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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

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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