acting as ...
• endothelial-derived relaxing factors (EDRF) for blood vessels^ref.
• in the gastrointestinal pathway, NO and CO appear to function as coneurotransmitters, both stimulating sGC to cause smooth muscle relaxation
NO also performs a post translational S-nitrosylation on cysteine residues of proteins as diverse as glutamate receptors, a-tubulin (the main component of microtubules), the sodium pump, and metabolic enzymes including glyceraldehyde-3-phosphate dehydrogenase. NOS binds to carrier proteins, which, in turn, bind targets for nitrosylation : this cascade means that nitrosylation is selective.
• sugars

name	producing cell(s)	receptor(s)
advanced glycation end-products (AGE), involved in the pathogenesis of diabetic complicationsref, are also filtered by glomeruli and reabsorbed and metabolized by renal proximal tubular cells (PTC)ref1, ref2. In renal failure, AGE increase in serum and are associated with the pathophysiology of uremic complications such as DRAref and atherosclerosisref, suggesting that they also represent a uremic toxinref1, ref2. AGE are involved in the pathogenesis of diabetic glomerulopathyref1, ref2 as well as tubulopathyref1, ref2, ref3, ref4 Ne-(carboxymethyl)lysine (CML) protein adductsref		RAGEref galectin-3ref macrophage scavenger receptor class A types I and II (SR-A)ref1, ref2 CD36ref scavenger receptor class B type I (SR-BI)ref LOX-1ref FEEL-1 FEEL-2ref

• lipids

name				receptor(s)
lysophospholipids (LPs)			lysophosphatidic acid (LPA) : 3 different stimulus-coupled cellular pathways for rapid synthesis and release of this mediator are known. sphingomyelinase conditioning of cell-derived plasma membrane vesicles, PL-C and/or PL-D-dependent liberation of phosphatidic acid (PA) and its conversion to LPA by secretory type II PL-A2 activated DGK generates PA, which again can be converted by secretory type II PL-A2 to LPA production of LPA in minimal oxidized LDLs results from specific oxidative degradation Independently of the generation process, LPA is stored within the cell at concentrations up to 60 mM and it may accumulate in ECF such as the inflammatory exudate at concentrations as high as 10 mM. Found associated with serum albumin in plasma. Catabolyzed by lipid phosphate phosphohydrolase (LPP) (similar to Wunen in Drosophila melanogaster). Enhanced secretion of LPA may be a characteristic of some ovarian cancer cells, with potential as a plasma marker.	EDG2 EDG4 EDG7
			=sphingomyelinase=> ? =ceramidase=> sphingosine =sphingosine kinase=> sphingosine-1-phosphate (S1P) : biosynthetic enzymes are thought to function in the cytosol. Howevere, recent data indicate that these enzymes are also secreted by cells, suggesting that S1P can also be formed extracellulary. Found associated with serum albumin in plasma. Catabolyzed by lipid phosphate phosphohydrolase (LPP) (similar to Wunen in Drosophila melanogaster)	EDG1 EDG3 EDG5 EDG8
			1-O-alkyl-2-acyl-sn-glyceryl-3-phosphorylcholine =PL-A2=> 1-O-alkyl-lysoPtC ==+ acetyl-CoA + lyso-PAF transacetylase=> CoA + platelets-activating factor (PAF) / antihypertensive polar renal lipid (APRL) / acetylglyceryletherphosphorylcholine (AGEPC) Inactivated by PAF acetylhydrolase.	PAFR
			lysophosphatidylcholine (LPC)	G2A / LPC1
			sphingosylphosphoryl choline (SPC)	GPR68 / OGR-1 / SPC1
			psychosine / galactosylsphingosine	GPR65 / TDAG8
prostanoids (a subscript is used to indicate the number of double bonds in the fatty acid)		prostaglandins (analogs of the unnatural compound prostanoic acid)  dihomo-g-linolenic acid (DHLA) is the precursor of the 1 series w6 PUFAs are the precursors for the 2 series (the major prostaglandins in mammals) w3 PUFAs are the precursors of the 3 series	PGG2
			PGH2	TP
			PGA2
			PGD2	DP1 DP2 / CRTH2 / GPR44 PPAR-g
			9a,11b-PGF2
			PGD-M
			15-deoxy-D12,14-PGD2 (15dPGD2)
			PGE1	IP
			PGE2	EP1 EP2 EP3 EP4
			PGE3
			PGE-M
			PGF2a	FP
			PGF-M
			PGI2 / prostacyclin (PC) (have half-lives on the order to seconds to a few minutes)	IP PPAR-g
			6-keto-PGF1a
			2,3-dinor-6-keto-PGF1a
			PGJ2	PPAR-g
			5-deoxy-D12,14-PGJ2 (15dPGJ2)	PPAR-g
		leukotrienes. LTC4, LTD4 and LTE4 are collectivelly referred as cysteinyl leukotrienes or slow-reacting substance of anaphylaxis (SRS-A).  arachidonic acid is the precursor of the 4 series 5,8,11,14,17-eicosapentaenoic acid (EPA) is the precursor of the 5 series	LTA4
			LTB4 (exits cell via ?)	B-LT1 / P2Y7 B-LT2 (they reside intertwined, one within the promoter of the other)  PPAR-a PPAR-g (intranuclear signaling for negative feedback loop)
			LTC4 (exits cell via MRP1 and ABCC1 / MDR-associated protein type 2 (MRP2))	cysLT1 cysLT2
			LTD4 (generated extracellularly)	cysLT1 cysLT2
			LTE4 (generated extracellularly)	cysLT1 cysLT2
		thromboxans (analogs of the unnatural compound thrombanoic acid; have half-lives on the order to seconds to a few minutes)	TXA1	TXA1R
			TXA2	TP
			TXB2
			2,3-dinor-TXB2
		lipoxins	LXA4	FPR-like (FPRL) 1 / ALXR AHR
			aspirin-triggered lipoxin (ATL) / 15(R)-epi-LXA4 (due to acetylation of COX-2 by acetylsalicylic acid)	FPR-like (FPRL) 1 / ALXR
			LXB4
		5-oxo-ETE
		hydroxy-ETE (HETE)
		epoxy (EET)

• peptides
• growth factor : an imprecise term denoting any of numerous substances that promote normal or pathological growth of cells or tissue, including ...
• epidermal growth factors
• insulin-like growth factors
• nerve growth factors
• platelet-derived growth factors
• transforming growth factors
• hematopoietic growth factors : a group of substances with the ability to support hematopoietic colony formation in vitro, including erythropoietin, interleukin-3, and colony-stimulating factors. All except erythropoietinstimulate mature cells, have overlapping capabilities to affect progenitor cells of several blood cell lines, and also affect cells outside the hematopoietic system.
• cytokines : proteins with 6 < M_r < 60 kDa, inducible expression, pleiotropic and redundant and variable (sometimes antagonistic !) effects during time course, cross-regulated at both cytokine and receptor levels. Mannoside acetylglucosaminyltransferase 5 (MGAT5) modifies cytokine-receptor N-glycans and that this regulates cytokine-mediated signalling. MGAT5-mediated N-glycan modifications generate ligands for the galectin (GAL) family of lectins. It has previously been shown that GAL3 — which binds N-glycans modified by MGAT5 — can oligomerize and form a molecular lattice of galectins and glycoproteins at the cell surface and that GAL3 binding of MGAT5-modified N-linked glycans on the TcR opposes antigen-induced clustering^ref. MGAT5-mediated modification of N-linked glycans on these cytokine receptors allows the formation of molecular lattices that oppose receptor endocytosis.

family	subfamily	cytokine name(s)	producer cell(s)	receptor(s)
Hematopoietins (4-helix bundles)		erythropoietin (EPO) / hematopoietin / hemopoietin; monomer or dimer of a 165 amino-acid sequence glycoprotein	interstitial cells which are localized around the proximal renal tubule (90%), hepatocytes (10%; higher in fetal liver). Paracrine and autocrine functions in  endometrial cells in the secretory > proliferative phase, placenta, astrocytes, Sertoli and peritubular myoid cells, and capillary endothelium	EPOR
		interleukin 2 (IL-2) / BF / EDF / KHF / LMF / LCM factor / LPF / MAF-C I / PFC-EA / SCIF / T-cell growth factor (TCGF) / TCPA / TDF / TGP-3 / TMF / TRF-3 / TSF ; monomer	T lymphocytes	IL-2R
		IL-3 / multicolony stimulating factor (multi-CSF); monomer	all classes of T and NK2 lymphocytes, thymic epithelial cells (TECs), mast cells, eosinophils, and basophils	IL-3R
		IL-4 / BCGF-1 / TCGF-2 / B lymphocyte stimulatory factor 1 (BSF-1); monomer : the one interchain disulfide bond is required for biologic activity	Th2 lymphocytes, basophils, mast cells, neutrophils, GC B lymphocytes	IL-4R
		IL-5 / BCGF-2 / Eo-CSF ;  homodimer	Th2 lymphocytes, mast cells, eosinophils, basophils, NK2 lymphocytes	IL-5R
		IL-6 / IFN-b2 / B lymphocyte stimulatory factor 2 (BSF-2) / BCDF; monomer	white adipose tissue (30% of plasma IL-6 under basal conditionsref; visceral > subcutaneousref), T lymphocytes, macrophages, endothelial cells (stimulated by CRP), TECs, B lymphocytes, fibroblasts, keratinocytes, synovial cells B	IL-6R
		IL-7 / TCGF-b; monomer or dimer	bone marrow, TECs	IL-7R
		thymic stromal lymphopoietin (TSLP)
		IL-9 / TCGF-3; monomer	T lymphocytes	IL-9R
		IL-11; monomer	stromal fibroblasts in bone marrow	IL-11R
		IL-13 / P600; monomer	Th2 lymphocytes, NK cells, eosinophils, basophils, mast cells	IL-13R
		granulocyte colony stimulating factor (G-CSF) / CSF-3 ; monomer or dimer	fibroblasts,  monocytes, macrophages, stimulated endothelial cells, TECs, stromal cells	G-CSFR
		macrophage colony stimulating factor (M-CSF) / CSF-1	fibroblasts, stimulated endothelial cells, bone-marrow stroma, monocytes, macrophages, T lymphocytes, B lymphocytes, epithelial cells (including TECs)	M-CSFR / CD115
		IL-15 / IL-T; monomer (48 aa-long signal sequence isoform localizes in plasma membrane or is secreted; 21 aa-long signal sequence isoform is found within the cytoplasm or  nucleus	activated monocytes and macrophages, dendritic cells, skeletal muscle, kidney, lung, heart, and placenta	IL-15R
		granulocyte and macrophage colony stimulating factor (GM-CSF) / CSF-2 / BPA ; monomer or dimer	monocytes, macrophages, all classes of T and NK lymphocytes, epithelial cells (including respiratory epithelial cells, stimulated endothelial cells and TECs), fibroblasts, eosinophils	GM-CSFR soluble GM-CSFR a subunit (sGMRa) arises through alternative splicing or ectodomain shedding by MMPs
		oncostatin M (OSM / OM); monomer	T lymphocytes, activated monocytes and macrophages, bone marrow stromal cells, some lines of mammary carcinoma and myeloma	OSMR LIFR
		leukemia inhibiting factor (LIF); monomer	bone marrow stromal cells, fibroblasts, osteoblasts, TECs, activated T lymphocytes	LIFR
		ciliary neurotrophic factor (CNTF)		CNTFR
		neurotrophin 1 (NTF-1 / NT-1) / B-cell stimulatory factor-3
		cardiotrophin-1
Interferons (IFNs) => viral interference within 4÷6 hrs, induction of CXCL10 / IP-10	type I interferons (=> IRF => ISRE => IFN-stimulated genes (ISGs))	IFN-a ; 18 paralogous intron-less genes on 9p : 6 of them are pseudogenes;  a1 a2 a4 a5 a6 a7 a8 a10 a13 a14 a16 a17  a21 monomer; high diffusibility, induces up-regulation of MHC class I and b2-microglobulin	most cell types : leukocytes (including B lymphocytes and macrophages)	IFNAR1 / CD118 IFNAR2
		IFN-b ; b1 and b3 (b2 is now renamed IL-6); low diffusibility, induces up-regulation of MHC class I and b2-microglobulin ; monomer	most cell types : fibroblasts and some epithelia	IFNAR1 / CD118 IFNAR2
		IFN-k	unstimulated keratinocytes, peripheral blood monocytes, and monocyte-derived dendritic cells (up-regulated by type I and type II IFNs)	IFNAR1 / CD118 IFNAR2
		IFN-l2 / IL-28A		IL-28 and IL-29 R
		IFN-l3 / IL-28B
		IFN-l1 / IL-29
		IFN-w1		IFNAR1 / CD118 IFNAR2
	type II interferon	IFN-g / macrophage-activating factor (MAF); homodimer ; 12q; induces temporary expression of MHC class II molecules on fibroblasts and other cell types and up-regulation of MHC class I and b2-microglobulin	Th1 lymphocytes, CTL, NK and NKT lymphocytes, B cells, macrophages, dendritic cells	IFNGR1 / CD119 IFNGR2
immunoglobulin superfamily (IgSF)		B7.1 / CD80 ; dimer	APCs	CD28 CD152 / CTLA-4
		B7.2 / B70 / CD86	APCs	CD28 CD152 / CTLA-4
TNF (ligand) superfamily (TNFSF)		TNFSF1 / TNF-b/ lymphotoxin (LT) -a (LT-a) ; a3 homotrimer or a2b1 heterotrimer with LT-b, which anchors it to the cell surface	activated monocytes and macrophages, activated T lymphocytes, B lymphocytes and NK cells and a wide variety of other cells	CD120a / p55TNFRI CD120b / p75TNFRII
		TNFSF2 / TNF-a / cachectin ; soluble homotrimer lymphokine capable of causing in vivo hemorrhagic necrosis of certain tumor cells, but not affecting normal cells; it has been used as an experimental anticancer agent. It can also induce shock when bacterial endotoxins cause its release	macrophages, NK cells, B cells, T cells, mast cells, basophils, eosinophils, keratinocytes, fibroblasts, TECs, cytotrophoblast	CD120a / p55TNFRI CD120b / p75TNFRII
		TNFSF3 / LT-b ; a and b isoforms; transmembrane, b3 homotrimer or  a1b2 heterotrimer with TNF-b / LT-a, anchoring it to the cell surface	T lymphocytes, B lymphocytes (?)	LTbR HVEM
		TNFSF4 / OX40L / CD134L / gp34	activated CD4+ T lymphocytes	OX40 / CD134
		TNFSF5 / CD154 / 40L / TRAP ; homotrimer	T lymphocytes, mast cells	CD40
		the external domain of TNFSF6 / CD178 / CD95L /FasL / Apo-1 (soluble FasL); homotrimer	T lymphocytes, B lymphocytes, eye (choroid, retinal pigment epithelial cells, photoreceptors, corneal epithelial cell, corneal endothelial cell, vitreous, iris, ciliary body), Clara cells, follicular epithelial cells of the thyroid, RA-treated dermal fibroblasts, UV-irradiated keratinocytes, hepatocytes and enterocytes during immune responses, ovary , Sertoli cells and/or spermatogonia, respiratory epithelial cells, neurons, melanoma and astrocytoma cells	CD95 / Apo1 / Fas
		TNFSF7 / CD70 / CD27L / Ki-24 ; homotrimer	activated T and B lymphocytes	CD27
		TNFSF8 / CD153 / 30L ; homotrimer	T lymphocytes	CD30
		TNFSF9 / CD137L / 4-1BBL ; homotrimer	T lymphocytes, carcinoma cell lines	CD137 / 4-1BB
		TNFSF10 / Apo-2L / TL2 / TRAIL ; homotrimer	T lymphocytes, monocytes, eye (corneal epithelium, corneal endothelium, iris, retina pigment epithelium)	death receptors (DR) : with a death domain (DD), expressed on transformed cells  DR4 / TRAIL-R1  DR5 / TRAIL-R2  decoy receptors (DcR) : with no death domain (DD), expressed on normal cells  DcR1  / TRAIL-R3  DcR2 / TRAIL-R4  OPG
		TNFSF11 / TRANCE / osteoprotegerin ligand (OPG-L) / RANK ligand (RANK-L) / osteoclast differentiation factor (ODF) ; isoform 1 and 2 ; homotrimer ; expression up-regulated by PTH	stromal cells/osteoblasts, T lymphocytes	RANK OPG
		TNFSF12 / Apo-3L / TWEAK / DR3L ; isoforms 1 and 2	T lymphocytes, wide tissue distribution	TWEAKR
		TNFSF13 / APRIL / TALL-2 (a, b, d and g isoforms ; virus-like structures composed of multiple homotrimers, or heterotrimer with BAFF)	myeloid cells	TACI BCMA HVEM CD95 / Apo1 / Fas
		TNFSF13B / TNF210 / BLys / BAFF / THANK / TALL-1 / zTNF4 (soluble and membrane-bound isoforms; homotrimer or heterotrimer with APRIL)	B cell lineage cells	TACI BCMA BAFF-R / BLyS receptor 3 (BR3)
		TNFSF14 / LIGHT / TL5 / TR2 / LT-g / HVEML	?	HVEM
		TNFSF15 / TL1A / VEGI ; isoforms 1 and 2	endothelial cells	DR6 TRAMP / DR3
		TNFSF18 / TL6 / GITRL / AITRL	endothelial cells	GITR /AITR
		TNFSF19 / DEDD ; 2 isoforms	?	?
		anhidrotic ectodermal dysplasia 1 (ED-1) / ectodysplasin A (EDA)	isoform 1 (EDA1)	EDAR
			isoform 2 (EDA2)	XEDAR
IL-10 family		IL-10 / cytokine synthesis inhibitor F ; homodimer => decrease MMPs and proinflammatory cytokine  production, induce TIMP-1 expression	Th1 lymphocytes and Th2 lymphocytes, macrophages with bound Fcg, EBV-transformed B cells, keratinocytes, mast cells	IL-10R
		IL-19	LPS- or GM-CSF-activated monocytes	IL-19R
		IL-20	monocytes	IL-20R
		IL-22	IL-9 induced Th1 lymphocytes and NK lymphocytes	IL-22R
		IL-24 / MDA-7	monocytes, T lymphocytes
		IL-26 / AK155	Th1 lymphocytes and NK lymphocytes
B and T lymphocyte attenuator (BTLA)			induced during activation of T cells, and BTLA remains expressed on Th1 lymphocytes but not Th2 cells	HVEM B7H4

TGF-b superfamily : all of which are found in hematopoietic tissue, stimulate wound healing, and in vitro are antagonists of lymphopoiesis and myelopoiesis.	NODAL		TGF-bRIB / ALK-4 activin type IB receptor / ALK-7 activin type II receptor
	TGF-b1; homo-and heterotrimers	most cell types : chondrocytes (including chondrosarcoma), monocytes, T lymphocytes, B lymphocytes, macrophages, platelets, bone-marrow stroma, eye, testis, glioblastoma	TGF-bR
	TGF-b2; homo-and heterotrimers	chondrosarcoma, glioblastoma	TGF-bR
	TGF-b3;  homo-and heterotrimers	chondrosarcoma	TGF-bR
	Mullerian inhibiting factor (MIF) / Mullerian inhibiting substance (MIS) / anti-Mullerian hormone (AMH)	immature Sertoli cells	AMHR
	neurturin (NTN / NRTN)		HGFR / c-Met and a GPI-linked coreceptor
	endometrial bleeding associated factor (EBAF) / left-right determination, factor A encodes a secreted protein that plays a role in left-right asymmetry determination of organ systems during development and in endometrial bleeding. Mutations in this gene have been associated with left-right axis malformations, particularly in the heart and lungs. Some types of infertility have been associated with dysregulated expression of this gene in the endometrium. Alternative processing of this protein can yield 3 different products. This gene is closely linked to both a related family member and a related pseudogene.
	transforming growth factor a (TGF-a) : stimulates growth of microvascular endothelial cells	pancreatic endocrine tumors	EGFR
IL-1 family	IL-1a / BAF / BCAF / EP / lymphocyte-activating factor (LAF) / LEM / macrophage chemotactic factor (MCF) / MNCF / MP / TRF-3 ; monomer	macrophages, dendritic cells, epithelial cells (TECs, endothelial cells, ...), activated B lymphocytes, NK cells	CD121a / IL-1RI CD121b / IL-1RII
	IL-1b / catabolin / H1 / OAF ; proteolytically processed to its active form by caspase 1 / CASP1 / ICE ; monomer. IL-1b, lacking a secretory signal peptide, follows a nonclassical pathway of secretion. In a first step, pro-caspase-1 and endotoxin-induced pro-IL-1b are targeted in part to specialized secretory lysosomes. Externalization of mature IL-1b and caspase-1 together with lysosomal proteins is then facilitated by extracellular ATP. ATP triggers the efflux of K+ from the cell,  is responsible for phosphatidylcholine-specific phospholipase C induction, which in turn allows the rise in intracellular free Ca2+ concentration required for activation of phospholipase A2. This activation is ultimately responsible for lysosome exocytosis and IL-1b secretion. Whereas calcium-independent phospholipase A2 is involved in processing, phosphatidylcholine-specific phospholipase C and calcium-dependent phospholipase A2 are required for secretionref	macrophages, dendritic cells, epithelial cells (TECs, endothelial cells, ...), B lymphocytes, NK cells	CD121a / IL-1RI CD121b / IL-1RII
	IL-1 receptor antagonist (IL-1RA / IL-1RN) ; 4 isoforms ; monomer		CD121a / IL-1RI (IL-1RAP is not recruited by IL-1RA, that fails to induce signal transduction)  CD121b / IL-1RII
	IL-1d, member 5
	IL-1e, IL-1RA homolog / member 6	keratinocytes	CD121a / IL-1RI (IL-1RAP is not recruited by IL-1RA, that fails to induce signal transduction)  CD121b / IL-1RII
	IL-1z, member 7 ; 5 isoforms		IL-18R IL-18BP (soluble decoy)
	IL-1h, h2, member 8 ; 2 isoforms
	IL-1rp2, h1, e, member 9		IL-1R-like 2
	IL-1R-like 1 ligand	Th2 lymphocytes, Tc2 and NK2 lymphocytes	IL-1R-like 1
	IL-18 / IFN-g inducing factor (IGIF) ; monomer	keratinocytes, activated macrophages and Kupffer cells	IL-18R IL-18BP (soluble decoy)
	IL-12 / NK cell stimulatory factor ; p70 heterodimer with p35A and p40B subunits	B lymphocytes, activated mature DCs, macrophages not inhibited by IFN-b or by Fcg bound, naive T cells, neutrophils	IL-12R
	IL-23 = IL-12p40 "soluble receptor" subunit + p19a subunit	memory T lymphocytes, monocyte-derived macrophages	IL-23R
	macrophage inhibitory factor / migration inhibition factor (MIF) ; monomer	T lymphocytes, pituitary cells, macrophages, eosinophils, fibroblasts, keratinocytes
	IL-14 / HMW-BCGF	T lymphocytes	?
	IL-16 ; homotetramer	CD8+ T lymphocytes, mast cells, eosinophils, airway epithelium	CD4
	IL-17 / mCTLA-8; monomer	CD4+ (both Th1 lymphocytes and Th2 lymphocytes) and CD8+ memory T lymphocytes	IL-17R
	IL-17B		IL-17BR
	IL-17C		?
	IL-17D		?
	IL-17E / IL-25 (isoforms 1 and 2)		IL-17BR
	IL-17F
	IL-21	T lymphocytes	IL-21R
	IL-27 / SF20 (homolog to mouse IL-25)	bone marrow stroma	LY6E IL-27Ra / WSX1
	IL-31ref (4-helix bundle)	Th2 lymphocytes	IL-31RA and OSMR
	thrombopoietin (TPO)		THPO
	vascular endothelial growth factor (VEGFA) : 4 isoforms :  VEGFA121 : lacks exons 6 and 7 => weakly acidic => does not bind heparin => soluble VEGFA165 (the most abundant; basic => binds to heparin => some is bound to the cell surface) VEGFA189 (even more basic => binds to heparin with more affinity => almost all is bound to ECM) VEGFA206 (human fetal liver cells)		VEGFR1 / Flt-1 VEGFR2 / Flk-1 / KDR
	VEGFB		VEGFR1 / Flt-1
	VEGFC		VEGFR3 / Flt-4 > VEGFR2 / Flk-1 / KDR
	VEGFD		VEGFR3 / Flt-4 > VEGFR2 / Flk-1 / KDR
	VEGFE		VEGFR2 / Flk-1 / KDR
	placental growth factor (PlGF)		VEGFR1 / Flt-1
	angiopoietin (Ang-1)		Tie-1 CD202b / Tie-2
	Ang-2		Tie-1 CD202b / Tie-2
	Ang-3 / angiopoietin-like 1	widely expressed in adult tissues with mRNA levels highest in highly vascularized tissues	Tie-1 CD202b / Tie-2
	Ang-4		Tie-1 CD202b / Tie-2
	fibroblast growth factor (FGF-1 / aFGF)		FGFR1 FGFR2 FGFR3 FGFR4
	FGF-2 / bFGF		FGFR1 FGFR2 FGFR3 FGFR4
	FGF-3		FGFR1 FGFR2 FGFR3 FGFR4
	FGF-4		FGFR1 FGFR2 FGFR3 FGFR4
	FGF-5		FGFR1 FGFR2 FGFR3 FGFR4
	FGF-6		FGFR1 FGFR2 FGFR3 FGFR4
	FGF-7 / keratinocyte growth factor (KGF)		FGFR1 FGFR2 FGFR3 FGFR4
	FGF-8		FGFR1 FGFR2 FGFR3 FGFR4
	FGF-9		FGFR1 FGFR2 FGFR3 FGFR4
	FGF-10 / KGF-2		FGFR1 FGFR2 FGFR3 FGFR4
	FGF-11		FGFR1 FGFR2 FGFR3 FGFR4
	FGF-12		FGFR1 FGFR2 FGFR3 FGFR4
	FGF-13		FGFR1 FGFR2 FGFR3 FGFR4
	FGF-14		FGFR1 FGFR2 FGFR3 FGFR4
	FGF-16		FGFR1 FGFR2 FGFR3 FGFR4
	FGF-17		FGFR1 FGFR2 FGFR3 FGFR4
	FGF-18		FGFR1 FGFR2 FGFR3 FGFR4
	FGF-19		FGFR1 FGFR2 FGFR3 FGFR4
	FGF-20	substantia nigra	FGFR1 FGFR2 FGFR3 FGFR4
	FGF-21		FGFR1 FGFR2 FGFR3 FGFR4
	FGF-22		FGFR1 FGFR2 FGFR3 FGFR4
	FGF-23		FGFR1 FGFR2 FGFR3 FGFR4
	epidermal growth factor (EGF) / b-urogastrone : a mitogenic polypeptide originally extracted from the submandibular glands of male mice; it is produced by many cell types and is made in large amounts by some tumors. It promotes growth and differentiation, is essential in embryogenesis, and is also important in wound healing. It has been found to be part of a family of compounds that includes human epidermal growth factor, transforming growth factors, and amphiregulin.  human epidermal growth factor : a mitogenic polypeptide found in humans that is 70 per cent homologous with the epidermal growth factor of mice; it promotes growth and differentiation, is essential in embryogenesis, and is important in wound healing. It is produced by many normal cell types and is made in large amounts by some tumors; the kidneys are the major source of the circulating factor	, cytotrophoblast	ERBB1 / EGFR
	hepatocyte growth factor (HGF) / scatter factor (SF) : a potent mitogen and inducer of hepatocyte proliferation	nonparenchymal cells in the liver and by mesenchymal cells in many other organs.	HGFR / c-Met
	brain-derived neurotrophic factor (BDNF) (in contrast to their slow effect on neuronal survival or differentiation (hours or days), their modulation of synaptic transmission is much faster (seconds or minutes))		TrkA TrkB TrkC p75NTR
	glial-derived neurotrophic factor (GDNF)		TrkA TrkB TrkC p75NTR
	pigment epithelium-derived factor (PEDF) / SERPINF1
	persephin
	artemin / enovin / neuroblastin		RET (uses GPI-linked GDNF family receptor (GFR)-a3 as a coreceptor)
	nerve growth factor (NGF) : a protein consisting of two identical polypeptide chains associated with 2 gamma subunits (enzymes) and 2 alpha subunits; first isolated from mouse sarcoma and later from snake venom and mouse salivary glands, it stimulates the growth of sensory and sympathetic nerve cells and of the adrenal medulla and has been found to be secreted by a variety of normal and neoplastic cells, including those in humans.		TrkA TrkB TrkC p75NTR
	stem cell factor (SCF) (a.ka. steel factor (SLF) in Mus)		CD117 / c-Kit
	neurotrophin 2 (NTF-2 / NT-2)
	neurotrophin 3 (NTF3 / NT-3) / HDNF / NGF-2		TrkB TrkC
	neurotrophin 4/5 (NTF-4/5 / NT-4/5)
	platelet derived growth factor (PDGF) a+a, a+b/ c-sisorb/ c-sis+b/ c-sis: capable of inducing proliferation of vascular endothelial cells, vascular smooth muscle cells, fibroblasts, and glia cells; its action contributes to the repair of damaged vascular walls.	alpha granules of platelets, cytotrophoblast	PDGFR
	connective tissue growth factor (CTGF) / IGF-binding protein 8 (IGFBP8)
	FLT3L		FLT-3
	neuromedin B		neuromedin B receptor
	neuregulin 1 / heregulin / NDF (4 isoforms)		ERBB1 / EGFR ERBB2 / ERBB3 heterodimer  ERBB4
	neuregulin 2		ERBB3 ERBB4
	betacellulin (BTC)		ERBB1 / EGFR ERBB4
	megakaryocyte potentiating factor (MPF), an isoform of mesothelin
urocortins human homologues of fish urotensin I, are member of the sauvagine/corticotropin-releasing factor/urotensin I family. Each of these 4 genes is highly conserved during evolution and the identity between mammalian and teleost orthologs ranges from >96% for CRF to >55% for SCP. Phylogenetic studies showed that the origin of each of these peptides predates the evolution of tetrapods and teleosts, and that this family of peptide hormones evolved from an ancestor gene that developed the CRF/urocortin and SCP/SRP branches through an early gene duplication event. These 2 ancestral branches then gave rise to additional paralogs through a second round of gene duplication. Consequently, each of these peptides participates in the regulation of stress responses over the 550 million years of vertebrate evolution. The study also suggested that the fight-or-flight and stress-coping responses mediated mainly by CRF types 1 and 2 receptors evolved early in chordate evolution. The CRF/CRF receptor signaling evolved from the same ancestors that also gave rise to the diuretic hormone/diuretic hormone receptors in insects. Thus, a complete inventory of CRF family ligands and their receptors in the genomes of different organisms provides an opportunity to reveal an integrated view of the physiology and pathophysiology of the CRF/SCP family peptides, and offers new insights into the evolution of stress regulation in vertebrates.	urocortin 1 (Ucn 1)		CRHR1 CRHR2
	urocortin II (UcnII) / stresscopin-related peptide (SRP)		CRHR2
	urocortin 3 (Ucn 3) / stresscopin (SCP) : CRF type 2 receptor is thought to mediate the stress-coping responses, such as anxiolysis, anorexia, vasodilatation, a positive inotropic action on myocardium and dearousal. Ucn 1 and 3 appear to have important pathophysiological roles in some cardiovascular diseases. Urocortins show 'stress-coping' responses such as anxiolysis and dearousal in the brain. In the periphery, recent studies show the potent effects of urocortins on the cardiovascular and immune systems. In the brain it may be responsible for the effects of stress on appetite. In spite of the gene family name similarity, the product of this gene is not homologous to urotensin II. mRNA expression of urocortin was low during the last weeks of pregnancy in the placenta, myometrium and choriodeciduaref. SCP and UCN are potent activators of the p42/44 MAPK pathway, with SRP able to induce phosphorylation of p42/44 MAPK as well, albeit not as pronouncedref. Adipose tissue expressed urocortin and stresscopin, the predominant ligands of peripheral CRH-R2ref. Human cord blood-derived cultured mast cells (hCBMC) at 10 wk, but not at 2 wk, are IHC positive for CRH and UCNref. A highly significant, but negative, correlation has been found between Ucn levels and gastric inflammation, suggesting that Ucn may exert an antiinflammatory effect in gastric mucosaref.	pituitary gland, adrenal gland, gastrointestinal tract, ovary, spleen, brain, cardiomyocytes and sital tubules	CRHR2
	urotensin II (UII) is a vasoactive cyclic undecapeptide originally isolated from the teleost urophysis. It stimulates cardiomyocytes and vascular smooth muscle hypertrophy and also shows inotropic properties. It induces biphasic (brief- and long-lasting) contractions and the brief contraction was mediated by acetylcholine release from ganglionic cholinergic neurons in a segment of guinea-pig ileum The bioactive, mature form contains a cyclic heptapeptide perfectly preserved across species spanning 550 million years of evolution. In man short term cardiovascular responses to administered urotensin II are small or absent. The place of urotensin II in the chronic trophic responses to cardiac and vascular injury and its possible roles as a neurotransmitter and/or regulator of renal and endocrine function remain largely unexplored. Initially found to have potent vasoconstrictive activities in a variety of vessels from diverse species, it has also been shown to exert vasodilatation in certain vessels in the rat and human by various endothelium-dependent mechanisms.Moreover, UII has also been implicated as a mitogen of vascular smooth muscle cells suggesting a deleterious role in atherosclerosis and coronary artery disease. In addition, there is evidence to demonstrate that UII has multiple metabolic effects on cholesterol metabolism, glycemic control and hypertension and therefore may be implicated in the development of insulin resistance and the metabolic syndrome. UII is a potent vasoconstrictor peptide, whose potency is greater than any other vasoconstrictors thus far known. .The common structural feature of U-II peptides from different species is the C-terminal portion, characterized by the disulfide bridged cyclic hexapeptide Cys-Phe-Trp-Lys-Tyr-Cys. The few SAR studies reported to date attributed a critical role to this portion, with the Trp-Lys-Tyr motif appearing as the key determinant of U-II bioactivity. Consequently, this shorter cyclic peptide was used as a template for the development of several synthetic analogues, among which a superagonist, termed P5U: H-Asp-cyclo(Pen-Phe-Trp-Lys-Tyr-Cys)-Val-OH. Conformational studies confirmed the important role of hU-II C-terminal cyclic portion, enabling the development of 3D pharmacophore models. Despite the gene family name similarity, this gene is not homologous to urocortin. Most of the proprotein is cleaved to make the mature peptide. Transcript variants encoding different preproprotein isoforms have been described for this gene. Urotensin II may have an aetiological role in hypertension and its complicationsref. Possible role for U-II in the pathophysiology of atherosclerosisref. In addition to direct effects on the myocardium, U-II may contribute to the increased peripheral vascular tone that is characteristic of human CHFref. levated in the aortic root of congestive heart failure. Cleared at least in part from the microcirculationref. Urotensin II gene may contribute to the genetic susceptibility to type 2 diabetes in Chinese populationref. S89N polymorphism in the UTS2 gene is associated with the development of Type 2 diabetes, via insulin sensitivity, in Japanese subjectsref. ECirculating urotensin-II appears not to play a major role in human congestive heart failure (CHF)ref. Regulative effect of human urotensin-II on cardiovascular systemref. Structure-function analysis and its use in the construction of a ligand-receptor working modelref. Urocortin II exhibits motor suppressive and delayed anxiolytic-like effects, suggesting a time-dependent role in the regulation of stress-related behaviorref	strong expression of urotensin II in the cardiomyocytes, and to a lesser extent in the vascular smooth muscle cells, endothelial cells, and inflammatory cells of patients with end-stage chronic heart failure, central nervous system (a subset of ventral horn motoneuronesref) and many peripheral tissues (including heart, blood vessels, kidneys and endocrine organs)	UTII receptor (UTR) / GPR14
	urotensin II (UII)-related peptide (URP) has been isolated from the rat brain and its sequence has been established as H-Ala-Cys-Phe-Trp-Lys-Tyr-Cys-Val-OH (ACFWKYCV) also binds (UTR)

Web resources :
•  Cytokine Family Database (dbCFC) at Kumamoto University
• Related resources
• Cytokines Online Pathfinder Encyclopaedia (COPE) by Horst Ibelgaufts
• Cytokine Site by the Institute of Clinical Immunology (ICI), FSU Jena, Germany
• NIH Cytokine Interest Group
• The Cytokines Web
• Journals
• Cytokine
• Cytokines, Cellular & Molecular Therapy
• Cytokine and Growth Factor Reviews (CGR)
• Cytokine Reference
• Journal of Interferon & Cytokine Research
• The Journal of Interferon and Cytokine Research
Cytokines were once grouped according to main producer cell : anyway most cytokines can enter in more than one group and so such a classification is nowadays useless.
• interleukins
• lymphokines : e.g. MAF, MIF, MCF, IL-2, IL-3, IL-4, TNF-b, ...
• monokines : e.g. TNF-a, IL-1, ...
• Minicytokines (tachykinins ,...)
• Chemotactic cytokines (a.k.a. chemokines)

chemokine NTD	chemokine subclass	chemokine name(s)	producer cell(s)	chemokine GPCR(s)
a-chemokines : CXC motif (on Homo 4q12-21 chromosome region)	ELRCXC or ELR+ CXC chemokines (chemotactic for neutrophils)	CXCL1 / KC / MGSA-a / GRO-1 / GRO-a (GRO-KC in mouse)	activated granulocytes, monocytes, macrophages, epithelial cells, lymphatic endothelial cells (LEC)	CXCR2 / CDw128b / IL-8RB >> CXCR1 / CDw128a / IL-8RA Duffy antigen-related receptor for chemokines (DARC) (decoy)
		CXCL2 / GRO-2 /  GRO-b / MGSA-b / MIP-2a (GRO-KC in mouse)	activated granulocytes, monocytes, macrophages	CXCR2 / CDw128b / IL-8RB
		CXCL3 / GRO-3 / GRO-g / MGSA-g / MIP-2b (GRO-KC in mouse)		CXCR2 / CDw128b / IL-8RB
		CXCL5 / ENA-78 (LIX in mouse)		CXCR1 / CDw128a / IL-8RA CXCR2 / CDw128b / IL-8RB Duffy antigen-related receptor for chemokines (DARC) (decoy)
		CXCL6/ GCP-2 (Cka-3 in mouse)		CXCR1 / CDw128a / IL-8RA CXCR2 / CDw128b / IL-8RB
		CXCL7 / LDGF-PBP / NAP-2 / CTAP-II (from proteolytic truncation of CTAP-III at the N terminus by a cathepsin G-like enzyme on surfaces of neutrophils)	platelets	CXCR2 / CDw128b / IL-8RB
		CXCL8 / IL-8 / NAP-1 / TCF / NAF / neutrophil chemotactic factor (NCF)	alveolar macrophage, sweat	CXCR1 / CDw128a / IL-8RA CXCR2 / CDw128b / IL-8RB Duffy antigen-related receptor for chemokines (DARC) (decoy)
	XXXCXC or ELR- CXC chemokines (chemotactic for lymphocytes)	CXCL9 / monokine induced by IFN-g (MIG / MIG-1) (catabolysed by CD26 / DPPIV)	monocytes, macrophages, T lymphocytes, fibroblasts, lymphatic endothelial cells (LEC)	CXCR3 / CD183
		CXCL4 / PF4	megakaryocytes, platelets	unknown
		CXCL10  / IP-10 (catabolysed by CD26 / DPPIV)	monocytes, macrophages, T lymphocytes, fibroblasts, epithelial cells (including endothelial cells), lymphatic endothelial cells (LEC)	CXCR3 / CD183
		CXCL11 / IFN-inducible T cell a chemoattractant (I-TAC) / H174 (catabolysed by CD26 / DPPIV)		CXCR3 / CD183
		CXCL12 / PBSF / stromal cell-derived factor 1a (SDF-1a/b) (catabolysed by CD26 / DPPIV)	fibroblasts, HIV-1 infected macrophages	CD184 / CXCR4 / fusin / LESTR
		CXCL13 / BCA-1 / BLC	FDC	CD195 / CXCR5 / BLR-1
		CXCL16 / BUNZO / STRC33 / scavenger receptor PSOX (SR-PSOX)	APC (also membrane bound)	CXCR6
	chemotactic for monocytes only	CXCL14 / BMAC / BRAK / MIP-2g / bolekine / KEC / KS1 / NJAC		?
		CXCL15 / lungkine in mouse		CD195 / CCR5 / BLR-1
b-chemokines : CC motif (on Homo 17q11-32 chromosome region; chemotactic for monocytes and plasma cells)		CCL1 / I-309 (TCA-3 / P500 in mouse)	activated T lymphocytes	CCR8
		CCL2 / MCF / MCAF / monocyte chemoattractant protein (MCP) / MCP-1 (JE in mouse)	epithelial cell, fibroblast, smooth muscle cells, monocytes, alveolar macrophage, lymphatic endothelial cells (LEC)	CCR2 Duffy antigen-related receptor for chemokines (DARC) (decoy)  D6 / chemokine binding protein 2 (CBBP) (decoy)
		CCL3 / LD78 / MIP-1a (catabolysed by CD26 / DPPIV)	epithelial cells, monocytes, macrophages, T lymphocytes	CCR1 CD195 / CCR5 / BLR-1
		CCL3L1		CD195 / CCR5 / BLR-1 CCR9
		CCL4 / AT744.1 / LAG-1 / MIP-1b	monocytes, macrophages, T lymphocytes	CCR1 CD195 / CCR5 / BLR-1
		CCL5 / RANTES (catabolysed by CD26 / DPPIV)	T lymphocytes, activated NKT lymphocytes, epithelial cell, smooth muscle cell,eosinophils, monocytes, macrophages, fibroblast, lymphatic endothelial cells (LEC)	CCR1 CCR3 CD195 / CCR5 / BLR-1 Duffy antigen-related receptor for chemokines (DARC) (decoy)
		CCL6 (C10 / MRP-1 in mouse)	, lymphatic endothelial cells (LEC)	?
		CCL7 / MCP-3 (MARC / FIC in mouse)	epithelial cell, fibroblasts, activated monocytes	CCR1 CCR2 CCR3 Duffy antigen-related receptor for chemokines (DARC) (decoy)
		CCL8 / MCP-2 / HC14	fibroblasts, activated monocytes	CCR1 CCR2 CCR3 CD195 / CCR5 / BLR-1
		CCL9 (MRP-2 / CCF18 / MIP-1g in mouse)	APCs	?
		CCL10 / MIP-1g		?
		CCL11 / eotaxin / eotaxin-1 (catabolysed by CD26 / DPPIV)	epithelial cell (including pneumocytes and endothelial cell), alveolar macrophage, smooth muscle cell, fibroblast, eosinophils, lymphocyte, cardiomyocytes	CCR2 (both agonist and antagonist)  CCR3 CD195 / CCR5 / BLR-1
		CCL12 (MCP-5 in mouse)		CCR2
		CCL13 / MCP-4 / CKb-10 / NCC-1	epithelial cell (including pneumocytes, enterocytes and activated endothelial cells)	CCR1 CCR2 CCR3 CD195 / CCR5 / BLR-1
		CCL14a / HCC-1 / NCC-2		CCR1 CCR3 CD195 / CCR5 / BLR-1
		CCL14b / HCC-3		CCR1 CCR3 CD195 / CCR5 / BLR-1
		CCL15 / HCC-2 / leukotactin / Lkn-1 / MIP-1d / MIP-5 / NCC-3		CCR1 CCR3 CD195 / CCR5 / BLR-1
		CCL16 / HCC-4 / SexCkine / LEC / NCC-4 (LCC-1 in mouse)		CCR1 CCR2 CD195 / CCR5 / BLR-1 CCR8
		CCL17 / thymus and activation-regulated chemokine (TARC) / dendrokine	bronchiolar epithelial cells, thymus, dendritic cells, activated T lymphocytes	CCR4
		CCL18 / PARC / DC-CK-1 / MIP-4 / SCYA18 / AMAC-1	dendritic cells in secondary lymphoid organs	unknown
		CCL19 / MIP-3b / EBV-induced gene 1 ligand chemokine (ELC) / exodus-3 / CKb-11	thymus, lymph nodes, appendix	CCR7 / CDw197
		CCL20 / MIP-3a / exodus-1 / LARC	dendritic cells, fetal hepatocytes, activated T lymphocytes	CCR6
		CCL21/ 6Ckine / exodus-2 / SLC / TCA-4	TECs, lymph nodes, appendix and spleen, lymphatic endothelial cells (LEC)	CCR7 / CDw197 CXCR3 / CD183 (in mice but not in humans)
		CCL22 / macrophage-derived chemokine (MDC) / STCP-1 (ABCD-1 in mouse) (catabolysed by CD26 / DPPIV)	smooth muscle cell, dendritic cells, monocytes, alveolar macrophage, bronchiolar epithelium, thymus	CCR4
		CCL23 / CKb-8 / MPIF-1		CCR1 (?)
		CCL24 / eotaxin-2 / MPIF-2		CCR3 CCR4 (?)
		CCL25 / TECK	dendritic cells, thymus, hepatocytes, small bowel	CCR9
		CCL26/ eotaxin-3		CCR3
		CCL27 / CTACK / ALP / ILC (ESkine in mouse; the alternative spliced isoform PESKY lacks a signal peptide and is translocated to the nucleus acting as an intrakine; also ESkine has a NTS)	keratinocytes	CCR10
		CCL28 / MEC	mucosal epithelial cells (expecially salivary and mammary glands => in saliva and breast milk)	CCR3 CCR10
d-chemokines : CXXXC or CX3C motif		CX3CL1 / fractalkine / neurotactin / ABCD-3	activated endothelial cells	CX3CR1
g-chemokines : C motif (the prefix "X" is used to avoid confusion between g-chemokines receptors and complement receptors !)		XCL1 / lymphotactin (Lptn or Ltn) /  SCM-1a / ATAC	NK cells, DN thymocytes, activated CD8+ lymphocytes, lymphatic endothelial cells (LEC)	XCR1
		XCL2 / SCM-1b		XCR2
pleiotrophin / heparin binding growth factor 8 / neurite growth-promoting factor 1 (NGPF1)
midkine (MDK) / neurite growth-promoting factor (NGPF2)			esophageal carcinoma, astrocytes,

• eosinophil chemotactic factor of anaphylaxis (ECF-A) : eosinophil chemoattractants released by basophils and mast cells in immediate hypersensitivity reactions. ECF-A activity is associated with
• 2 acidic tetrapeptides
• Val-Gly-Ser-Glu (VGSE)
• Ala-Gly-Ser-Glu (AGSE)
• less well characterized larger peptides, which are chemotactic for eosinophils and, to a lesser degree, for neutrophils
• arachidonic acid metabolites (leukotriene B, 12-HETE, and 12-HHT)
• motogenic cytokines
• CSFs
• neuropoietins
• neurotrophins
• other peptides

	peptide	producer cell(s)	receptor
	bradykinin (BK)		B1
	Lys-BK / kallidin		B1
	Lys-des-Arg-BK		B2
endothelins are produced endogenously from preproendothelin to give big endothelins, which are cleaved by endothelin-converting enzymes ECE1 and ECE2 to yield the active protein.	endothelin-1	endothelial cells, neutrophils, mast cells, macrophages, mesangial cells of glomeruli and inner medullary collecting duct	ETA ETB
	endothelin-2		ETB
	endothelin-3	glomeruli and all the tubule segments	ETB
	thrombin		PAR-1 PAR-3 PAR-4
Hedgehog (hh) homologs : the mature signaling forms (HhNp) are covalently coupled to cholesterol at their COOH-terminal ends by the polytopic transmembrane acyl transferase rasp / skinny hedgehog / sightless (ski/sit), allowing insertion into lipid rafts. Autoproteolytic alternative splicing of intein and exteins from the 45-kDa precursor. Dispatched is a Ptc-related protein that mediates the release of at least some of the proteins from the membranes of the cells in which it is produced. The type II transmembrane protein tout-velu (ttv) (homologous to the vertebrate Ext proteins) is thought to function by synthesizing a heparan sulfate proteoglycan (HSPG) that binds HhNp in responding cells, facilitating its transfer between cells while at the same time possibly increasing its effective concentration for presentation to Ptc. The NH2-terminal palmitoyl adduct is not sufficient to limit Hh movement in vivo. It is however, possible that acylation of the cholesterol-modified form increases its membrane affinity.	desert hedgehog (Dhh) homolog (DHH)	during embryogenesis	Hedgehog interacting protein (Hip1 / HHIP) (no homolog in Drosophila)  Patched (ptc) homolog (PTCH) (contains a sterol-sensing domain (SSD); binding removes inhibition on Smoothened (smo) homolog (SMOH), which in turn is redistributed from unidentified intracellular compartments to the plasma membrane and whose GLI-mediated STP is activated). The Ptc gene itslef is a target of Hh activity, and thus Hh effectively promotes its own sequestration by up-regulating ptc transcription, a negative feedback mechanism that restrains its signaling range.
	Indian hedgehog (Ihh) homolog (IHH)	during embryogenesis
	sonic hedgehog  (Shh) homolog (SHH) NTD (secreted isoform generated from autocleavage by the CTD)	during embryogenesis
WNT	WNT1	during embryogenesis and oncogenesis	Frizzled homolog 1 (FZD1) Frizzled homolog 2 (FZD2) Frizzled homolog 3 (FZD3) Frizzled homolog 4 (FZD4) Frizzled homolog 5 (FZD5) Frizzled homolog 6 (FZD6) Frizzled homolog 7 (FZD7) Frizzled homolog 8 (FZD8) Frizzled homolog 9 (FZD9) Frizzled homolog 10 (FZD10) + LRP5 / LRP7 + LRP6 => b-catenin => HMGs => FOXN1 / WHN
	WNT2	during embryogenesis and oncogenesis
	WNT2B / WNT13	during embryogenesis and oncogenesis
	WNT3	during embryogenesis and oncogenesis
	WNT3A	during embryogenesis and oncogenesis
	WNT4	during embryogenesis and oncogenesis
	WNT5A	during embryogenesis and oncogenesis
	WNT5B	during embryogenesis and oncogenesis
	WNT6	during embryogenesis and oncogenesis
	WNT7A	during embryogenesis and oncogenesis
	WNT7B	during embryogenesis and oncogenesis
	WNT8A	during embryogenesis and oncogenesis
	WNT8B	during embryogenesis and oncogenesis
	WNT9	during embryogenesis and oncogenesis
	WNT10A	during embryogenesis and oncogenesis
	WNT10B / WNT12	during embryogenesis and oncogenesis
	WNT11	during embryogenesis and oncogenesis
	WNT14	during embryogenesis and oncogenesis
	WNT15	during embryogenesis and oncogenesis
	WNT16	during embryogenesis and oncogenesis
Ephrin A class (anchored to the membrane by a GPI linkage)	Ephrin-A1	developmental events, particularly in the nervous system. Posttranslational modifications determine whether this protein localizes to the nucleus or the cytoplasm	EphA1 EphA2 EphA4 EphA5 EphA7 EphA8
	Ephrin-A2		EphA1 EphA2 EphA4 EphA5 EphA7 EphA8
	Ephrin-A3		EphA1 EphA2 EphA4 EphA5 EphA7 EphA8
	Ephrin-A4		EphA1 EphA2 EphA4 EphA5 EphA7 EphA8
	Ephrin-A5		EphA1 EphA2 EphA4 EphA5 EphA7 EphA8
Ephrin B class (transmembrane proteins)	Ephrin-B1		EphB1 EphB2 EphB3 EphB6
	Ephrin-B2		EphA3 EphB4
	Ephrin-B3 (forebrain)		EphB1 EphB2 EphB3 EphB6
Jelly belly (Jeb)			anaplastic lymphoma kinase (Alk)
HMG proteins	high-mobility group B1 protein (HMGB1)		RAGE

Please note that Epo, TGF-b, M-CSF and SCF can reach high local concentrations and hence significant concentrations in blood, too : so they can also be considered in endocrine signalling.
• neuromodulators or neuromediators (volume transmission)
• ions (Ca²⁺, Mg²⁺)

nucleotides			produced by...	receptor(s)
purines	adenosine triphosphate (ATP)			P2X1 P2X2 P2X3 P2X4 P2X5 P2X6 P2X7 / P2Z P2Y2 / P2U / P2N P2Y11
	extracellular derivatives of ATP	adenosine diphosphate (ADP)		P2Y1 P2T
		adenosine monophosphate (AMP)
		adenosine (Ado)		P1  A1 A2a A2b A3
pyrimidines		UTP		P2Y2 / P2U / P2N P2Y4
		UDP		P2Y6 cysLT1
the first dinucleotide isolated from living organisms that contains both purine and pyrimidine moieties	uridine adenosine tetraphosphate (Up4A)ref		human endothelial cells obtained from dermal vessels stimulated with adenosine 5'-triphosphate (ATP), uridine 5'-triphosphate (UTP), acetylcholine, endothelin, A23187 and mechanical stress	P2X1 receptors, and probably also through P2Y2 / P2U / P2N and P2Y4

• neuropeptides or neuroactive peptides co-released with classical neurotransmitters (often involved also in endocrine signalation) pmol/g

message domain	endogenous opiates / opioid peptides / endorphins (sensu latu) / narcotics and related peptides (close physiological linkage between the stress axis and opioid system)	produced by...	receptor(s)
Tyr-Gly-Gly-Phe	proopiomelanocortin (POMC) (239 amino acids) => g-melanocyte stimulating hormone (g-MSH) g2-melanocyte stimulating hormone (g2-MSH) g1-melanocyte stimulating hormone (g1-MSH) / desGly-g2-MSH g3-melanocyte stimulating hormone (g3-MSH) adrenocorticotropic hormone (ACTH) / corticotropin a-melanocyte stimulating hormone (a-MSH) corticotropin-like intermediate peptide (CLIP) b-lipotropin (b-LPH) / adipokinin g-lipotropin (g-LPH) b-melanocyte stimulating hormone (b-MSH) b-endorphin (b-END) (31 amino acids). b-endorphin peptides may be N-acetylated to inactivated forms, while C-terminal processing may alter or regulate physiological functions.  a-endorphin g-endorphin Met-enkephalin (M-ENK) Melanocortins is the name given to peptides which share the common His-Phe-Arg-Trp core (i.e. MSHs and ACTH).	long interneurons in :  anterior hypophysis (=> ACTH : hormone but also retrograde portal flux to CNS) corticotropic cells of intermediate hypophysis  (=> a-MSH) arcuate nucleus neurons producing also CART (=> a-MSH) => anterior septum, paraventricular nucleus of the thalamus, parabranchial nucleus, periaqueductal grey (PAG) nucleus tractus solitarius =>  limbic and brainstem areas and spinal cord spinal cord pancreatic islet cells  syncitiotrophoblast	MC1R MC2R / ACTHR MC3R MC4R MC5R m d k1 k2 s1 s2
	proenkephalin A (256 amino acids) => Met-enkephalin (M-ENK) : Tyr-Gly-Gly-Phe-Met  peptide F Met-enkephalin (M-ENK) (N-terminus) Met-enkephalin (M-ENK) (C-terminus) peptide E octapeptide : Tyr-Gly-Gly-Phe-Met-Arg-Gly-Leu Met-enkephalin (M-ENK) Leu-enkephalin (L-ENK) : Tyr-Gly-Gly-Phe-Leu They are catabolyzed by leucine aminopeptidase (LAP), carboxypeptidase A (CPA) and dipeptidyl-dipeptidase (DAP) / enkephalinase. The Tyr moiety is important for activity and probably corresponds to the 3-hydroxyl group on morphine. C-terminal amidation of peptides can occur following the enzymatic cleavage and removal of basic amino acids. The activity of the enkephalin peptides can be enhanced by replacement of Gly2 with D-Ala which decreases the hydrolysis of enkephalins by enkephalinases between the Tyr and Gly amino acids. Met5-amides also are resistant to hydrolysis. Met-enkephalin (M-ENK) heptapeptide : Tyr-Gly-Gly-Phe-Met-Arg-Phe  Met-enkephalin (M-ENK)	CNS : short interneurons in  :  globus pallidus caudate nucleus amygdala hippocampus locus ceruleus hypothalamus cerebellum substantia nigra thalamus medulla oblungata median eminence cortex laminae I and II of the spinal cord spinal trigeminal nucleus periaqueductal grey (PAG) PNS  CSF posterior hypophysis celial ganglion upper cervical ganglion salivary glands nerve plexuses and exocrine glands of the stomach and intestine adrenal medulla blood	m d k1 k2 s1 s2
	proenkephalin B / prodynorphin neoendorphin a-neoendorphin (10 amino acids) Leu-enkephalin (L-ENK) b-neoendorphin (9 amino acids) dynorphin A (17 amino acids) : Tyr-Gly-Gly-Phe-Leu-Arg-Ile8-Arg-Pro-Lys-Leu-Lys-Trp-Asp-Asn-Gln Leu-enkephalin (L-ENK) dynorphin A1-32 dynorphin A1-17 dynorphin A1-13 dynorphin A1-8 dynorphin B (13 amino acids) Leu-enkephalin (L-ENK)	short interneurons in  posterior hypophysis CNS : hypothalamus => magnocellular nucleus striatonigral bundle mesencephalus hippocampus pons bulb spinal cord (=> dorsal horns, marginal zone, deep laminae) cortex cerebellum GI tract skeletal muscles pancreas heart lungs liver kidneys testes ovaries	m d k1 k2 s1 s2
	proorphanin / pronociceptin (in Mus musculus) nocistatin (110MPRVRSLFQEQEEPEPGMEEAGEMEQKQLQ127) nociceptin / orphanin FQ (N/OFQ) (130FQFGGFTGARKSARKLANQ146) orphanin-2 (149FSEFMRQYLVLSMQSSQ165)	hippocampus  cortex  periaqueductal grey  median raphe  superficial dorsal horn  rostral ventromedial medulla (RVM)  numerous sensory sites	m d k1 k2 s1 s2 ORL-1
Tyr-Pro-Trp/Phe	endomorphin 1 (Tyr-Pro-Trp-Phe-NH2)		m
	endomorphin 2 (Tyr-Pro-Phe-Phe-NH2)		m

• preprotachykinins (PPT)
• TAC1 =>
• isoform a
• substance P (SP) / neurokinin 1 (NK1) / tachykinin 1 binds to NK₁> NK₂ = NK₃
• isoform b
• substance P (SP) / neurokinin 1 (NK1) / tachykinin 1
• substance K (SK) / neurokinin A (NK-A) / NK2 / NK-a / neuromedin L (NM-L) / tachykinin 2 binds to NK₂ > NK₃ = NK₁
• neuropeptide K
• neuropeptide g (NPg)
• isoform g
• substance P (SP) / neurokinin 1 (NK1) / tachykinin 1
• substance K (SK) / neurokinin A (NK-A) / NK2 / NK-a / neuromedin L (NM-L) / tachykinin 2
• neuropeptide g (NPg)
• isoform d
• substance P (SP) / neurokinin 1 (NK1) / tachykinin 1
• TAC3 => neurokinin B (NK-B) / NK3 / NK-b / neuromedin K (NM-K) binds to NK₃ > NK₂ > NK₁
• preprotachykinin C (PPT-C) / hemokinin 1
• neuromedin U (NMU) is a hypothalamic neuropeptide that plays an important role in the regulation of feeding behavior and energy metabolism independent of the leptin signaling pathway^ref
• neuromedin U receptor 1 (NMUR1)
• neuromedin U receptor 2 (NMUR2)
• eledoisin from Eledone cirrhosa
• hylambatin from Kassina maculata (a.k.a. Hylambates maculatus)
• kassinin from Kassina senegalensis
• physalaemin from Physalaemus fuscumaculatus
• phyllomedusin from Phyllomedusinae
• G-KI
• uperolein from Uperoleia rugosa and Uperoleia marmorata
• ranatachykinin A
• ranakinin
• scyliorhinin I and II from Scyliorhinus canicula
• urechistachykinin I and II from Urechis unicinctus
Co-released neurotransmitters and neuromodulators :
• ACh and vasointestinal peptide (VIP)
• NE and neuropeptide Y (NPY)
• DA and cholecystokinin (CCK)
• undefined mediators
• transforming growth factor (TGF) : any of several proteins secreted by transformed cells and stimulating growth of normal cells, although not causing transformation
• basophil chemotactic factor (BCF) : a lymphokine produced by activated lymphocytes that is chemotactic for basophils, possibly responsible for the influx of basophils into sites of inflammation (Jones-Mote reaction).
• eosinophil chemotactic factor (ECF) : a lymphokine produced by activated lymphocytes that is chemotactic for eosinophils.
• B cell differentiation factors (BCDF) :  factors derived from T cells that stimulate B cells to differentiate into antibody-secreting cells
• B cell growth factors (BCGF) : factors derived from T cells that stimulate B cells to proliferate in vitro but (unlike B cell differentiation factors) do not stimulate antibody secretion
• B lymphocyte stimulatory factors (BSF) : a system of nomenclature for factors that stimulate B cells, replacing individual factor names (e.g., B cell differentiation factor). Each factor is designated by BSF and a number, BSF1, BSF2, etc., with the letter p prefixed to the number for factors that have not been purified or whose structure has not been identified. BSF1 is IL-4 and BSF2 is IL-6.
• crystal-induced chemotactic factor (CCF) : a glycoprotein produced by neutrophils upon ingestion of monosodium urate or calcium pyrophosphate crystals, which is directly chemotactic for neutrophils and is thought to be involved in the inflammatory process in gouty arthritis.
• histamine-releasing factor (HRF) : a lymphokine, believed to be produced by macrophages and B lymphocytes, that induces the release of histamine by IgE-bound basophils occurring in late phase allergic reaction in sensitive individuals.
• macrophage-derived growth factor : a substance released by macrophages below the surface of a wound that induces the proliferation of fibroblasts, with consequent deposition of collagen, fibronectin, and glycosaminoglycan.
• macrophage growth factor (MGF) : any of various glycoproteins that permit macrophages harvested from peritoneal exudates to proliferate in liquid-suspension cultures and form colonies consisting solely of mononuclear phagocytes.
• immunoglobulin-binding factor (IBF) : a lymphokine having the ability to bind IgG complexed with antigen and prevent complement activation, possibly Fc receptors shed from T cells.
• leukocyte inhibitory factor (LIF) : a lymphokine that inhibits the migration of polymorphonuclear leukocytes but not macrophages.
• lymphocyte blastogenic factor (BF) / lymphocyte mitogenic factor (LMF) / lymphocyte-transforming factor (LTF) : a nondialyzable heat-stable macromolecule, mol. wt. approximately 20,000–30,000, released by lymphocytes stimulated by specific antigen, that causes nonstimulated lymphocytes to undergo blast transformation and cell division.
• lymph node permeability factor (LNPF) : a vasoactive factor, distinct from histamine, serotonin, bradykinin, and kallikrein, that is released without immunologic stimulus from many tissues, including lymph nodes, spleen, kidney, liver, and muscle.
• myocardial depressant factor (MDF) : a peptide putatively formed in response to a fall in systemic blood pressure related to sepsis; it has a negatively inotropic effect on myocardial muscle fibers.
• neutrophil chemotactic factor (NCF) : 1. a poorly characterized chemotactic factor, mol. wt. approximately 750,000, that attracts neutrophils but not eosinophils or monocytes and is released by basophils or mast cells in immediate hypersensitivity reactions. Called also high-molecular-weight neutrophil chemotactic factor (HMW-NCF).  2. a lymphokine produced by activated lymphocytes that is chemotactic for neutrophils.
• skeletal growth factor : a protein that stimulates growth of osteocytes.
• skin reactive factor (SRF) : a lymphokine derived from antigen-stimulated lymphocytes that augments delayed hypersensitivity skin reaction, increasing capillary permeability and infiltration of monocytes; perhaps a mixture of other lymphokines.
• osteoclast-activating factor (OAF) : a lymphokine that stimulates bone resorption; it is a small protein unrelated to parathyroid hormone and may be involved in the bone resorption associated with multiple myeloma and other hematologic neoplasms or inflammatory disorders such as rheumatoid arthritis and periodontal disease.
• autocrine signalling (the receptor is found on cells of the same type of the producer one, included the producer cell itself)
• exocrinia
• ptyocrinous : elaborating secretion in the form of granules which are eventually extruded; said of unicellular glands, as goblet cells, which secrete in this way.
• diacrinous : giving off secretion directly, as from a filter; said of gland cells, as those of the kidney.
• endocrine signalling (incretions signal through massive flow in the bloodstream, free or bound to hepatic seroprotein carriers, up to target organs(s) ; if the endocrine cell is a neuron => neuro(endo)crine)
• granins
• properly said hormones (regulated incretion; if the endocrine cell is a neuron => neurohormones) : common vertebrate hormones
• liposoluble
• binding an inhibited transcription factor located in ...
• cytosol
• steroids
• cortical steroids / corticosteroids
• glucocorticoids : they are generated

hormone	produced by	receptor
cortisol	zonae fasciculata and reticularis of adrenal cortex	GR >  MR
corticosterone
hydrocortisone

• mineralocorticoids

hormone	produced by	receptor
aldosterone	zona glomerulosa of adrenal cortex	MR

• sexual steroids
• androgens

hormone	produced by	receptor
testosterone (T)	zonae fasciculata and reticularis of adrenal cortex and ovary (50%), androgen-sensitive peripheral tissues (50%; prostate, from androstenedione)	AR
dihydrotestosterone (DHT) is generated by 5a-reductase-mediated conversion of testosterone	androgen-sensitive peripheral tissues (prostate, from androstenedione and testosterone)	AR
androstenedione (A)		AR
deihydroepiandrosterone (DHEA)	zonae fasciculata and reticularis of adrenal cortex (90%)	AR
dehydroepiandrosterone sulfate (DHEA-S)	zonae fasciculata and reticularis of adrenal cortex	AR

• estrogens

hormone	produced by	receptor
estrone (E1)	premenopausal ovary
17b-estradiol (E2)	premenopausal ovary, syncitiotrophoblast	ERa ERb
estriol (E3)	hepatocytes (from estrone and estradiol in premopausal females), fatty tissue (from adrenal androstenedione in postmenopausal females), syncitiotrophoblast

• progestins

hormone	produced by	receptor
progesterone	corpus luteum syncitiotrophoblast	PR

• cell nucleus

hormone	produced by	receptor
all-trans-retinoic acid (ATRA)	retinol <=>	RARa RARb RARg
9-cis-retinoic acid	retinol <=>	RXRa RXRb RXRg
3,5,3'-T3	thyroid epithelial cells	T3Ra T3Rb
1a,25-(OH)2-vitamin D3 / calcitriol	vitamin D2 and vitamin D3	VDR
3-iodothyronamine (T1AM)	thyroid epithelial cells	trace amine receptor 1 (TAR1)

• without receptor (binding directly to effector molecules)
• not liposoluble hormones : signal transduction by a bi- or polytopic plasma-membrane integral protein
• nonpeptide hormones

hormone	produced by	receptor(s)
melatonin (MLT) / N-acetyl-5-methoxytryptamine	pineal gland	MLT1 MLT2
adrenoglomerulotropin (AGTH) / 6-methoxy-1-methyl-1,2,3,4-tetrahydroharman / pinoline / 6-methoxy-1-methyl-1,2,3,4-tetrahydro-b-carboline	pineal gland	?
adrenaline / epinephrine (E)	adrenal medulla	a1A / 1C a1B a1D a2A a2B a2C b1 b2 b3
noradrenaline / norepinephrine (NE)	adrenal medulla	a1A / 1C a1B a1D a2A a2B a2C b1 b2 b

• oligopeptides and proteins (nomenclature of peptide hormones)

hormone		produced by	receptor(s)
insulin		b / B cells of Langerhans' islets of endocrine pancreas	InsR
insulin-like growth factors (IGF) / sulfation factors :  insulin-like growth factor (IGF-1) / non-suppressible insulin-like acting (substance) 1 (NSILA(S)-1) / somatomedin C (SM-C)		hepatocytes and other mesenchymal tissues	IGF-1R / CD221
insulin-like growth factor 2 (IGF-2) / non-suppressible insulin-like acting (substance) 2 (NSILA(S)-2) / somatomedin A (SM-A) / multiplication stimulating activity (MSA)			IGF-2R
insulin-like 3 / relaxin-like factor (RLF) (after proteolytic processing of the C-peptide, consists of a 32-residue-long B-chain and a 26-residue-long A-chain and has a molecular size of 6.25 kDa.)		Leydig cells
insulin-like 4 (precursor that undergoes post-translational cleavage to produce 3 polypeptide chains, A-C, that form tertiary structures composed of either all three chains, or just the A and B chains)		early placental cytotrophoblast and syncytiotrophoblast
preproglucagon =proconvertase 3 (PC3)=>  glicentin (1-69; containing GRPP, glucagon, and IP-1)=proconvertase 2 (PC2)=> glicentin-related pancreatic polypeptide (GRPP) (1-30) glucagon C-terminal peptide / major proglucagon fragment (MPGF) (containing IP-1, GLP-1, IP-2, and GLP-2)		a / A cells of Langerhans' islets of endocrine pancreas and stomach	glucagon receptor
preproglucagon / enteroglucagon =proconvertase 3 (PC3)=>  glicentin (1-69; containing GRPP, glucagon, and IP-1)=proconvertase 2 (PC2)=> glicentin-related pancreatic polypeptide (GRPP) (1-30) glucagon / hyperglycemic-glycogenolytic factor (HGF) oxyntomodulin (33-69) C-terminal peptide / major proglucagon fragment (MPGF) (70-158)=proconvertase 3 (PC3)=> glucagon-like peptide 1 (GLP-1) (78-107 amide) intervening peptide-2 (IP-2) (111-122 amide) glucagon like peptide 2 (GLP-2) (126-158)		brain, L cells in jejunum, ileum, and colon	glucagon receptor GLP1R GLP2R
precursor of pancreatic polypeptide (PPY) and pancreatic icosapeptide		PP / F cells of Langerhans' islets of endocrine pancreas head, fundus and pylorus of stomach, and colon	PPYR1
pancreatic polypeptide 2 (PPY2)		PP / F cells of Langerhans' islets of endocrine pancreas head
neuropeptide Y (NPY)		arcuate nucleus neurons producing also AgRP, cytotrophoblast	Y1 Y2 Y5
peptide YY (PYY) (36 amino acids) : the cleaved subpeptide PYY[3-36] is biologically active and may constitute the majority of circulating PYY-like immunoreactivity.		ileal L cells postprandially in proportion to the calorie content of a meal	Y2
peptide YY 2 (PPY2) / seminalplasmin
atrial natriuretic peptide (ANP) (processed by corin)		atrial cardiomyocytes	NPR1 / ANP-A / GC-A
brain natriuretic peptide (BNP) (high-MW BNP and low-MW BNP)		ventricular cardiomyocytes	NPR1 / ANP-A / GC-A
C-type natriuretic peptide (CNP)		tubular cells and glomeruli	NPR2 / ANP-B / GC-B
adrenomedullin (AM / ADM)		blood vessel endothelial and smooth muscle cells, and microvasculature-rich tissues	adrenomedullin receptor (ADMR)
guanylin / guanylate cyclase activator 2A		enterocytes, tubular cells	GC-C
uroguanylin / guanylate cyclase activator 2B		enterocytes, tubular cells	GC-C
antidiuretic hormone (ADH) / Arg vasopressin (AVP) (processing of the 168-amino acid human AVP preprohormone by endopeptidase, exopeptidase, monooxygenase, and lyase generates AVP, the carrier protein neurophysin II / VP-neurophysin, and VP-glycopeptide) (human beings & other mammals)		perikarya of magnocellular neurons in the paraventricular nucleus (PVN) and the supraoptic nucleus (SON) (separate from those synthetizing oxytocin), heart blood vessels, adrenal medulla	V1b / V3 > V1a > V2
lypressin (pigs, marsupials)
phenypressin (macropodids)
vasotocin (nonmammalian vertebrates)
arginine conopressin (Conus striatus)
lysine conopressin (Conus geographicus)
locust subesophageal ganglia peptide
oxytocin (OT) (the carrier protein neurophysin I arises from alternative splicing of the same mRNA)		perikarya of magnocellular neurons in the paraventricular nucleus (PVN) and the supraoptic nucleus (SON) (separate from those synthetizing oxytocin)	OT receptor
TSH-releasing hormone (TRH) (GlpHisPro-NH2)		hypothalamic nuclei, cytotrophoblast	TRH-R
heterodimeric glycoproteins with common a chain (96 amino acids ; 14 kDa)	thyroid stimulating hormone (TSH) : + b chain (112 amino acids)	thyroid epithelial cells	TSH-R
	follicle-stimulating hormone (FSH) : + b chain (120 amino acids)	gonadotropic cells of anterior pituitary gland	FSH-R
	luteinizing hormone (LH) : + bchain (121 amino acids)	gonadotropic cells of anterior pituitary gland	LH / hCG-R
	human chorionic gonadotropin (hCG) : +  b chains (b1, b2, b3, b5, b7 or b8) (147 amino acids)	syncitiotrophoblast	LH / hCG-R
gonadotropin-releasing hormone (GnRH) 1 (10 amino acids)		arcuate nucleus and preoptic area of medial hypothalamus, cytotrophoblast, T cells	GnRH-R
gonadotropin-releasing hormone (GnRH) 2		brain, T cells	?
follistatin (2 isoforms from alternative splicing : FST317 and FST344)		autocrine and/or paracrine growth factor	activin A activin AB
follistatin-like 1 (FSTL1)
follistatin-like 2 (FSTL2) / IGFBP7
follistatin-like 3 (FSTL3) / follistatin-related protein (FSRP)			activin A
somatostatin (SST) : Pro-9 and Pro-5, located near the processing sites (Arg-15 and Arg-2Lys-1) of human prosomatostatin are important for cleavage of the precursor into  SST-14 (paracrine effects) SST-28 (endocrine effects)		d / D cells of Langerhans' islets of endocrine pancreas, thymus, cytotrophoblast	SST1 SST2A SST2B SST3 SST4 SST5
cortistatin =>  cortistatin 14		immune cells (up-regulated during differentiation of monocytes into macrophages and dendritic cells), lymphoid tissues, and bone marrow	SST1 SST2A SST2B SST3 SST4 SST5 GHSR
calcitonin-1 gene encodes for procalcitonin (PCT) (14 kDa), whose processing generates :  calcitonin (CT) katacalcin (KC)  procalcitonin NH2-terminal cleavage peptide (N-ProCT)		thyroid medullary C cells; TNF-a-stimulated monocytes and granulocytes	calcitonin receptor
calcitonin gene-related peptide (CGRP) 1		thyroid, neurons	CGRP receptor
calcitonin gene-related peptide (CGRP) 2			CGRP receptor
parathormone (PTH)		parathyroid epithelial cells	PTHR1 PTHR2
PTH-related protein (PTHrp)		90% of primary prostate and lung spindle cell carcinomas and 50% of primary breast cancers, fetal tissues (parathyroids), low levels in keratinocytes, uterus, mammary glands during lactation	PTHR1
corticotropic releasing factor (CRF) / hormone (CRH)		hypophysary corticotropic cells, cytotrophoblast	CRHR1 (high affinity)  CRHR2 (low affinity)
adrenocorticotropic hormone (ACTH) (from POMC gene)		corticotropic anterior pituitary cells	MC2R / ACTHR
growth hormone releasing hormone (GHRH)		hypothalamic nuclei	GRP39 GRP38 / MTLR1
ghrelin		stomach	GHSR
growth hormone (GH) / somatotropic hormone (STH) 1 (191 amino acids)  hyperglycemic-glycogenolytic factor (HGF) : the hyperglycemic component of growth hormone extracts		somatotropic cells of pituitary gland, cytotrophoblast	GHR
growth hormone (GH) / somatotropic hormone (STH) 2		somatotropic cells of pituitary gland	GHR
choriosomatomammotropin (hCS) 1 / placental lactogen (hPL)		syncitiotrophoblast	GHR
choriosomatomammotropin (hCS) 2		syncitiotrophoblast	GHR
motilin (Mo / MTL)		Mo cells in jejunum and ileum	GRP38 / MTLR1
relaxin 1 (RLX1)			RLXR
relaxin 2 (RLX2)			RLXR
relaxin 3 (RLX3)			RLXR
inhibin A (= inhibin a or bC homodimer)		pituitary	activins and inhibin receptor
inhibin B =
activin A (= inhibin bA homodimer)		autocrine and/or paracrine growth factor in pituitary, testis, epididymis and prostate	activins and inhibin receptor follistatin follistatin-like 3 (FSLT3)
activin AB (= inhibin bA and bB heterodimer)		autocrine and/or paracrine growth factor in pituitary, testis, epididymis and prostate	activins and inhibin receptor follistatin
bone morphogenetic proteins (BMPs)	bone morphogenetic protein (BMP) 1		BMP receptor
	bone morphogenetic protein (BMP) 2		BMP receptor
	bone morphogenetic protein (BMP) 3		BMP receptor
	bone morphogenetic protein (BMP) 4		BMP receptor
	bone morphogenetic protein (BMP) 5		BMP receptor
	bone morphogenetic protein (BMP) 6		BMP receptor
	bone morphogenetic protein (BMP) 7		BMP receptor
	bone morphogenetic protein (BMP) 8		BMP receptor
	bone morphogenetic protein (BMP) 9		BMP receptor
	bone morphogenetic protein (BMP) 10		BMP receptor
	bone morphogenetic protein (BMP) 11		BMP receptor
	bone morphogenetic protein (BMP) 15		BMP receptor
galanin			galanin receptor 1 galanin receptor 2 galanin receptor 3
kisspeptins derive from the product of KiSS-1 : common RF-amide C terminus	kisspeptin 13		GRP54
	kisspeptin 14
	kisspeptin 54 / metastin	placenta, melanoma
xenin consists of the N-terminal 25 amino acids of alpha-COP
secretin		S cells in jejunum and ileum	secretin receptor
vasointestinal peptide (VIP) precursor encodes :  vasointestinal peptide (VIP) peptide histidine isoleucine (PHI) peptide histidine methionine (PHM) peptide histidine valine (PHV)			VIPR1 / PACAPR2 VIPR2
helodermin-like peptide		thyroid parafollicular C cells
pituitary adenylate cyclase activating hormone (PACAP)			VIPR1 / PACAPR2 VIPR2 PACAPR1
cholecystokinin (CCK)		I cells in jejunum and ileum	CCK1 / CCKA CCK2 / CCKB
neurotensin		N cells in ileum	neurotensin receptor 1 neurotensin receptor 2
agouti-related peptide (AgRP) homolog (2 isoforms which differ in 5'UTRs)		arcuate nucleus neurons producing also NPY	antagonist on  MC3R  MC4R
cocaine- and amphetamine-regulated transcript (CART)		arcuate nucleus neurons producing also a-MSH	?
repulsive guidance molecule (RGM) domain family, member A			neogenin (NGN)homolog 1 (chicken) is a dependence receptor inducing cell death in the absence of RGM, whereas the presence of RGM inhibits this effectref
gastrin		G cells in pylorus and duodenum, TG cells in jejunum	CCK2 / CCKB
gastrin-releasing peptide (GRP) / bombesine			GRP / bombesine receptor
gastric inhibitory polypeptide (GIP) / glucose-dependent insulinotropic peptide (GIP)		K cells of the duodenum, jejunum, and ileum	GIP receptor
prolactin (PRL) (199 amino acids)		lactotropic cells of pituitary gland, placenta, decidua and endometrium in the second half of the menstrual cycle	PRLR
leptin		white adipocytesref, stomachref, placentaref, brainref, and pituitary glandref	LEPR
adiponectin (APM1) / adipocyte complement-related protein of 30 kDa (ACRP30) / adipocyte, C1Q and collagen domain containing (ACDC)		adipocytes	adipoR1 adipoR2
visfatin (for visceral fat protein)		visceral adipocytes
resistin family : the characteristic feature of this family is the C-terminal stretch of 10 cys residues with identical spacing.	resistin (RETN)	adipocytes	?
	resistin-like b (RETNLB)	colon and small intestine	?
	resistin-like g (RETNLG)	?	?
angiotensinogen ==  ==renin or chymase ==> angiotensin I (ANG) ==somatic ACE, ACE2, cathepsin G, chymostatin-sensitive angiotensin II-generating enzyme, or heart chymase 1==> angiotensin II ==cathepsin G or tonin==> angiotensin II		hepatocytes	AT1a AT1b AT2
endosulfines (for endogenous sulfonylureas)	a-endosulfine (ENSA) (121-amino acids protein of 19 kDa)	muscle, brain, and d cells of pancreas	ABCC8 / sulfonylurea receptor 1 (SUR1) voltage-gated calcium channels
	b-endosulfine (ENSB) (more basic, only from ovine and porcine  brain)

islet amyloid polypeptide (IAPP) / amylin		b cells of pancreas
Klotho protein functions as a circulating hormone that binds to a cell-surface receptor and represses intracellular signals of insulin and IGF1, an evolutionarily conserved mechanism for extending life span. Alleviation of aging-like phenotypes in Klotho-deficient mice was observed by perturbing insulin/IGF1 signaling, suggesting that Klotho-mediated inhibition of insulin/IGF1 signaling contributes to its anti-aging properties. Klotho protein may function as an anti-aging hormone in mammalsref

• both receptor and ligand on plasma-membrane : juxtacrinesignalling (although there is no real "crinia" !)
• some cluster determinant (CD)antigens
• Boss & Sev proteins

Notch homolog 1 (NOTCH1) : member of a Type 1 transmembrane receptor family that shares structural characteristics including an extracellular domain consisting of multiple EGF-like repeats, and an intracellular domain consisting of multiple, different domain types. Notch family members play a role in a variety of developmental processes by controlling cell fate decisions.  Notch homolog 2 (NOTCH2) Notch homolog 3 (NOTCH3) Notch homolog 4 (NOTCH4)

delta-like 1 (DLL1) delta-like 1 homolog (DLK1) delta-like 3 (DLL3) delta-like 4 (DLL4) deltex homolog 1 (DTX1) hairy and enhancer of split 1 (HES1) jagged 1 (JAG1)

• intracrinesignaling

CELL MEMBRANE TRANSPORT

• across plasma membrane
• passive diffusion (DG < 0)
• through the bilayer (i.e. without transmembrane proteins help)
• facilitated by transmembrane proteins
• channel proteins
• mediated (=> reversible) by solute carrier proteins / transporters / permeases : 12x
• uniport
• cotransport
• symport
• antiport
• active transport, mediated (=> reversible) by solute carrier proteins / transporters / permeases : 12x) binding the transported molecule (DG > 0)
• combined to modifications of the transported molecule (group translocation : only in anaerobic Prokarya !)
• without modification of the transported molecule
• with no other protein needed
• primary active transport
• using ATPases
• using electromagnetic radiation
• secondary active transport or cotransport or combined transport
• antiport or countertransport
• symport or cotransport in the literal sense
• with other proteins needed (only in Gram -ve Bacteria)
• around membrane
• passive or facilitated diffusion (DG < 0)
• nuclear pore complex (NPC)
• cytosis (i.e. : by creating vesicle) (DG > 0)
• emiocytosis / emeiocytosis : the ejection of material from a cell
• exocytosis : the discharge from a cell of particles that are too large to diffuse through the wall
• constitutive
• regulated
• following a secretory stimulus newly assembled vesicles dock rapidly to the cell membrane and are releases first, whereas older vesicles are removed from the membrane and relocated deeper in the cytoplasm.

Prioritizing younger vesicles for recruitment for exocytosis
• result in the secretion of fresher and perhaps more biologically active agents
• ensure that upregulation or downregulation of the genes encoding vesicle components is rapidly translated to changes in the readily releasable vesicle pool.
• endocytosis : the uptake by a cell of material from the environment by invagination of its plasma membrane; it includes :
• phagocytosis (only by "professional" phagocytes, i.e. by cells capable of pseudopodia formation) : endocytosis of particulate material, such as microorganisms or cell fragments. The material is taken into the cell in membrane-bound vesicles (phagosomes) that originate as pinched off invaginations of the plasma membrane : early phagosome (ectoplasmic, pH 6.5) => late phagosome (endoplasmic, pH 4.5). Phagosomes fuse with lysosomes, forming phagolysosomes in which the engulfed material is killed and digested. According to receptors it can be classified as :
• immune, induced or opsonic phagocytosis : phagocytosis aided by subjecting bacteria to the action of opsonins in the blood
• type I : C3bi-opsonized particles --- CR2 or CR3 or CR4
• type II : IgG coated particles --- FcgRs
The calcium-promoted RASA4 / Ras inactivator (CAPRI), a Ras GTPase-activating protein, functions as an adaptor for Cdc42 and Rac1^ref
• non-immune, non-opsonic or surface phagocytosis : enhanced phagocytosis by macrophages and neutrophils of microorganisms or other particulate antigens that are trapped against surfaces, e.g., other leukocytes, fibrin clots, or tissue surfaces; it does not require opsonins (i.e. mediated by other ligand--receptors, even if CR3 also mediates nonopsonic phagocytosis through engagement of distinct sites).
• spontaneous phagocytosis : phagocytosis of bacteria taking place in an indifferent medium, or phagocytosis of nonantigenic particles
It depends on several proteins : PI3K => PIP₃ => myosin X / Myo10
According to unidirectionality it can be classified as :
• "normal" phagocytosis
• frustrated or reverse phagocytosis
Accordint to size it can be classified as :
• ultraphagocytosis : ingestion of particles of submicroscopic dimensions
According to involvement of ER in phagosome formation it can be classified as
• ER-mediated : ER is directly recruited to the PM to form phagosomes
• non-ER mediated
• pinocytosis : the imbibition of liquids by cells, especially the mechanism by which cells ingest extracellular fluid and its contents; it involves the formation of minute incuppings or invaginations (caveolae) by the cell membrane, which close and pinch off to form free, small particles- and fluid-filled vesicles (pinosomes /  pinocytotic vesicles) in the cytoplasm; no pseudopodia formation occurs. It is thought to be a method of active transport across the cell membrane.
• micropinocytosis : the taking up into a cell of specific macromolecules by invagination of the plasma membrane which is then pinched off, resulting in small vesicles in the cytoplasm.
• macropinocytosis
• potocytosis represents a mechanism by which small and large molecules as well as macromolecular complexes are sequestered and transported by caveolae. Caveolae are flask-shaped plasma membrane specializations characterized by a filamentous coat consisting of caveolins that decorates the inside surface of each caveola membrane. They have endocytotic functions that differ from the clathrin-coated pit pathway. Ligands bound to receptors that are internalized by caveolae can be delivered to 4 different locations in the cell bypassing the lysosome and at least 4 different caveolae membrane traffic patterns during potocytosis can be distinguished. Hence, cells have two endocytic machines and each is designed to accomplish different tasks^{ref1, ref2}
• receptor-mediated endocytosis (RME) :
• clathrin is the main structural component of the lattice covering the cytoplasmic face of the coated pits and coated vesicles in which specific macromolecules are entrapped in RME. Clathrin is a large, soluble protein composed of
• heavy chains
• clathrin, heavy polypeptide (Hc) (CLTC)
• clathrin, heavy polypeptide-like 1 (CLTCL1)
• light chains are believed to be regulatory elements in clathrin function. The brain-specific light chain variant contains an insert ecoding 30 amino acids immediately downstream of the region encoding the heavy chain binding domain.
• clathrin, light polypeptide (Lca) (CLTA)
• clathrin, light polypeptide (Lcb) (CLTB)
• clathrin-ordered protein (COP)
It interacts with clathrin interacting protein localized in the trans-Golgi region
 / epsin 4 (EPN4) / enthoprotin (ENTH),
Epsin 1 (EPN1) and epsin 2 (EPN2) may play a role in clathrin-mediated endocytosis of synaptic vesicles
• adaptor protein (AP) complexes are heterotetramers composed of two large adaptins (a or b), a medium adaptin (m), and a small adaptin (s) subunit
• adaptor protein 1 (AP-1) complex
• b₁ subunit
• g₁ subunit
• g₂ subunit
• m₁ subunit
• m₂ subunit
• s₁ subunit
• s₂ subunit
• s₃ subunit
• adaptor protein 2 (AP-2) complex
• a₁ subunit
• a₂ subunit
• b₁ subunit
• m₁ subunit
• s₁ subunit
• adaptor protein 3 (AP-3) complex
• b₁ subunit
• b₂ subunit
• d₁ subunit
• m₁ subunit
• m₂ subunit
• s₁ subunit
• s₂ subunit
• adaptor protein 4 (AP-4) complex
• b₁ subunit
• e₁ subunit
• m₁ subunit
• s₁ subunit
• In eukaryotic cells, protein transport between the endoplasmic reticulum and Golgi compartments is mediated in part by non-clathrin-coated vesicular coat proteins (COPs).
• coatomer protein complex, subunit a (COPA)
• coatomer protein complex, subunit b (COPB)
• coatomer protein complex, subunit z₁ (COPZ1)
• coatomer protein complex, subunit z₂ (COPZ2)
Early or recyclingendosome (EE) (ectoplasmic, pH 6.5) => multivesicular endosome (MVE), where the membrane receptors are separated from the internalized molecules for recycling => late endosome (LE) (endoplasmic, pH 4.5). In reticulocytes and certain APCs, MVE are routed to plasma membrane rather than the lysosome, releasing 60-90 nm membrane vesicles called exosomes back into the ECM. They are secreted from most hematopoietic and epithelial cells in vitro. B cell derived-exosome antigenicity was first reported in 1996 in MHC class II restricted CD4+ T lymphocytes. In 1998, it was reported that dendritic cell derived-exosomes are immunogenic in mice leading to tumor rejection.
• bacterium-mediated endocytosis (e.g. Salmonella typhi)
Please note :
• endosome and phagosome may fuse each other.
• both late endosomes and late phagosomes can undergo fusion with a lysosome to create a phagolysosome.
• transcytosis (= endocytosis followed by exocytosis)

SIGNAL TRANSDUCTION PATHWAYS (STPs)
(signal transduction tools are listed in the Analysis tools section)

• Graphical symbols
• Abbreviations and acronyms
• Some personal remarks on molecular interaction maps

Web resources :
• Signal transduction from the THCME Biochemistry Page
• Signal transduction lectures by George M. Helmkamp, Jr. at University of Kansas Medical Center
• The Cell Signaling Networks Database (CSNDB) of human cells at National Institute of Health Science (NIHS), Japan
• Stanford University & Science Magazine's Signal Transduction Knowledge Environment (STKE) [free registration required !]
• The Signaling PAthway Database (SPAD) : growth factor, cytokine, hormone and stress
• Alliance For Cellular Signalling (AfCS) and Nature Publishing Group
• Signaling Gateway
• Signaling Update
• The Samuel Lunenfeld Research Institute
• Biomolecular Interaction Network Database (BIND)
• The Pawson Lab by Tony Pawson
• Modular protein domains in STP : simplified version
• Biochemical mechanisms through which specificity is generated during STP
• Signalling from the membrane to the nucleus : online poster by Nature Reviews Molecular Cell Biology
•  receptors : receptor transmodulation

Ligand binding domain (LBD) => the receptor uses the free energy of ligand binding to shift the conformation of its  effector domain to the active state => [transducer(s) => ] proximal effector protein => second messenger =>  ...
Receptors whose ligands are unknown are termed "orphans".
All physiological receptors act catalytically (enzymes, ion channels, transcription factors, ...)
• membrane receptors : cytokine receptor families
• ionotropic receptors (5x)
• metabotropic or seven transmembrane (7TM) or heterotrimeric G protein-coupled receptors (GPCR) receptors

Some GPCRs are palmitoylated at the CTD and N-glycosylated in the extracellular loops.
GPCR dimers and oligomers : please note some GPCRs form homodimers or homooligomers / homomers :
• M₃
• [Ca²⁺]_ECM sensor
• AT₁
... or heterodimers, creating a novel ligand-binding site ...
• D₂ + SST₅
• g₂ subunit-containing GABA_A + D₅
• GABA_BR1 + GABA_BR2
• P2X₂ + P2X₃
• P2X₄ + P2X₆
• P2X₁ + P2X₅
• AT₁ + B₂
• opioid d + opioid k : the opioid agonist ligand 6'-guanidinonaltrindole (6'-GNTI) has the unique property of selectively activating only opioid receptor heterodimers but not homomers. Importantly, 6'-GNTI is an analgesic, thereby demonstrating that opioid receptor heterodimers are indeed functionally relevant in vivo. However, 6'-GNTI induces analgesia only when it is administered in the spinal cord but not in the brain, suggesting that the organization of heterodimers is tissue-specific. Importantly, targeting opioid heterodimers could provide an approach toward the design of analgesic drugs with reduced side effects^ref.
• CCR2 + CXCR4 / CD184 / fusin / LESTR
• CCR2 + CCR5
Ligand-bound GPCR acts as the equivalent of GNRP / GEF / GDS for monomeric G protein, promoting replacement of GDP with GTP on a subunit of the heterotrimeric G protein.
Upon activation, the GPCR is phosphorylated by a G protein-coupled receptor kinases (GRKs) :

GRK	substrate GPCR(s)
GRK1 / rhodopsin kinase (RK)	rhodopsin
GRK2 / bARK1	b1-AR
GRK3 / bARK2	b2-AR
GRK4 / IT-11	unidentified
GRK5	b2-AR
GRK6	b2-AR
GRK7	unidentified

Phosphorylated GPCR binds an arrestin :

b-arrestin 1 (A and B isoforms)	b1-AR
b-arrestin 2	b1-AR
X arrestin / arrestin 3	rhodopsin
S-arrestin / S antigen	rhodopsin

Arrestin competes with the heterotrimeric G protein for binding and (arrestins 2 and 3) promotes endocytosis in clathrin-coated vesicles CCV). When in lysosomes the GPCR can be degraded or dephosphorylated by a G protein receptor phosphatase (GRP). The heterotrimeric G protein is made up of one among 20 different a subunits, one among 6 different b subunits and one among 12 different g subunits : a subunits are miristoylated, while g ones are farnesylated or geranylgeranylated.
• G_sPCRs
• G_iPCRs
• G_qPCRs
• G_12/13PCRs
The GTPase activity of Ga may be ...
• intrinsic
• stimulated by extrinsic molecules (equivalent to GAPs for monomeric G proteins)
• the effector molecule (e.g. PL-Cb on Ga_q family members)
• regulator of G-protein signalling (RGS) proteins.
Apart from heterotrimeric G protein to which they couple, GPCRs can be classified into 5 analog families (due to convergent evolution) on the basis of the whole amino acid sequence.
GPCRs represent the target of 50% of actual pharmacopeia.
Web resources : GPCRDB
• receptors Tyr kinase (RTKs)
• Tyr kinase-coupled receptors (TKCRs)
• receptors Tyr phosphatase (RTPs)
• receptors Ser/Thr kinase (RSTK)
• receptors guanylate cyclase (RGCs)
• receptors coupled to intracellular adapters (RCIAs)
• nuclear receptors
Web resources : Dynamic Signaling Maps (DSM)
Metabolism of electrolytes (see also plasma concentrations and kidney dynamics)
• hydrogen (₁¹H⁺) metabolism

H⁺ ionophores :
• nigericin
• dinitrophenyl (DNP)
• carbonylcyanide p-trifluoromethoxyphenyl hydrazone (FCCP)
• fluoride (₉¹⁹F^-) : a nonmetallic, gaseous element, belonging to the halogen group; symbol, F; atomic number, 9; atomic weight, 18.998. Fluorine, in the form of fluoride, is incorporated into the structure of bone and teeth by displacing hydroxyl groups in hydroxyapatiteto create fluoroapatite and provides protection against dental caries; 85% of dietary intake is excreted in urine, stools, saliva, and milk. See also fluorosis.
• sodium (₁₁²³Na⁺) metabolism

Dietary intake : 150 mmol/die. The recommended daily intake for a child aged 4 to 6 is 3 g a day while for adults it is 6 g a day.
Intracellular concentration : 5 mEq/L
Extracellular concentration = 120 mEq/L (80-95%)
Web resources : Na⁺ and Ca²⁺ channels
Na⁺ ionophores
• monensin (high affinity) has a number of uses in cattle, including weight gain
• gramicidin A
• magnesium (₁₂²⁴Mg²⁺) metabolism

30% of dietary magnesium is absorbed in small bowel
Mg²⁺ ionophores
• A23187
• phosphorus (₁₅³¹P) metabolism

Total body content : 600 mg
• bones : 85%. Only 0.15-0.3 g/die are exchanged with ECF
Daily diet introduction : 0.6-2 g/die (milk and derivatives, meat, egg-yolk, gaseous drinks with phosphoric acid)
• 60-70% (0.5-1.4 g/die) is passively absorbed in small bowel
Absorption up-regulating hormones :
• 1,25-(OH)₂-vitamin D₃ (expecially in jejunum and ileum, also inhibts PTH secretion, down-regulating urinary excretion)
Absorption down-regulating hormones :
• PTH
Excretion :
• daily stool excretion : 0.2-0.6 g/die
• daily urine excretion : 0.5-1.4 g/die
• chlorine (₁₇³⁵Cl^-) metabolism

Dietary intake : 150 mmol/die
Web resources : Cl^- channel family and cystic fibrosis (CF)
• potassium (₁₉³⁹K⁺) metabolism

Daily dietary intake : 40-120 mEq/die = 1 mmol/die/kg
90% is absorbed
Intracellular concentration : 150 mmol/L
Body distribution : 2,500-4,500 mmol
• 4.2 mEq/L x 14 L = 59 (30-70) mEq in extracellular fluid (< 2%)
• 140 mEq/L x 28 L = 3,920 mEq in intracellular fluid
Web resources : Family of K⁺ channels
K⁺ ionophores :
• valinomycin
• nigericin
• gramicidin A
• monensin (low affinity) has a number of uses in cattle, including weight gain
• calcium (₂₀⁴¹Ca²⁺) metabolism

Total body content : 1-2 kg
• bones : 900-1400 g  (98%). Only 0.5% (0.25-0.5 g/day) is exchangabe with ECF
• blood : 0.9 g
Daily diet introduction : 0.6-1.5 g/day = 15-37 mol/day
• only 50% (0.25-0.5 g/die) is absorbed actively in duodenum or by passive diffusion in distal bowel, more in growing babies, pregnancy, and lactation, less in ageing. CaCl₂ is absorbed better than other forms.
Excretion :
• daily stool excretion : 0.35-1 g/day
• daily urine excretion : 0.10-0.4 g/day = 2.5-10 mmol/day
• daily sweat ecretion : up to 100 mg/day
Intracellular concentration : 0.1 mmol/L => ECF/ICF gradient = 1:10,000
Absorption up-regulating hormones :
• PTH
• 1,25-(OH)₂-vitamin D₃
Absorption down-regulating hormones :
• calcitonin
Chemical forms :
• extracellular calcium
• plasma calcium : 10 mg/dl
• diffusible calcium (6.5 mg)
• free Ca²⁺ ion / ionized calcium (Ca(I)) (50% : 5.3 mg) is the active fraction. On almost all laboratories, only total calcium is routinely measured, and ionized calcium concentration is calculated based on calcium, protein or albumin concentrations for many plasma sample or with others parameters like pH. Since 1935, the literature was abounted with "correction" formulae of varying degree of sophistication. Many laboratories routinely use correction formulae to either calculate an "adjusted" or "corrected" total calcium, or "ionized" fraction is calculated,but these determinations lack of accuracy or precision. Errors associated with the measurement of the other variables contribuate to the difficulty in producing a useful correction formulae. Direct measurement of ionized calcium by potentiometry is the method of choice for this assay. Improvements in ion selective electrodes (ISE) technology make possible the routine clinical measurement of Ca²⁺. However this technology implies several obligations for its use, particulary in blood ampling, storage and transport. In this review, characteristics of different available analysers are described. Ca²⁺ should be systematically performed and not calculated in pathological situations where an possible alteration of the calcium metabolism is found especially in multiple myeloma in which paraprotein may bind calcium^ref. Other techniques include atomic absorption spectrometry, spectrophotometry, fluorometry, complexometric titration, and flame photometry^ref. Determining ionized calcium after CO2 equilibration of serum with subsequent electronic conversion to pH 7.40 (Ca2+corr) gives a practicable value for the diagnosis of calcium metabolism. "Anaerobic" sampling, necessary for the measurement of the actual calcium ion concentration, is obviated. Protein or albumin concentration in serum and complex-bound calcium do not interfere. Comparison of sera from 54 patients with bone metastases or myeloma, as well as from 300 patients with other diseases, indicate that the sensitivity of Ca2+corr in the diagnosis of hypercalcaemia is about twice or three times that of total calcium and that the latter's specificity - at least when ignoring protein concentration - is unsatisfactory with 18-45% "falsely" reduced values^ref.
• nonionized acid-bound calcium (6% : 1.2 mg)
• Ca²⁺-citrate
• CaCO₃
• Ca(HCO₃)₂
• CaHPO₄
• Ca₁₀(PO₄)₆(OH)₂
• Ca²⁺-oxalate
• nondiffusible protein-bound calcium (3.5 mg; not ionized) (46%) : it is reduced in acidosis and increased in alkalosis
• albumin (0.7 mg Ca²⁺/g albumin = 2.8 mg)
• globulins (0.7 mg)
• extracellular matrix calcium
• intracellular calcium
• Ca²⁺-calmodulin
Calcification : the process by which organic tissue becomes hardened by a deposit of calcium salts within its substance. Mineralized tissue is vital to many characteristic adaptive phenotypes in vertebrates. 3 primary tissues, enamel (enameloid), dentin, and bone, are found in the body armor of ancient agnathans and mammalian teeth, suggesting that these 2 organs are homologous. Genes for 3 major enamel matrix proteins, 5 proteins necessary for dentin and bone formation, and milk caseins and salivary proteins arose from a single ancestor by tandem gene duplications and form the secretory calcium-binding phosphoprotein (SCPP) family. SPARC gene existed before the split occurred between invertebrates and vertebrates during the Precambrian, 500 to 600 million years ago. Sometime after vertebrates arose, a gene called SPARC-like 1 (SPARCL1) developed. Gene structure and protein characteristics show that SCPP genes arose from the 5' region of ancestral SPARCL1. Phylogenetic analysis on SPARC and SPARCL1 suggests that the SCPP genes arose after the divergence of cartilaginous fish and bony fish, implying that early vertebrate mineralization did not use SCPPs and that SPARC may be critical for initial mineralization. Consistent with this inference, SPP1 has been identified in a teleost genome but no genes orthologous to mammalian enamel proteins have been found. Based on these observations, a scenario for the evolution of vertebrate tissue mineralization is suggested, in which body armor initially formed on dermal collagen, which acted as a reinforcement of dermis. Mammalian enamel is distinct from fish enameloid. Their similar nature as a hard structural overlay on exoskeleton and teeth is because of convergent evolution^ref. Birds have a gene to make hard egg shells, but they do not have genes for making tooth components
Ca²⁺ chelators :
• ethylenediaminetetraacetic acid (EDTA)
• ethylene glycol-bis(b-aminoethylether)-N,N,N',N'-tetraacetic acid (EGTA)
• 1, 2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid acetoxymethyl ester (BAPTA)
Ca²⁺ ionophores :
• A23187 / calcimycin is an artificial mobile Fe carrier that normally acts as an ion-exchange shuttle molecule transporting 1 Ca²⁺ ion into the cell in exchange of 2 H⁺.


• 4-bromo-A23187
• ionomycin
• lasalocid / X-537A
Binding proteins : calmodulin (antagonist : calmidazolium)
Web resources :
• Protein oxidation and age-dependent alterations in Ca²⁺ homeostasis
• Electrophysiology
• chromium (₂₄⁵²Cr) metabolism

After absorption in the gastrointestinal tract, chromium is most likely transported to cells bound to the plasma protein transferrin. Insulin initiates chromium transport into the cells where it is bound to the oligopeptide apochromodulin. This oligopeptide combined with 4 Cr³⁺ atoms forms chromodulin, which is important for amplifying the insulin signalling effect. After binding to insulin-activated InsR, chromodulin increases tyrosine kinase activity by one order. Chromium is available for dietary supplementation. See also chromium toxicity
• manganese (₂₅⁵⁵Mn) metabolism
• iron (₂₆⁵⁶Fe) metabolism (see also Disordered iron metabolism at Harvard University)

No physiologic mechanism of iron excretion exists, so absorption alone regulates body iron stores. Prolonged storage of canned foods may release iron from some cans and increase the total amount of iron absorbed in absolute terms. As at physiological pH, Fe²⁺ is rapidly oxidized to the insoluble Fe³⁺ form, dietary inorganic iron is mostly Fe³⁺: nonheme iron is bound to some other organic constituent of the food and cooking tends to break these interactions and increase iron availability. Iron is available for dietary supplementation.
This is solubilized at the acid pH level of the stomach where it chelates mucins and certain dietary constituents to keep them soluble and available for absorption in the more alkaline duodenum and upper jejunum : gastric acid lowers the pH in the proximal duodenum, enhancing the solubility and uptake of ferric iron. When gastric acid production is impaired (for instance by H⁺ / K⁺ ATPase inhibitors), iron absorption is reduced substantially. Further the low pH allows transiton of part of the colloidal Fe³⁺ species to hydrated Fe²⁺ ion.
Nonheme iron uptake is enhanced by :
• ascorbate (vitamin C) acts by
• promoting acid conditions within the stomach so that the dietary iron is efficiently solubilized
• reducing Fe³⁺ to its better absorbed Fe²⁺ form
• forming chelates with iron in the stomach
• maintaining the solubility of nonheme iron when the food enters the alkaline environment of the small intestine -- which counteracts the inhibitory effect of dietary ligands such as phytates and tannins. The latter effect can be explained by the fact that ascorbic acid forms complexes with soluble food iron at a lower pH than do inhibitory ligands.
Heating foods and storing cooked foods can destroy ascorbic acid and subsequently decrease iron absorption
• muscle proteins amino acids
• meat, fish, and poultry (MFP)
• citrate
• malate
• tartrate
• lactate
• fructose
• lactose
• sorbitol
• mannitol
• xylose
They in part act as weak chelators to help to solubilize the metal in the duodenum : iron is readily transferred from these compounds into the mucosal lining cells.
Conversely, nonheme iron absorption is inhibited by :
• ethylenediaminetetraacetic acid (EDTA)
• therapeutic chelators
• phosphate
• formaldehyde
• plant dietary molecules : these compounds chelate Fe, but prevent its uptake by the absorption machinery.
• fibers (polysaccharides other than starch (cellulose, glycans, hemicelluloses, pectins, and gums) and lignin)
• phytates : phytic acid (myoinositol hexaphosphate; not to be confused with phytanic acid !) is associated with the soluble fiber components of whole-grain cereals, nuts, seeds, and legumes : during some types of food processing (fermentation, germination, baking, etc.), and to a limited extent with the action of endogenous phytases in some cereals, phytic acid is dephosphorylated to yield lower inositol phosphates such as myoinositol bis-, tris-, and penta-phosphates (IP₂, IP₃, and IP₅ respectively) that do not inhibit iron absorption; because phytic acid is the major site for the storage of phosphorus in seeds, cereals and soybeans grown in low phosphorus soils or environments contain dramatically less phytate
• oxalates (in spinach)
• polyphenols
• tannates (in tea, coffee, and certain vegetables (legumes, ...))
• high molecular weight peptides
• divalent cations that act as competitive inhibitors of the transport machinery
• Ca²⁺ (also inhibits phytases)
• Pb²⁺
• Zn²⁺
• Sn²⁺
• Mn²⁺
• Co²⁺
Only 5÷20 % of the 30÷50 mg Fe^{2+ / 3+} /day ingested can be absorbed : in adult males an absorption of 1 mg/day is sufficient to compensate losses. 3 pathways for uptake of Fe³⁺ introduced with diet by lumenal cell membrane of enterocytes have been proposed :
• extracellular reduction of Fe³⁺ to Fe²⁺ by membrane-bound duodenal cytochrome b (Dcytb) (whose expression is up-regulated during iron deficits in a IRE-independent manner) and absorption via divalent metals transporter 1 (DMT-1) / NRAMP2 / DCT-1 pathway (major pathway)
• direct absorption of Fe³⁺ (minor pathway)
• heme iron : this process is more efficient than capture of non-heme iron and is independent of duodenal pH. Consequently red meats are excellent nutrient sources of iron.
• non-heme, mucin-bound iron : mobilferrin (a 56 kDa cytosolic isoform of calreticulin)-b₃-integrin / CD61 / gpIIIa pathway (MIP)
The transferrin gene is not expressed in intestinal cells. Later work indicated that transferrin found in the intestinal lumen is derived from plasma. Plasma transferrin entering bile is fully saturated with iron, obviating any intraluminal chelating function. Exogenous transferrin cannot donate iron to intestinal mucosal cells, and the brush boarder membrance lacks transferrin receptors (although they are present on the basolateral surface of enterocytes).
The Fe³⁺ storage form must be reduced to Fe²⁺ in order to cross the plasma membrane. In the cytosol of the absorptive cell, Fe³⁺ is associated with a 520-kDa complex known as paraferritin which contains b₃-integrin / CD61 / gpIIIa, mobilferrin and a flavin-containing monooxygenase (FMO). This complex serves as a ferrireductase to reduce Fe³⁺ to Fe²⁺. Fe²⁺ exits from the basolateral cell membrane of enterocytes via SLC11A3 / ferroportin 1 (FP-1) (homolog to yeast Ftr1), becomes reoxidixed to Fe³⁺ by a membrane-bound hephaestin (Hp) / ferroxidase II (a Cu-binding ferroxidase homolog to mammalian ceruloplasmin / ferroxidase and yeast Fet3), and partly binds to transferrin (Tf), synthetised in liver, testes and CNS (hepatocytes secrete it in plasma, where its concentration is 25 mM and its t_1/2 is 8 days). Transferrin binds iron avidly with K_d = 10²² M^-1. Fe³⁺ couples to transferrin only in the company of an anion (usually HCO₃^-) that serves as a bridging ligand between metal and protein, excluding water from 2 coordination sites. Without the anion cofactor, iron binding to transferrin is negligible. With it, Fe³⁺ transferrin is resistant to all but the most potent chelators. The remaining 4 coordination sites are provided by the transferrin protein - a His nitrogen, an Asp carboxylate oxygen, and 2 Tyr phenolate oxygens. Available evidence suggests that anion-binding takes place prior to iron-binding.
Total iron binding capacity (TIBC) of serum ~ 250÷450 mg_Fe / dL_serum ~ 44.8÷73.4 µmol / L_serum (the sum of all iron binding sites on transferrin). It is measured as follows : excess Fe³⁺ is added to the specimen to saturate the transferrin. Remaining Fe³⁺ is furtherly absorbed by MgCO₃. Bound iron in the supernatant is what has been named TIBC, assayed in the same manner as in iron determination. Assuming 1 mg of transferrin may bind 1.2 µg of iron, [apotransferrin]_serum = 1000 x TIBC / 1.2  ~ 210÷360 mg / dL_serum. The unsaturated or latent iron-binding capacity (UIBC) is easily measured with radioactive iron or by spectrophotometric techniques. The sum of the UIBC and the plasma iron represent TIBC, which may also be measured directly.
About 1/9 of the transferrin molecules have iron bound at both sites, about 4/9 of them have iron bound at one site, and about 4/9 have no iron bound. This means that transferrin is normally only about 1/3 saturated with iron (apotransferrin saturation = sideremia / TIBC = 20-50 %).
Unsaturated iron binding capacity (UIBC) = TIBC - [Fe]_serum ~ 160÷280 mg_Fe  / dL_serum ~ 22÷60 µmol / L_serum.
Plasma iron turnover (PIT) = [mg iron released from transferrin / Kg / day]
Nonintestinal cells can acquire from plasma ...
• transferrin-bound Fe³⁺ (major pathway), by ...
• RME via CD71 / TfR (a disulfide-linked homodimer of bitopic palmitoylated monomers) or TfR2 is the principal mechanism (high affinity, low capacity; even for re-entry in enterocytes via the basolateral cell membrane : this keeps the absorptive cell informed of the iron repletion of the host) : CD71 / TfR is expressed on surfaces of all proliferating cells, expecially erythroblasts. Iron deficiency allows iron regulatory proteins (IRP1 / aconitase 1 and IRP2) to bind IREs on mRNAs : this in turn post-transcriptionally up-regulates expression of TfR and DMT-1 by stabilizing their 3' UTR and down-regulates expression of apoferritin heavy and light chains by destabilizing their 5' UTR (while FP-1 mRNA is stabilized by IREs at 5'-UTR). TfR has greater affinity at physiologic pH for diferric (2 Fe³⁺)-Tf (K_d = 10^-7-10^-9 M) than monoferric (1 Fe³⁺)-Tf (K_d = 10^-6 M) or the apo form of the protein. Iron release from transferrin involves protonation of the carbonate anion, loosening the metal-protein bond : the acidification of the endosome weakens the association between iron and transferrin, but even at pH 5.5, Fe³⁺ would not normally dissociate from transferrin in the several minutes between its endocytosis and the return of apotransferrin to the cell surface. A yet uncharacterized plasma membrane reductase reduces transferrin bound iron from the Fe³⁺ state to Fe²⁺, directly or indirectly facilitating the removal of iron from the protein. The Fe²⁺ is then transported to the cytoplasm through the action of the proton-coupled divalent metal ion transporter SLC11A2 / DMT-1 / NRAMP2 / DCT-1 : the TfR is then recycled to the plasma membrane, where apoTf is released from the Tf receptor. The efficiency of Fe acquisition from Tf is influenced by the association of HFE / HLA-H and b₂-microglobulin with TfR : the absence of functional HFE plays a critical role in hereditary hemochromatosis.
• a transferrin-associated transferrin receptor independent pathway (TRIP) with low affinity and high capacity, used when Tf receptors become saturated at physiological concentrations of iron and Tf.
While the transferrin pathway is important for meeting the needs of the erythron, it is not essential for iron uptake by all tissues.
• non-transferrin-bound iron (NTBI; including desferrioxamine-chelatable iron (DCI)), i.e. soluble Fe³⁺ salts (minor pathway, important only in overloads)
• mobilferrin-b₃-integrin / CD61 / gpIIIa pathway (MIP), used efficiently only for mucosal uptake of iron and iron-overloaded individuals with fully saturated Tf. Alternatively, it may facilitate iron uptake from the TRIP after degradation of Tf near the surface of the cell.
• divalent metals transporter 1 (DMT-1) / NRAMP2 / DCT-1 pathway
• melanotransferrin / p97, a plasma membrane-associated Fe-binding protein originally found in human melanoma cells and whose expression has been then detected in many other normal cell lines (expecially from salivary glands)
• stimulator of Fe transport (SFT)
• low-m.w. organic chelating agents
When inside the cytoplasm, iron binds to apoferritin, (normal plasma concentration : 20-400 ng/mL or mg/l; if < 15 mg/l iron stores are completely depleted) a complex 24 subunit polymer of H (for heavy or heart) and L (for light or liver) protein subunits, both APPs: the composition of ferritin shells varies from H-subunit homopolymers to L-subunit homopolymers, and includes all possible combinations between the 2, with isoferritins showing tissue-specific variation. Increased H subunit content correlates with increased iron utilization, while increased L subunit content correlates with increased iron storage. The H:L ratio rises with activation of heme synthesis or cell proliferation. The subunits of the ferritin molecule form a sphere with a central cavity in which up to 4,500 atoms of crystalline iron is stored in the form of poly-iron-phosphate oxide : 8 hydrophilic channels through the sphere provide the route for iron entry and exit from the ferritin shell. H ferritin has ferroxidase activity, converting Fe²⁺ to Fe³⁺, and promoting its incorporation into ferritin. 1 mg / L [apoferritin]_plasma ~ 10 mg [apoferritin]_{intracellular} : anyway such a measure depends on hemolysis and contamination. Ferritin molecules aggregate over time to form clusters, which are engulfed by lysosomes and degraded. The end-product of this process, hemosiderin, is an amorphous agglomerate of denatured protein and lipid interspersed with iron oxide molecules. In cells overloaded with iron, lysosomes accumulate large amounts of hemosiderin which can be visualized by Perls staining. Although the iron enmeshed in this insoluble compound constitutes an endstage product of cellular iron storage, it remains in equilibrium with soluble ferritin but the bioavailability of hemosiderin iron is much lower than that of iron stored in ferritin. Iron can also enter mitochondria via frataxin (whose deficit causes Friedrich's ataxia) and stored by mitochondrial ferritin (MTF): once in mitochondria, Fe²⁺ is incorporated into protoporphyrin IX by ferrochelatase to create heme. Heme is then transported in cytosol by ABC7. Oxidized heme can be reduced to ferrous heme by cytochrome b₅ reductase / diaphorase / methemoglobin reductase. Heme is vehicled in plasma by hemopexin and Fe²⁺ is freed from heme by heme oxygenases. See also kinds of haem in haemproteins.

In vivo, free iron is kept to a minimum. The vast majority of extracellular Fe is chelated to siderophilins (transferrin (Tf) and lactoferrin / lactotransferrin) : Tf serves as the principal chelator in serum and bile, whereas both serve this function at mucosal surfaces (lactoferrin is found in tears, saliva, sweat, and colostrum : it arises mainly in secondary / specific granules of neutrophils). In addition, extracellular iron is also bound to a variety of low-m.w. organic chelating agents (albumin, citrate, amino acids and sugars), whose amount increases in some pathologic states and under conditions of relative iron overload.
Fe²⁺ distribution in body (globally : 35 mg / weight Kg in females; 50 mg / weight Kg in males) :
• 96.1 % in heme :
• 66% in Hb (an average adult produces 2 x 10¹¹ RBCs daily, for a RBCs renewal rate of 0.8 % per day. Each RBC contains > 10⁹ atoms of iron, and 1 mg of iron / mL RBC. This means a daily need for 2 x 10²⁰ atoms (or 20 mg) of elemental iron.
• 3% in Mb
• 0.1% in tissue heme enzymes
• 30% in ferritin intracellular storages
• 1% intracellular labile iron (chelatable iron)
• 0.1% bound to transferrin
• 0.1% free in soluble salts
• 0.0001% in non-heme enzymes
Iron detection techniques.
• copper (₂₉⁶⁴Cu) metabolism

Daily RDA (mg) :
• 0-6 mo. : 200
• 7-12 mo. : 220
• 1-3 yr : 340
• 4-8 yr : 440
• 9-13 yr : 700
• 14-18 yr : 890
• > 19 yr : 900
In hepatocytes ATP7B incorporates Cu²⁺ in apoceruloplasmin / ferroxidase to form ceruloplasmin, whose catabolism includes biliary ion excretion; in fetal liver ATP7A incorporates Cu²⁺ in apoceruloplasmin to form ceruloplasmin, whose catabolism terminates with hepatic retention of copper ions.
Metallothionein (MT) proteins are highly conserved low-molecular-weight cysteine-rich conjugated proteins that are induced by and bind to heavy metal ions (cadmium, mercury, zinc), oxidative stress, glucocorticoid, and anticancer agents and have no enzymatic activity
• metallothionein 1A (MT1A) (functional)
• metallothionein 1B (MT1B) (functional)
• metallothionein 1E (functional)
• metallothionein 1F (functional)
• metallothionein 1G (MT1G)
• metallothionein 1H (MT1H)
• metallothionein 1I (MT1I)
• metallothionein 1J (MT1J)
• metallothionein 1K (MT1K)
• metallothionein 1L (MT1L)
• metallothionein 1Q (MT1Q)
• metallothionein 1S (MT1S)
• metallothionein 1X (MT1X)
• metallothionein 2A (MT2A)
• metallothionein 3 (growth inhibitory factor (neurotrophic)) (MT3)
• metallothionein IV (MT4)
• metallothionein E (MTE)
• metallothionein-like 1 (MTL1)
• metallothionein-like 2 (MTL2)
• metallothionein-like 3 (MTL3)
• metallothionein-like 4 (MTL4)
• metallothionein-like 5, testis-specific (tesmin) (MTL5)
• metallothionein M (MTM)
Biological oxidants such as disulfides and S-nitrosothiols oxidize the zinc/thiolate clusters in metallothionein with concomitant zinc release. In addition, selenium compounds that have the capacity to form selenol(ate)s catalytically couple with the glutathione/glutathione disulfide and metallothionein/thionein redox pairs to either release or bind zinc. In this pathway, selenium expresses its antioxidant effects through redox catalysis in zinc metabolism. Selenium affects the redox state of thionein, an endogenous chelating agent. With its 20 cysteines, thionein contributes significantly to the zinc- and thiol-redox-buffering capacity of the cell.
• zinc (₃₀⁶⁵Zn) metabolism

Daily RDA (mg) :
• 0-6 mo. : 2
• 7-12 mo. : 3
• 1-3 yr : 3
• 4-8 yr : 5
• 9-13 yr : 8
• 14-18 yr : 11 in males, 9 in females
• > 19 yr : 11 in males, 8 in females
Zinc homeostasis results from a coordinated regulation by different membranous transporters, belonging to the ZIP and ZnT families, and metallothioneins. Zinc acts as an inhibitor of apoptosis, while its depletion induces programmed cell death in many cell lines. It acts as a paracrine regulator in pancreatic cell, neuron (released in the hippocampus at glutamatergic synapses) or neutrophil activity by a mechanism of vesicles-mediated metal excretion and uptake
• selenium (₃₄⁷⁹Se) metabolism

Selenium-binding proteins :
• SELENBP1
• deiodinase, iodothyronine, type I
• deiodinase, iodothyronine, type II
Selenocysteine-containing proteins : 25 mammalian selenoproteins
• selenoprotein P, plasma, 1 is the only selenoprotein known to contain multiple selenocysteine residues
• selenoprotein T
• 15-kDa selenoprotein (SEP15)
• selenophosphate synthetase (SPS) and selenophosphate synthetase 2 (SPS) synthesize selenophosphate (the selenium donor used to synthesize selenocysteine) from selenide and ATP
• thioredoxin reductase 1 and thioredoxin reductase 2
• glutathione peroxidases
• molybdenum (₄₂⁹⁶Mo) metabolism
• iodine (₅₃¹²⁶I^-) metabolism

Iodine RDA : 150 mg/die for adults, 90-120 mg/die for babies (during pregnancyhyperestrogenism up-regulates synthesis of thyroid carriers TBG and TBPA, leading to a fall in [FT₄]_plasma and hence a compensatory increase in [TSH]_plasma that leads to increased [TT₄]_plasma => increased iodine RDA to 200 mg / die)
In plasma it binds to albumin and other plasma proteins.
Daily iodine metabolism (mg/die) :
• dietary intake : 500 mg/die
• 420 mg/die => urine
• 80 mg/die (10-25%) => thyroid (additional 110 in storages). Thyroideal iodine pool = 7,500-8000 mg (reserve for 3 months of life)
• 4 mg/die => 3,5,3'-T₃
• 2 mg/die => 3,3',5'-rT₃
• 80 mg/die => T₄ =>
• 27 mg/die => 3,5,3'-T₃
• 36 mg/die => 3,3',5'-rT₃
• 17 mg/die => conjugated to carriers
=>
• 60 mg/die urine
• 20 mg/die stools
Renal iodine clearance : 30 mL / min
Thyroideal clearance = 15 mL / min.
• Intracellular STP enzymes
• Phosphoinositol lipids metabolism : single or combinatorial phosphorylation of the D-3, D-4, and D-5 positions of the inositol ring of PtdIns can generate at least 7 unique PI derivatives.
• PI(3)K pathway at STKE [free registration required !] : all catalytic subunits have a catalytic domain and a PIK domain.
• MAPK / ERK in growth and differentiation
• p38^MAPK signaling pathways
• SAPK / JNK signaling cascades
• MAPK signaling cascades
• Jak / STAT signaling : IL-6 receptor family
• Jak / STAT utilization
Web resources :
• Detection of MAPK signaling at STKE [free registration required !]
• Rac page
• The Grb7, Grb10 and Grb14 protein family by the Dave Thomas Laboratory
• Protein tyrosine kinase at COPE
• Jak-STAT pathway at STKE [free registration required !]
• STAT3 pathway at STKE [free registration required !]
• JAK3base
• Cross-talking among STPs
• GPCR signaling to MAPK/ERK
Web resources :
• Regulation of MAPK signaling networks by GPCR
• Integrating signaling pathways: p90^Rsk, Smad & STATs, Wnt & Dishevelled
• Scaffolds in STPs
• Scaffolds in signaling networks : Jip1, Erk, cyclins, Yotiao AKAP
• Guidance receptor signaling to the cytoskeleton
• Integration of signals to the cytoskeleton by modular proteins
• A kinase anchoring proteins (AKAPs) drive PKAs in the right subcellular compartment :

AKAP78 => cytoskeleton
ezrin => cytoskeleton
MAP2 => cytoskeleton
AKAP1 / AKAP84 / AKAP149 => mitochondria
AKAP2
AKAP3 / AKAP110
AKAP4 / AKAP82
AKAP5 / AKAP75 / KAP79 (h) => membranes (it drives also AC, PP2B and PKC)
AKAP6 / AKAP100 => ER
AKAP7 / AKAP15 / AKAP18 => L-type Ca2+ channels
AKAP8 / 95 / n150 => nucleus
AKAP9 / AKAP450 / AKAP350 / CG-NAP / Yotiao => drives PKA and PP1 to NR1 subunit of NMDA receptor and PKA to centrosome (also through pericentrin 1)
AKAP11 / AKAP220 => peroxisome
AKAP12 / AKAP250 / gravin
AKAP13
AKAP85 => Golgi apparatus
AKAP150 (m) => membranes

---

Copyright © 2001-2005 Daniele Focosi. All rights reserved  |  Terms of use  | Legal notices
About this site  |  Site map  |  Acknowledgements | Open forum  |  Tell a friend about this site  |  Current link partners
 Abbreviations and acronyms  |  Medical terminology  |  Add a link  |  Translate this site into your favourite language  |  Softwares

---

---

Search EntrezNCBI Web Site-------------PubMedGeneLocusLinkTaxonomyProteinNucleotideStructureGenomeBooksCancerChromosomesConserved Domains3D DomainsGEO ProfilesGEO DatasetsHomoloGeneJournalsMeSHNLM CatalogOMIMPMCPopSetPubChem BioAssayPubChem CompoundPubChem SubstanceSNPUniGeneUniSTS for

Search AboutAltaVistaAsk JeevesDictionaryDirectHitExciteFindWhatGoogleGoogle GroupsHotBotLookSmartLycosMetacrawlerMetaLocateNorthern LightOpen DirectorySnapThesaurusWebcrawlerYahoo for

Search Medical Dictionary  for

Let us know if this page contains pornographic, copyrighted, or hate content. 250Free proudly supports TheFreeSite.com