Table of contents  :  Signalling ways extra-individual signaling : pheromones intra-individual signaling cellular receptor and mobile ligand synaptic signaling paracrine signaling gasotransmitters / aerokines 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 Cross-talking among STPs Scaffolds in STPs Protein domains in STP 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
N-acetylaspartylglutamate (NAAG), a dipeptide derivative of N-acetylaspartate (NAA) and glutamate (Glu)	present in neurons. Upon neurostimulation, NAAG is exported to astrocytes where it activates mGluR3, and is then hydrolyzed by an astrocyte-specific enzyme, NAAG peptidase, liberating Glu, which can then be taken up by the astrocyte	mGluRII 3
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 / aerokines : endogenously produced gaseous transmitters that are freely permeable to membrnae and have well-defined specific functions at physiological concentrations, by modifying  cellular functions directly by chemically modfying molecular targets or indirectly by producing second messengers. 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 < 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. Mice were given hydrogen sulphide in an 80 ppm mixture with air – one-tenth of the dose that is lethal in humans : as expected, the rodents' heart rates dropped from 600 bpm to only about 200. But they also found that the animals' blood pressure stayed steady throughout. Further tests showed that the rodents' hearts were not pumping blood any harder than before. As a result, the scientists believe the gas somehow causes blood vessels to constrict slightly to retain their tone. The mice emerged from torpor within minutes of exposure to normal air (annual meeting of the American Physiological Society in Virginia Beach, 2006)
• 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) macrophages. Paracrine and autocrine functions in endometrial cells in the secretory > proliferative phase, placenta, astrocytes, Sertoli and peritubular myoid cells, and capillary endothelium. Neuronal and glial cells of the central nervous system and in the retinaref1, ref2. Excreted in urine	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
		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
		IL-31ref	Th2 lymphocytes	IL-31RA and OSMR
		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
		granulocyte colony stimulating factor (G-CSF) / CSF-3 ; monomer or dimer	TECs, stromal cells, inducible in tissues from fibroblasts and macrophages and from endothelial cells by inflammatory mediators (IL-1, IL-6, and TNF) in virtually all organs	G-CSFR
		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 DC, 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 / IL-36g	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-33		IL-1R-like 1
	IL-36a (IL-1F6)ref		IL-36R (IL-1Rrp2) IL-1RAcP
	IL-36b (IL-1F8) / IL-1h
	IL-36g (IL-1F9)
	IL-36Ra (IL-1F5)
	IL-37		IL-18Rα chain
	IL-38		IL 36R
	macrophage inhibitory factor / migration inhibition factor (MIF) ; monomer	activated T lymphocytes, pituitary cells, macrophages, eosinophils, fibroblasts, keratinocytes
IL-12 familyref : heterodimeric cytokines, composed of an a chain (p19, p28, or p35) and a beta chain (p40 or Ebi3), and signal through unique pairings of 5 receptor chains (IL-12Rb1, IL-12Rb2, IL-23R, gp130, and WSX-1).	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 = heterodimer with IL-12p40B "soluble receptor" subunit + p19a subunit	memory T lymphocytes, monocyte-derived macrophages, DCs, B cells	IL-23R
	IL-27 / SF20 (homolog to mouse IL-25) : heterodimer with EBI3/p28	bone marrow stroma, DCs, monocytes, macrophages, B cells	LY6E IL-27Ra / WSX1
	IL-35 : heterodimer with p35A/Epstein-Barr virus-induced gene 3 (EBI3)	stimulated human T effector cells,  B cell lymphoma, nasopharyngeal carcinoma, and melanoma, murine (but not human) Treg	IL-35R (a unique heterodimer of receptor chains IL-12Rβ2 and gp130 or homodimers of each chain)ref
	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-17RC
	IL-17B		IL-17BR
	IL-17C		?
	IL-17D		?
	IL-17E / IL-25 (isoforms 1 and 2)		IL-17BR
	IL-17F		IL-17RC
	IL-21	T lymphocytes	IL-21R
	IL-32ref : 4 splice variants (gamma isoform is the most activeref); induced in human pripheral lymphocytes folowing mitogen stimulation, in human epithelial cells by IFN-g, and in NK cells following exposure to the combination of IL-12 + IL-18; activated by cleavage by proteinase 3 (PR3)	immune tissue
	IL-34ref	embryonic brain and heart	M-CSFR / CD115
	small inducible cytokine subfamily E, member 1 (endothelial monocyte-activating) (SCYE1) / p43, an auxiliary factor of mammalian multiaminoacyl-tRNA synthetases, induces IL-12 production in macrophages via NF-kB activation, leading to enhanced IFN-g production in CD4+ T cells (Th1 lymphocytes)ref
	thrombopoietin (TPO)	constitutively by liver (50%), kidneys and skeletal muscles; inducible in the liver by inflammatory mediators (especially IL-6) and from bone marrow stromal cells by thrombocytopenia	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 Neuropilin 2 (NRP2)ref
	VEGFB		VEGFR1 / Flt-1
	VEGFC		VEGFR3 / Flt-4 > VEGFR2 / Flk-1 / KDR Neuropilin 2 (NRP2)ref
	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 connective tissue-activating peptide III (CTAP-III) (one of several molecular variants of -thromboglobulin-antigen (TG-Ag), a group of chemokines that differ by their degree of N-terminal truncation) by removing a stretch of 15 amino acids from the N terminus of the precursorref1, ref2. So far all evidence suggests that cell surface–bound cathepsin G (CathG), a chymotryptic serine protease also found in primary neutrophil granules, is responsible for CTAP-III processingref1, ref2, ref3, ref4. Among blood cells, only monocytes share the ability of neutrophils to convert CTAP-III into NAP-2ref1, ref2, albeit to a considerably lower extent than neutrophils, which argues against a relevant role for monocytes in NAP-2 formation during early inflammationref. Unstimulated MCs exceed the CTAP-III–processing potency of neutrophils about 30-fold thanks to chymase, whereas MCs activated by IgE cross-linking exhibit even 1000-fold higher CTAP-III–processing capacity than fMLP-stimulated neutrophils. Intriguingly, PF-4 counteracted MC- as well as neutrophil-mediated NAP-2 generation at physiologically relevant concentrationsref)	a-granules of activated human platelets	CXCR1 / CDw128a / IL-8RAref CXCR2 / CDw128b / IL-8RBref
		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; PF4 very efficiently stimulates firm adhesion of neutrophils to endothelial cells as well as the selective exocytosis of secondary granule markersref1, ref2)	CXCL4 / PF4	megakaryocytes, activated platelets	a cell surface–expressed chondroitin sulfate proteoglycanref1, ref2
		CXCL9 / monokine induced by IFN-g (MIG / MIG-1) (catabolysed by CD26 / DPPIV)	monocytes, macrophages, T lymphocytes, fibroblasts, lymphatic endothelial cells (LEC)	CXCR3 / CD183
		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 / pre-B cell growth-stimulating factor (PBSF) / stromal cell-derived factor 1a (SDF-1a/b) (catabolysed by  by marrow serine proteasesref1, ref2 and dipeptidylpeptidase IV (CD26)ref1, ref2)	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 / Scya9 / CCF18 / MIP-1gin 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 / secondary lymphoid tissue chemokine (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. SHH binds to 2 Robo-related proteins, Boc and Cdonref
	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  syncytiotrophoblast	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, syncytiotrophoblast	ERa ERb
estriol (E3)	hepatocytes (from estrone and estradiol in premopausal females), fatty tissue (from adrenal androstenedione in postmenopausal females), syncytiotrophoblast
estetrol (E4)

• progestins

hormone	produced by	receptor
progesterone	corpus luteum syncytiotrophoblast	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 (TAAR1)

• 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)	syncytiotrophoblast	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)		syncytiotrophoblast	GHR
choriosomatomammotropin (hCS) 2		syncytiotrophoblast	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) / pancreozymin		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