Serotonin

Serotonin
IUPAC name
5-Hydroxytryptamine or
3-(2-aminoethyl)-1H-indol-5-ol
Other names
5-Hydroxytryptamine, 5-HT
Identifiers
CAS number 50-67-9 YesY
PubChem 5202
ChemSpider 5013
MeSH Serotonin
IUPHAR ligand 5
Properties
Molecular formula C10H12N2O
Molar mass 176.215 g/mol
Appearance White powder
Melting point

167.7 °C, 441 K, 334 °F
Solubility in water slightly soluble
Dipole moment 2.98 D
Hazards
MSDS External MSDS
LD50 60 mg/kg (oral, rat)
 YesY (what is this?)  (verify)
Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa)
Infobox references

Serotonin (pronounced /ˌsɛrəˈtəʊnɪn/) or 5-Hydroxytryptamine (5-HT) is a monoamine neurotransmitter, biochemically derived from tryptophan, that is primarily found in the gastrointestinal (GI) tract, platelets, and central nervous system (CNS) of humans and animals. It is a well-known contributor to feelings of well-being.

Approximately 80 percent of the human body's total serotonin is located in the enterochromaffin cells in the gut, where it is used to regulate intestinal movements.[1][2] The remainder is synthesized in serotonergic neurons in the CNS where it has various functions, including the regulation of mood, appetite, sleep, muscle contraction, and some cognitive functions including memory and learning. Modulation of serotonin at synapses is thought to be a major action of several classes of pharmacological antidepressants.

Serotonin secreted from the enterochromaffin cells eventually finds its way out of tissues into the blood. There, it is actively taken up by blood platelets, which store it. When the platelets bind to a clot, they disgorge serotonin, where it serves as a vasoconstrictor and helps to regulate hemostasis and blood clotting. Serotonin also is a growth factor for some types of cells, which may give it a role in wound healing.

Serotonin is eventually metabolized to 5-HIAA by the liver, and excreted by the kidneys. One type of tumor, called carcinoid, sometimes secretes large amounts of serotonin into the blood, which causes various forms of the carcinoid syndrome of flushing, diarrhea, and heart problems. Because of serotonin's growth promoting effect on cardiac myocytes, persons with serotonin-secreting carcinoid may suffer a right heart (tricuspid) valve disease syndrome, caused by proliferation of myocytes onto the valve.

In addition to animals, serotonin is also found in fungi and plants.[3] Serotonin's presence in insect venoms and plant spines serves to cause pain, which is a side effect of serotonin injection. Serotonin is produced by pathogenic amoebas, and its effect on the gut causes diarrhea. Its widespread presence in many seeds and fruits may serve to stimulate the digestive tract into expelling the seeds.

Contents

History

In 1935, Italian Vittorio Erspamer showed that an extract from enterochromaffin cells made intestines contract. Some believed it contained adrenaline, but two years later Erspamer was able to show that it was a previously unknown amine, which he named enteramine.[4] In 1948, Maurice M. Rapport, Arda Green, and Irvine Page of the Cleveland Clinic discovered a vasoconstrictor substance in blood serum, and since it was a serum agent affecting vascular tone, they named it serotonin.[5] In 1952 it was shown that enteramine was the same substance as serotonin, and as the broad range of physiological roles were elucidated, the abbreviation 5HT of the proper chemical name 5-hydroxytryptamine became the preferred name in the pharmacological field.[6]

Functions

Serotonin is a neurotransmitter, and is found in all bilateral animals where it mediates gut movements and the animal's perception of resource availability. In the simplest animals resources are equivalent with food, but in advanced animals such as arthropods and vertebrates resources also can mean social dominance. In response to the perceived abundance or scarcity of resources the animal's growth, reproduction or mood may be elevated or lowered. Recent studies involving the serotonin transporter gene 5-HTT have shown that the short allele of this gene increase synaptic serotonin levels. These genetic studies have demonstrated that serotonin has strong associations with depression in regards to a negative environment.

Gauge of food availability

Serotonin functions as a neurotransmitter in the nervous systems of simple as well as complex animals. For example, in the roundworm C. elegans, which feeds by grazing on bacteria, serotonin is released as a signal in response to positive events, e.g., finding a new grazing ground or in male animals finding a hermaphrodite to mate. When a well-fed worm feels bacteria on its cuticle, dopamine is released, which slows it down; if it is starved, serotonin also is released, which slows the animal down further. This mechanism increases the amount of time animals spend in the presence of food.[7] The released serotonin activates the muscles used for feeding, while octopamine suppresses them.[8] Serotonin diffuses to serotonin-sensitive neurons, which control the animal's perception of nutrient availability. This system has been partially conserved during the 700 million years of evolution which separate C. elegans from humans. When humans smell food, dopamine is released to increase the appetite. But unlike in worms, serotonin does not increase anticipatory behaviour in humans; instead the serotonin released while consuming activates 5-HT2C receptors on dopamine-producing cells. This halts their dopamine release, and thereby serotonin decreases appetite. Drugs which block 5-HT2C receptors make the body unable to shut off appetite, and are associated with increased weight gain,[9] especially in people who have a low number of receptors.[10] The expression of 5-HT2C receptors in the hippocampus follows a diurnal rhythm,[11] just as the serotonin release in the ventromedial nucleus, which is characterised by a peak at morning when the motivation to eat is strongest.[12]

Effects of food content

In humans, serotonin levels are affected by diet. An increase in the ratio of tryptophan to phenylalanine and leucine will increase serotonin levels. Fruits with a good ratio include dates, papaya and banana. Foods with a lower ratio inhibit the production of serotonin. These include whole wheat and rye bread.[13] Research also suggests that eating a diet rich in carbohydrates and low in protein will increase serotonin by secreting insulin, which helps in amino acid competition.[14] However, increasing insulin for a long period may trigger the onset of insulin resistance, obesity, type 2 diabetes, and lower serotonin levels. Muscles use many of the amino acids except tryptophan, allowing men to have more serotonin than women.[15] Myo-inositol, a carbocyclic polyol present in many foods, is known to play a role in serotonin modulation.[16]

In the digestive tract

The gut is surrounded by enterochromaffin cells which release serotonin in response to food in the lumen. This makes the gut contract around the food. Platelets in the veins draining the gut collect excess serotonin.

If irritants are present in the food the enterochromaffin cells release more serotonin to make the gut move faster, i.e., to cause diarrhea so that the gut is emptied of the noxious substance. If serotonin is released in the blood faster than the platelets can absorb it, the level of free serotonin in the blood is increased. This activates 5HT3 receptors in the chemoreceptor trigger zone that stimulate vomiting.[17] The enterochromaffin cells not only react to bad food, they are also very sensitive to irradiation and cancer chemotherapy. Drugs that block 5HT3 are very effective in controlling the nausea and vomiting produced by cancer treatment and are considered the gold standard for this purpose.[18]

Gauge of social situation

How much food an animal gets not only depends on the abundance of food, but also on the animal's ability to compete with others. This is especially true for social animals, where the stronger individuals might steal food from the weaker. Thus, serotonin is not only involved in the perception of food availability, but also of social rank. If a lobster is injected with serotonin, it behaves like a dominant animal, while octopamine causes subordinate behavior.[19] A frightened crayfish flips its tail to flee, and the effect of serotonin on this behavior depends on the animal's social status. Serotonin inhibits the fleeing reaction in subordinates, but enhances it in socially dominant or isolated individuals. The reason for this is that social experience alters the proportion between serotonin receptors (5-HT receptors) that have opposing effects on the fight-or-flight response. The effect of 5-HT1 receptors predominates in subordinate animals while 5-HT2 receptors predominates in dominants.[20] In humans, levels of 5-HT1A receptor activation in the brain show negative correlation with aggression,[21] and a mutation in the gene that codes for the 5-HT2A receptor may double the risk of suicide for those with that genotype.[22] Most of the brain serotonin is not degraded after use, but is collected by serotonergic neurons by serotonin transporters on their cell surface. Studies have revealed that nearly 10% of total variance in anxiety-related personality depends on variations in the description of where, when and how many serotonin transporters the neurons should deploy,[23] and the effect of this variation was found to interact with the environment in depression.[24][25]

Effects on growth and reproduction

In C. elegans artificial depletion of serotonin or increase of octopamine cues behavior that is typical of a low-food environment: C. elegans becomes more active, and mating and egg-laying is suppressed, while the opposite occurs if serotonin is increased or octopamine is decreased in this animal.[26] Serotonin is necessary for normal male mating behavior,[27] and the inclination to leave food to search for a mate.[28] The serotonergic signaling used to adapt the worm's behaviour to fast changes in the environment affects insulin-like signaling and the TGF beta signaling pathway, which control long-term adaption.

In the fruitfly where insulin both regulates blood sugar and acts as a growth factor, serotonergic neurons regulate the adult body size by affecting insulin secretion.[29][30] Serotonin has also been identified as the trigger for swarm behavior in locusts.[31] In humans though insulin regulates blood sugar and IGF regulates growth, serotonin controls the release of both hormones so that serotonin suppresses insulin release from the beta cells in the pancreas,[32] and exposure to SSRIs reduces fetal growth.[33] Human serotonin can also act as a growth factor directly. Liver damage increases cellular expression of 5-HT2A and 5-HT2B receptors.[34] Serotonin present in the blood then stimulates cellular growth to repair liver damage.[35] 5HT2B receptors also activate osteoblasts, which build up bone[36] However, serotonin also activates osteoclasts, which degrade bone.[37]

Cardiovascular growth factor

Serotonin in addition evokes endothelial nitric oxide synthase activation and stimulates through a 5-HT1B receptor meditated mechanism the phosphorylation of p44/p42 mitogen-activated protein kinase activation in bovine aortic endothelial cell cultures.[24] In blood, serotonin is collected from plasma, by platelets which store it. It is thus active wherever platelets bind in damaged tissue, as a vasoconstrictor to stop bleeding, and also as a fibrocyte mitotic (growth factor), to aid healing.[38]

Some serotonergic agonist drugs also cause fibrosis anywhere in the body, particularly the syndrome of retroperitoneal fibrosis, as well as cardiac valve fibrosis.[39] In the past, three groups of serotonergic drugs have been epidemiologically linked with these syndromes. They are the serotonergic vasoconstrictive anti-migraine drugs (ergotamine and methysergide),[39] the serotonergic appetite suppressant drugs (fenfluramine, chlorphentermine, and aminorex), and certain anti-parkinsonian dopaminergic agonists, which also stimulate serotonergic 5-HT2B receptors. These include pergolide and cabergoline, but not the more dopamine-specific lisuride.[40] As with fenfluramine, some of these drugs have been withdrawn from the market after groups taking them showed a statistical increase of one or more of the side effects described. An example is pergolide. The drug was in decreasing use since reported in 2003 to be associated with cardiac fibrosis.[41] Two independent studies published in the New England Journal of Medicine in January 2007, implicated pergolide along with cabergoline in causing valvular heart disease.[42][43] As a result of this, the FDA removed pergolide from the U.S. market in March, 2007.[44] (Since cabergoline is not approved in the U.S. for Parkinson's Disease, but for hyperprolactinemia, the drug remains on the market. Treatment for hyperprolactinemia requires lower doses than that for Parkinson's Disease, diminishing the risk of valvular heart disease).[45]

Local effects of injection: venoms and pain

Since serotonin is an indicator of bleeding, a sudden large increase in peripheral levels causes pain. The reason for wasps, and deathstalkers to have serotonin in their venom [46][47] may be to increase the pain of their sting on large animals, and also to cause lethal vasoconstriction on smaller prey.

Deficiency

Genetically altered C. elegans that lack serotonin have an increased reproductive lifespan, may become obese, and sometimes present with arrested development at a dormant larval state.[48][49]

Serotonin in mammals is made by two different tryptophan hydroxylases: TPH1 produces serotonin in the pineal gland and the enterochromaffin cells, while TPH2 produces it in the raphe nuclei and in the myenteric plexus. Genetically altered mice that lack TPH1 develop progressive loss of heart strength early on. They have pale skin and breathing difficulties, are easily tired, and eventually die of heart failure.[50] Genetically altered mice that lack TPH2 are normal when they are born. However, after three days they appear to be smaller and weaker, and have softer skin than their siblings. In a purebred strain 50% of the mutants died during the first four weeks, but in a mixed strain 90% survived. Normally the mother weans the litter for three weeks, but the mutant animals needed five weeks. After that they caught up in growth and had normal mortality rates. Subtle changes in the autonomic nervous system are present, but the most obvious difference from normal mice is the increased aggressiveness and impairment in maternal care of young.[51] Despite the blood-brain barrier, the loss of serotonin production in the brain is partially compensated by intestinal serotonin. The behavioral changes become greatly enhanced if one crosses TPH1- with TPH2-lacking mice and gets animals that lack TPH entirely.[52]

In humans, defective signaling of serotonin in the brain may be the root cause of sudden infant death syndrome (SIDS). Scientists from the European Molecular Biology Laboratory in Monterotondo, Italy[53] genetically modified lab mice to produce low levels of the neurotransmitter serotonin. The results showed the mice suffered drops in heart rate and other symptoms of SIDS, and many of the animals died at an early age. Researchers now believe that low levels of serotonin in the animals' brainstems, which control heartbeat and breathing, may have caused sudden death, they said in the July 4, 2008 issue of Science.[34] If neurons that make serotonin — serotonergic neurons — are abnormal in infants, there is a risk of sudden infant death syndrome (SIDS).[54]

Low levels of serotonin may also be associated with intense spiritual experiences.[55]

Recent research conducted at Rockefeller University shows that, in both patients who suffer from depression and mice that model the disorder, levels of the p11 protein are decreased. This protein is related to serotonin transmission within the brain.[56]

Anatomy

A drawing of the brain, the serotonergic system is red and the mesolimbic dopamine pathway is blue. There is one collection of serotonergic neurons in the upper brainstem that sends axons upwards to the whole cerebrum, and one collection next to the cerebellum that sends axons downwards the spinal cord. Slightly forward the upper serotonergic neurons is the ventral tegmental area, the dopaminergic neurons there sends axons to the nucleus accumbens, hippocampus and the frontal cortex. Over the VTA is another collection of dopamine cells, the substansia nigra, which send axons to the striatum.
Serotonin system, contrasted with dopamine system.

Gross anatomy

The neurons of the raphe nuclei are the principal source of 5-HT release in the brain.[57] The raphe nuclei are neurons grouped into about nine pairs and distributed along the entire length of the brainstem, centered around the reticular formation.[58] Axons from the neurons of the raphe nuclei form a neurotransmitter system, reaching almost every part of the central nervous system. Axons of neurons in the lower raphe nuclei terminate in the cerebellum and spinal cord while the axons of the higher nuclei spread out in the entire brain.

Microanatomy

Serotonin is released into the space between neurons, and diffuses over a relatively wide gap (>20 µm) to activate 5-HT receptors located on the dendrites, cell bodies and presynaptic terminals of adjacent neurons.

Receptors

5-HT receptors are the receptors for serotonin. They are located on the cell membrane of nerve cells and other cell types in animals and mediate the effects of serotonin as the endogenous ligand and of a broad range of pharmaceutical and hallucinogenic drugs. With the exception of the 5-HT3 receptor, a ligand gated ion channel, all other 5-HT receptors are G protein coupled seven transmembrane (or heptahelical) receptors that activate an intracellular second messenger cascade.[59]

Termination

Serotonergic action is terminated primarily via uptake of 5-HT from the synapse. This is through the specific monoamine transporter for 5-HT, SERT, on the presynaptic neuron. Various agents can inhibit 5-HT reuptake including MDMA (ecstasy), amphetamine, cocaine, dextromethorphan (an antitussive), tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs). Interestingly, a 2006 study conducted by the University of Washington suggested that a newly discovered monoamine transporter, known as PMAT, may account for "a significant percentage of 5-HT clearance".[24] Contrasting with the high-affinity SERT, the PMAT has been identified as a low affinity transporter with an apparent Km of 114 micromoles/L for serotonin; approximately 230 times higher than that of SERT. However, the PMAT, despite its relatively low serotonergic affinity, has a considerably higher transport capacity than SERT, "..resulting in roughly comparable uptake efficiencies to SERT in heterologous expression systems." The study also suggests that some SSRIs, such as fluoxetine and sertraline, inhibit PMAT but at IC50 values which surpass the therapeutic plasma concentrations by up to four orders of magnitudes; therefore, SSRI monotherapy is ineffective in PMAT inhibition. At present, there are no known pharmaceuticals which would appreciably inhibit PMAT at normal therapeutic doses. The PMAT also suggestively transports dopamine and norepinephrine albeit at Km values even higher than that of 5-HT (330–15,000 μmoles/L).

Serotonylation

Serotonin can also signal through a nonreceptor mechanism called serotonylation. In this serotonin modifies proteins.[32] This process underlies serotonin effects upon platelet-forming cells (thrombocytes) in which it links to the modification of signaling enzymes called GTPases that then trigger the release of vesicle contents by exocytosis.[60] A similar process underlies the pancreatic release of insulin.[32] The effects of serotonin upon vascular smooth muscle "tone" (this is the biological function from which serotonin originally got its name) depend upon the serotonylation of proteins involved in the contractile apparatus of muscle cells.[61]

Biosynthesis

On top a L-tryptophan molecule with an arrow down to a 5-HTP molecule. Tryptophan hydroxylase catalyses this reaction with help of O2 and tetrahydrobiopterin which becomes hydroxytetrahydrobiopterin. From the 5-HTP molecule goes an arrow down to a serotonin molecule. Aromatic L-amino acid decarboxylase catalyses this reaction with help of pyridoxal phosphate. From the serotonin molecule goes an arrow to a 5-HIAA molecule at the bottom ot the image. Monoamine oxidase catalyses this reaction, in the process O2 and water is consumed, and ammonia and hydrogen peroxide is produced.
The pathway for the synthesis of serotonin from tryptophan.

In animals including humans, serotonin is synthesized from the amino acid L-tryptophan by a short metabolic pathway consisting of two enzymes: tryptophan hydroxylase (TPH) and amino acid decarboxylase (DDC). The TPH-mediated reaction is the rate-limiting step in the pathway. TPH has been shown to exist in two forms: TPH1, found in several tissues, and TPH2, which is a brain-specific isoform.[62]

Serotonin taken orally does not pass into the serotonergic pathways of the central nervous system because it does not cross the blood-brain barrier. However, tryptophan and its metabolite 5-hydroxytryptophan (5-HTP), from which serotonin is synthesized, can and do cross the blood-brain barrier. These agents are available as dietary supplements and may be effective serotonergic agents. One product of serotonin breakdown is 5-Hydroxyindoleacetic acid (5 HIAA), which is excreted in the urine. Serotonin and 5 HIAA are sometimes produced in excess amounts by certain tumors or cancers, and levels of these substances may be measured in the urine to test for these tumors.

Drugs targeting the 5-HT system

Several classes of drugs target the 5-HT system including some antidepressants, antipsychotics, anxiolytics, antiemetics, and antimigraine drugs as well as the psychedelic drugs and empathogens.

Psychedelic drugs

The psychedelic drugs psilocin/psilocybin, DMT, mescaline, and LSD are agonists primarily at 5HT2A/2C receptors.[63][64] The Empathogen-entactogen MDMA (ecstasy) releases serotonin from synaptic vesicles of neurons.[65]

Antidepressants

The most prescribed drugs in many parts of the world are drugs which alter serotonin levels. They are used in depression, Generalized anxiety disorder and social phobia. The MAOIs prevent the breakdown of monoamine neurotransmitters (including serotonin), and therefore increase concentrations of the neurotransmitter in the brain. MAOI therapy is associated with many adverse drug reactions, and patients are at risk of hypertensive emergency triggered by foods with high tyramine content and certain drugs. Some drugs inhibit the re-uptake of serotonin, making it stay in the synapse longer. The tricyclic antidepressants (TCAs) inhibit the re-uptake of both serotonin and norepinephrine. The newer selective serotonin re-uptake inhibitors (SSRIs) have fewer side-effects and fewer interactions with other drugs. The side effects that have become apparent in recent times include a decrease in bone mass in elderly and increased risk for osteoporosis. However, it is not yet clear whether it is due to SSRI action on peripheral serotonin production and or action in the gut or in the brain.[37] Certain SSRI medications have been shown to lower serotonin levels below the baseline after chronic use, despite initial increases in serotonin. This has been connected to the observation that the benefit of SSRI's may decrease in selected patients after a long-term treatment. A switch in medication will usually resolve this issue (up to 70% of the time).[66] The novel antidepressant tianeptine, a selective serotonin reuptake enhancer, has mood-elevating effects. This provides evidence for the theory that serotonin is most likely used to regulate the extent or intensity of moods.

Although phobias and depression might be attenuated by serotonin-altering-drugs this does not mean that the individual's situation has been improved, but only the individual's perception of the environment. Sometimes a lower serotonin level might be beneficial, for example in the ultimatum game, where players with normal serotonin levels are more prone to accept unfair offers than participants whose serotonin levels have been artificially lowered.[67]

Serotonin syndrome

Main article: Serotonin Syndrome

Extremely high levels of serotonin can have toxic and potentially fatal effects, causing a condition known as serotonin syndrome. In practice, such toxic levels are essentially impossible to reach through an overdose of a single anti-depressant drug, but require a combination of serotonergic agents, such as an SSRI with an MAOI.[68] The intensity of the symptoms of serotonin syndrome vary over a wide spectrum, and the milder forms are seen even at non-toxic levels.[69]

Antiemetics

5-HT3 antagonists such as ondansetron, granisetron, and tropisetron are important antiemetic agents. They are particularly important in treating the nausea and vomiting that occur during anticancer chemotherapy using cytotoxic drugs. Another application is in the treatment of post-operative nausea and vomiting.

In unicellular organisms

Serotonin is used by a variety of single-cell organisms for various purposes. Selective serotonin re-uptake inhibitors (SSRIs) have been found to be toxic to algae.[70] The gastrointestinal parasite Entamoeba histolytica secretes serotonin, causing a sustained secretory diarrhea in some patients.[71][72] Patients infected with Entamoeba histolytica have been found to have highly elevated serum serotonin levels which returned to normal following resolution of the infection.[73] Entamoeba histolytica also responds to the presence of serotonin by becoming more virulent.[74] This means that the serotonin secretion not only serves to increase the spread of enteamoebas by giving the host diarrhea, but also to coordinate their behaviour according to their population density, a phenomenon known as quorum sensing. Outside a host the density of entoamoebas is low, and hence also the serotonin concentration. Low serotonin signals to the entoamoebas that they are outside a host and they become less virulent in order to conserve energy. When they enter a new host they multiply in the gut and become more virulent as the serotonin concentration increases.

In plants

In drying seeds serotonin production is a way to get rid of the buildup of poisonous ammonia. The ammonia is collected and placed in the indole part of L-tryptophan, which is then decarboxylated by tryptophan decarboxylase to give tryptamine, which is then hydroxylated by a cytochrome P450 monooxygenase, yielding serotonin.[75]

However, since serotonin is a major gastrointestinal tract modulator, it may be produced by plants in fruits as a way of speeding the passage of seeds through the digestive tract, in the same way as many well known-seed and fruit associated laxatives. Serotonin is found in mushrooms, fruits and vegetables. The highest values of 25–400 mg/kg have been found in nuts of the walnut (Juglans) and hickory (Carya) genera. Serotonin concentrations of 3–30 mg/kg have been found in plantain, pineapple, banana, kiwifruit, plums, and tomatoes. Moderate levels from 0.1–3 mg/kg have been found in a wide range of tested vegetables.[76]

Serotonin is one compound of the poison contained in stinging nettles (Urtica dioica), where it causes pain on injection in the same manner as its presence in insect venoms (see above).

Unlike its precursors, 5-HTP and tryptophan, serotonin does not cross the blood–brain barrier, which means that ingesting serotonin in the diet has no effect on brain serotonin levels.

Methyl-tryptamines and hallucinogens

Several plants contain serotonin together with a family of related tryptamines that are methylated at the amino (NH2) and (OH) groups, are N-oxides, or miss the OH group. These compounds do reach the brain, although some portion of them are metabolized by MAO-B enzymes in the liver. Examples are plants from the Anadenanthera genus that are used in the hallucinogenic yopo snuff. These compounds are widely present in the leaves of many plants, and may serve as deterrents for animal ingestion.

References

  1. ↑ King MW. "Serotonin". The Medical Biochemistry Page. Indiana University School of Medicine. http://themedicalbiochemistrypage.org/nerves.html#5ht. Retrieved 2009-12-01. 
  2. ↑ Berger M, Gray JA, Roth BL (2009). "The expanded biology of serotonin". Annu. Rev. Med. 60: 355–66. doi:10.1146/annurev.med.60.042307.110802. PMID 19630576. 
  3. ↑ Kang K, Park S, Kim YS, Lee S, Back K (2009). "Biosynthesis and biotechnological production of serotonin derivatives". Appl. Microbiol. Biotechnol. 83 (1): 27–34. doi:10.1007/s00253-009-1956-1. PMID 19308403. 
  4. ↑ Negri L (2006). "[Vittorio Erspamer (1909-1999)]" (in Italian). Med Secoli 18 (1): 97–113. PMID 17526278. 
  5. ↑ Rapport MM, Green AA, Page IH (1948). "Serum vasoconstrictor, serotonin; isolation and characterization". J. Biol. Chem. 176 (3): 1243–51. PMID 18100415. 
  6. ↑ Feldberg W, Toh CC (1953). "Distribution of 5-hydroxytryptamine (serotonin, enteramine) in the wall of the digestive tract". J. Physiol. (Lond.) 119 (2-3): 352–62. PMID 13035756. 
  7. ↑ Sawin ER, Ranganathan R, Horvitz HR (2000). "C. elegans locomotory rate is modulated by the environment through a dopaminergic pathway and by experience through a serotonergic pathway". Neuron 26 (3): 619–31. doi:10.1016/S0896-6273(00)81199-X. PMID 10896158. 
  8. ↑ Niacaris T, Avery L (2003). "Serotonin regulates repolarization of the C. elegans pharyngeal muscle". J. Exp. Biol. 206 (Pt 2): 223–31. doi:10.1242/jeb.00101. PMID 12477893. 
  9. ↑ Stahl SM, Mignon L, Meyer JM (2009). "Which comes first: atypical antipsychotic treatment or cardiometabolic risk?". Acta Psychiatr Scand 119 (3): 171–9. doi:10.1111/j.1600-0447.2008.01334.x. PMID 19178394. 
  10. ↑ Buckland PR, Hoogendoorn B, Guy CA, Smith SK, Coleman SL, O'Donovan MC (2005). "Low gene expression conferred by association of an allele of the 5-HT2C receptor gene with antipsychotic-induced weight gain". Am J Psychiatry 162 (3): 613–5. doi:10.1176/appi.ajp.162.3.613. PMID 15741483. 
  11. ↑ Holmes MC, French KL, Seckl JR (June 1997). "Dysregulation of diurnal rhythms of serotonin 5-HT2C and corticosteroid receptor gene expression in the hippocampus with food restriction and glucocorticoids". J. Neurosci. 17 (11): 4056–65. PMID 9151722. 
  12. ↑ Leibowitz SF (1990). "The role of serotonin in eating disorders". Drugs 39 Suppl 3: 33–48. PMID 2197074. 
  13. ↑ Abu-Jayyab A. "Nutritional Pharmacology Of Sleep & Depression". SelfGrowth.com. http://www.selfgrowth.com/articles/Nutritional_Pharmacology_of_Sleep_Depression.html. Retrieved 2009-12-02. 
  14. ↑ Young SN (2007). "How to increase serotonin in the human brain without drugs". J Psychiatry Neurosci 32 (6): 394–9. PMID 18043762. 
  15. ↑ Grossman, Mary H.; Hart, Cheryle R. (2008). The Feel-Good Diet. New York: McGraw-Hill. p. 64. ISBN 0-07-154849-1. 
  16. ↑ Clements RS, Darnell B (1980). "Myo-inositol content of common foods: development of a high-myo-inositol diet". Am. J. Clin. Nutr. 33 (9): 1954–67. PMID 7416064. 
  17. ↑ Rang, H. P. (2003). Pharmacology. Edinburgh: Churchill Livingstone. p. 187. ISBN 0-443-07145-4. 
  18. ↑ de Wit R, Aapro M, Blower PR (2005). "Is there a pharmacological basis for differences in 5-HT3-receptor antagonist efficacy in refractory patients?". Cancer Chemother Pharmacol 56 (3): 231–8. doi:10.1007/s00280-005-1033-0. PMID 15838653. 
  19. ↑ Kravitz EA (1988). "Hormonal control of behavior: amines and the biasing of behavioral output in lobsters". Science 241 (4874): 1775–81. doi:10.1126/science.2902685. PMID 2902685. 
  20. ↑ Yeh SR, Fricke RA, Edwards DH (1996). "The effect of social experience on serotonergic modulation of the escape circuit of crayfish". Science 271 (5247): 366–9. doi:10.1126/science.271.5247.366. PMID 8553075. 
  21. ↑ Caspi N, Modai I, Barak P, Waisbourd A, Zbarsky H, Hirschmann S, Ritsner M. (2001 Mar). "Pindolol augmentation in aggressive schizophrenic patients: a double-blind crossover randomized study". Int Clin Psychopharmacol. 16(2) (2): 111–5. PMID 11236069. 
  22. ↑ Basky, Greg (May 2, 2000). "Suicide linked to serotonin gene". CMAJ 162 (9): 1343. http://www.cmaj.ca/cgi/content/full/162/9/1343-a. 
  23. ↑ Lesch KP, Bengel D, Heils A, Sabol SZ, Greenberg BD, Petri S, Benjamin J, Müller CR, Hamer DH, Murphy DL (1996). "Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region". Science 274 (5292): 1527–31. doi:10.1126/science.274.5292.1527. PMID 8929413. 
  24. ↑ 24.0 24.1 24.2 Caspi A, Sugden K, Moffitt TE, Taylor A, Craig IW, Harrington H, McClay J, Mill J, Martin J, Braithwaite A, Poulton R (2003). "Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene". Science 301 (5631): 386–9. doi:10.1126/science.1083968. PMID 12869766. 
  25. ↑ Levinson DF (2006). "The genetics of depression: a review". Biol. Psychiatry 60 (2): 84–92. doi:10.1016/j.biopsych.2005.08.024. PMID 16300747. 
  26. ↑ Srinivasan S, Sadegh L, Elle IC, Christensen AG, Faergeman NJ, Ashrafi K (2008). "Serotonin regulates C. elegans fat and feeding through independent molecular mechanisms". Cell Metab. 7 (6): 533–44. doi:10.1016/j.cmet.2008.04.012. PMID 18522834. 
  27. ↑ Loer CM, Kenyon CJ (1993). "Serotonin-deficient mutants and male mating behavior in the nematode Caenorhabditis elegans". J. Neurosci. 13 (12): 5407–17. PMID 8254383. 
  28. ↑ Lipton J, Kleemann G, Ghosh R, Lints R, Emmons SW (2004). "Mate searching in Caenorhabditis elegans: a genetic model for sex drive in a simple invertebrate". J. Neurosci. 24 (34): 7427–34. doi:10.1523/JNEUROSCI.1746-04.2004. PMID 15329389. 
  29. ↑ Kaplan DD, Zimmermann G, Suyama K, Meyer T, Scott MP (2008). "A nucleostemin family GTPase, NS3, acts in serotonergic neurons to regulate insulin signaling and control body size". Genes Dev. 22 (14): 1877–93. doi:10.1101/gad.1670508. PMID 18628395. 
  30. ↑ Ruaud AF, Thummel CS (2008). "Serotonin and insulin signaling team up to control growth in Drosophila". Genes Dev. 22 (14): 1851–5. doi:10.1101/gad.1700708. PMID 18628391. 
  31. ↑ Anstey ML, Rogers SM, Ott SR, Burrows M, Simpson SJ (2009). "Serotonin mediates behavioral gregarization underlying swarm formation in desert locusts". Science 323 (5914): 627–30. doi:10.1126/science.1165939. PMID 19179529. Lay summary – BBC News. 
  32. ↑ 32.0 32.1 32.2 Paulmann N, Grohmann M, Voigt JP, Bert B, Vowinckel J, Bader M, Skelin M, Jevsek M, Fink H, Rupnik M, Walther DJ (2009). "Intracellular serotonin modulates insulin secretion from pancreatic beta-cells by protein serotonylation". PLoS Biol. 7 (10): e1000229. doi:10.1371/journal.pbio.1000229. PMID 19859528. 
  33. ↑ Davidson S, Prokonov D, Taler M, Maayan R, Harell D, Gil-Ad I, Weizman A (2009). "Effect of exposure to selective serotonin reuptake inhibitors in utero on fetal growth: potential role for the IGF-I and HPA axes". Pediatr. Res. 65 (2): 236–41. doi:10.1203/PDR.0b013e318193594a. PMID 19262294. 
  34. ↑ 34.0 34.1 Lesurtel M, Graf R, Aleil B, Walther DJ, Tian Y, Jochum W, Gachet C, Bader M, Clavien PA (2006). "Platelet-derived serotonin mediates liver regeneration". Science 312 (5770): 104–7. doi:10.1126/science.1123842. PMID 16601191. 
  35. ↑ Matondo RB, Punt C, Homberg J, Toussaint MJ, Kisjes R, Korporaal SJ, Akkerman JW, Cuppen E, de Bruin A (2009). "Deletion of the serotonin transporter in rats disturbs serotonin homeostasis without impairing liver regeneration". Am. J. Physiol. Gastrointest. Liver Physiol. 296 (4): G963–8. doi:10.1152/ajpgi.90709.2008. PMID 19246633. 
  36. ↑ Collet C, Schiltz C, Geoffroy V, Maroteaux L, Launay JM, de Vernejoul MC (2008). "The serotonin 5-HT2B receptor controls bone mass via osteoblast recruitment and proliferation". FASEB J. 22 (2): 418–27. doi:10.1096/fj.07-9209com. PMID 17846081. 
  37. ↑ 37.0 37.1 Yadav VK, Ryu JH, Suda N, Tanaka KF, Gingrich JA, Schütz G, Glorieux FH, Chiang CY, Zajac JD, Insogna KL, Mann JJ, Hen R, Ducy P, Karsenty G (2008). "Lrp5 controls bone formation by inhibiting serotonin synthesis in the duodenum". Cell 135 (5): 825–37. doi:10.1016/j.cell.2008.09.059. PMID 19041748. Lay summary – Science Daily. 
  38. ↑ Marieb, Elaine Nicpon (2009). Essentials of human anatomy & physiology (Eighth ed.). San Francisco: Pearson/Benjamin Cummings. p. 336. ISBN 0-321-51342-8. 
  39. ↑ 39.0 39.1 Baskin SI (1991). Principles of cardiac toxicology. Boca Raton: CRC Press. ISBN 0-8493-8809-0. http://books.google.com/?id=AW7M6jBixj4C&pg=PA626. Retrieved 2010-02-03. 
  40. ↑ Jähnichen S, Horowski R, Pertz H. "Pergolide and Cabergoline But not Lisuride Exhibit Agonist Efficacy at Serotonin 5-HT2B Receptors". http://userpage.fu-berlin.de/~hpertz/Presentation001.pdf. Retrieved 2010-02-03. 
  41. ↑ ADRAC (2004). "Cardiac valvulopathy with pergolide". Aust Adv Drug React Bull 23 (4). http://www.tga.gov.au/adr/aadrb/aadr0408.htm.  Free full text from the Australian Therapeutic Goods Administration
  42. ↑ Schade R, Andersohn F, Suissa S, Haverkamp W, Garbe E (2007). "Dopamine agonists and the risk of cardiac-valve regurgitation". N. Engl. J. Med. 356 (1): 29–38. doi:10.1056/NEJMoa062222. PMID 17202453. 
  43. ↑ Zanettini R, Antonini A, Gatto G, Gentile R, Tesei S, Pezzoli G (2007). "Valvular heart disease and the use of dopamine agonists for Parkinson's disease". N. Engl. J. Med. 356 (1): 39–46. doi:10.1056/NEJMoa054830. PMID 17202454. 
  44. ↑ "Food and Drug Administration Public Health Advisory". 2007-03-29. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm152695.htm. Retrieved 2010-02-07. 
  45. ↑ "MedWatch - 2007 Safety Information Alerts. Permax (pergolide) and generic equivalents". U.S. Food and Drug Administration. March 29, 2007. http://www.fda.gov/medwatch/safety/2007/safety07.htm#Pergolide. Retrieved 2007-03-30. 
  46. ↑ Jaques R, Schachter M (1954). "The presence of histamine, 5-hydroxytryptamine and a potent, slow contracting substance in wasp venom". Br J Pharmacol Chemother 9 (1): 53–8. PMID 13149776. 
  47. ↑ Adam KR, Weiss C (1959). "Distribution of 5-hydroxytryptamine in scorpion venoms". Nature 183 (4672): 1398–9. doi:10.1038/1831398a0. PMID 13657136. 
  48. ↑ Ben Arous J, Laffont S, Chatenay D (2009). "Molecular and sensory basis of a food related two-state behavior in C. elegans". PLoS ONE 4 (10): e7584. doi:10.1371/journal.pone.0007584. PMID 19851507. 
  49. ↑ Sze JY, Victor M, Loer C, Shi Y, Ruvkun G (2000). "Food and metabolic signaling defects in a Caenorhabditis elegans serotonin-synthesis mutant". Nature 403 (6769): 560–4. doi:10.1038/35000609. PMID 10676966. 
  50. ↑ Côté F, Thévenot E, Fligny C, et al. (2003). "Disruption of the nonneuronal tph1 gene demonstrates the importance of peripheral serotonin in cardiac function". Proc. Natl. Acad. Sci. U.S.A. 100 (23): 13525–30. doi:10.1073/pnas.2233056100. PMID 14597720. 
  51. ↑ Alenina N, Kikic D, Todiras M, Mosienko V, Qadri F, Plehm R, Boyé P, Vilianovitch L, Sohr R, Tenner K, Hörtnagl H, Bader M (2009). "Growth retardation and altered autonomic control in mice lacking brain serotonin". Proc. Natl. Acad. Sci. U.S.A. 106 (25): 10332–7. doi:10.1073/pnas.0810793106. PMID 19520831. 
  52. ↑ Savelieva KV, Zhao S, Pogorelov VM, et al. (2008). "Genetic disruption of both tryptophan hydroxylase genes dramatically reduces serotonin and affects behavior in models sensitive to antidepressants". PLoS ONE 3 (10): e3301. doi:10.1371/journal.pone.0003301. PMID 18923670. 
  53. ↑ Audero, Enrica; Coppi, Elisabetta; Mlinar, Boris; Rossetti, Tiziana; Caprioli, Antonio; Al Banchaabouchi, Mumna; Corradetti, Renato; Gross, Cornelius (2008). "Sporadic Autonomic Dysregulation and Death Associated with Excessive Serotonin Autoinhibition". Science 321 (5885): 130–133. doi:10.1126/science.1157871. PMID 18599790. 
  54. ↑ Paterson DS, Trachtenberg FL, Thompson EG, Belliveau RA, Beggs AH, Darnall R, Chadwick AE, Krous HF, Kinney HC (2006). "Multiple serotonergic brainstem abnormalities in sudden infant death syndrome". JAMA 296 (17): 2124–32. doi:10.1001/jama.296.17.2124. PMID 17077377. 
  55. ↑ Borg J, Andrée B, Soderstrom H, Farde L (2003). "The serotonin system and spiritual experiences". Am J Psychiatry 160 (11): 1965–9. doi:10.1176/appi.ajp.160.11.1965. PMID 14594742. Lay summary – BeliefNet. 
  56. ↑ Svenningsson P, Chergui K, Rachleff I, Flajolet M, Zhang X, El Yacoubi M, Vaugeois JM, Nomikos GG, Greengard P (2006). "Alterations in 5-HT1B receptor function by p11 in depression-like states". Science 311 (5757): 77–80. doi:10.1126/science.1117571. PMID 16400147. 
  57. ↑ Frazer, A.; and Hensler, J. G. (1999). "Understanding the neuroanatomical organization of serotonergic cells in the brain provides insight into the functions of this neurotransmitter". In Siegel, G. J.. Basic Neurochemistry. Agranoff, Bernard W.; Fisher, Stephen K.; Albers, R. Wayne; Uhler, Michael D. (Sixth ed.). Lippincott Williams and Wilkins. ISBN 0-397-51820-X. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Search&db=books&doptcmdl=GenBookHL&term=raphe+AND+serotonin+release+AND+bnchm%5Bbook%5D+AND+160428%5Buid%5D&rid=bnchm.section.946#949. "In 1964, Dahlstrom and Fuxe (discussed in [2]), using the Falck-Hillarp technique of histofluorescence, observed that the majority of serotonergic soma are found in cell body groups, which previously had been designated as the raphe nuclei." 
  58. ↑ The Raphe nuclei group of neurons are located along the brain stem from the labels 'Mid Brain' to 'Oblongata', centered on the pons. (See relevant image.)
  59. ↑ Hannon J, Hoyer D (2008). "Molecular biology of 5-HT receptors". Behav. Brain Res. 195 (1): 198–213. doi:10.1016/j.bbr.2008.03.020. PMID 18571247. 
  60. ↑ Walther DJ, Peter JU, Winter S, Höltje M, Paulmann N, Grohmann M, Vowinckel J, Alamo-Bethencourt V, Wilhelm CS, Ahnert-Hilger G, Bader M (2003). "Serotonylation of small GTPases is a signal transduction pathway that triggers platelet alpha-granule release". Cell 115 (7): 851–62. doi:10.1016/S0092-8674(03)01014-6. PMID 14697203. 
  61. ↑ Watts SW, Priestley JR, Thompson JM (2009). "Serotonylation of vascular proteins important to contraction". PLoS ONE 4 (5): e5682. doi:10.1371/journal.pone.0005682. PMID 19479059. 
  62. ↑ Walther DJ, Peter JU, Bashammakh S, Hörtnagl H, Voits M, Fink H, Bader M (2003). "Synthesis of serotonin by a second tryptophan hydroxylase isoform". Science 299 (5603): 76. doi:10.1126/science.1078197. PMID 12511643. 
  63. ↑ Titeler M, Lyon RA, Glennon RA (1988). "Radioligand binding evidence implicates the brain 5-HT2 receptor as a site of action for LSD and phenylisopropylamine hallucinogens". Psychopharmacology (Berl.) 94 (2): 213–6. PMID 3127847. 
  64. ↑ Nichols DE (2000). "Role of serotonergic neurons and 5-HT receptors in the action of hallucinogens". In Baumgarten HG, Gothert M. Serotoninergic Neurons and 5-HT Receptors in the CNS. Santa Clara, CA: Springer-Verlag TELOS. ISBN 3-540-66715-6. 
  65. ↑ Johnson MP, Hoffman AJ, Nichols DE (1986). "Effects of the enantiomers of MDA, MDMA and related analogues on [3H]serotonin and [3H]dopamine release from superfused rat brain slices". Eur. J. Pharmacol. 132 (2-3): 269–76. doi:10.1016/0014-2999(86)90615-1. PMID 2880735. 
  66. ↑ Benmansour S, Cecchi M, Morilak DA, Gerhardt GA, Javors MA, Gould GG, Frazer A (1999). "Effects of chronic antidepressant treatments on serotonin transporter function, density, and mRNA level". J. Neurosci. 19 (23): 10494–501. PMID 10575045. 
  67. ↑ Crockett MJ, Clark L, Tabibnia G, Lieberman MD, Robbins TW (2008). "Serotonin modulates behavioral reactions to unfairness". Science 320 (5884): 1739. doi:10.1126/science.1155577. PMID 18535210. Lay summary. 
  68. ↑ Isbister, G. K.; Bowe, S. J.; Dawson, A.; Whyte, I. M. (2004). "Relative toxicity of selective serotonin reuptake inhibitors (SSRIs) in overdose". J. Toxicol. Clin. Toxicol. 42 (3): 277–85. doi:10.1081/CLT-120037428. PMID 15362595. 
  69. ↑ Dunkley EJ, Isbister GK, Sibbritt D, Dawson AH, Whyte IM (2003). "The Hunter Serotonin Toxicity Criteria: simple and accurate diagnostic decision rules for serotonin toxicity". QJM 96 (9): 635–42. doi:10.1093/qjmed/hcg109. PMID 12925718. 
  70. ↑ Johnson DJ, Sanderson H, Brain RA, Wilson CJ, Solomon KR (2007). "Toxicity and hazard of selective serotonin reuptake inhibitor antidepressants fluoxetine, fluvoxamine, and sertraline to algae". Ecotoxicol. Environ. Saf. 67 (1): 128–39. doi:10.1016/j.ecoenv.2006.03.016. PMID 16753215. 
  71. ↑ McGowan K, Kane A, Asarkof N, Wicks J, Guerina V, Kellum J, Baron S, Gintzler AR, Donowitz M (1983). "Entamoeba histolytica causes intestinal secretion: role of serotonin". Science 221 (4612): 762–4. doi:10.1126/science.6308760. PMID 6308760. 
  72. ↑ McGowan K, Guerina V, Wicks J, Donowitz M (1985). "Secretory hormones of Entamoeba histolytica". Ciba Found. Symp. 112: 139–54. PMID 2861068. 
  73. ↑ Banu N, Zaidi KR, Mehdi G, Mansoor T (2005). "Neurohumoral alterations and their role in amoebiasis" (PDF). Indian J. Clin Biochem 20 (2): 142–5. doi:10.1007/BF02867414. 
  74. ↑ Acharya DP, Sen MR, Sen PC (1989). "Effect of exogenous 5-hydroxytryptamine on pathogenicity of Entamoeba histolytica in experimental animals". Indian J. Exp. Biol. 27 (8): 718–20. PMID 2561282. 
  75. ↑ Schröder P, Abele C, Gohr P, Stuhlfauth-Roisch U, Grosse W. (1999). "Latest on enzymology of serotonin biosynthesis in walnut seeds". Adv Exp Med Biol. 467: 637–644. PMID 10721112. 
  76. ↑ Feldman, J. M.; Lee, E. M. (1985). "Serotonin content of foods: effect on urinary excretion of 5-hydroxyindoleacetic acid". Am. J. Clin. Nutr. 42 (4): 639–43. PMID 2413754. 

External links

Neurotransmitters
Amino acids

Alanine · Aspartate · Cycloserine · DMG · GABA · Glutamate · Glycine · Hypotaurine · Kynurenic acid (Transtorine) · NAAG (Spaglumic acid) · NMG (Sarcosine) · Serine · Taurine · TMG (Betaine)
Endocannabinoids

2-AG · 2-AGE (Noladin ether) · AEA (Anandamide) · NADA · OAE (Virodhamine) · Oleamide
Gasotransmitters
Monoamines

Dopamine · Epinephrine (Adrenaline) · Melatonin · NAS (Normelatonin) · Norepinephrine (Noradrenaline) · Serotonin (5-HT)
Purines

Adenosine · ADP · AMP · ATP
Trace amines

3-ITA · 5-MeO-DMT · Bufotenin · DMT · NMT · Octopamine · Phenethylamine · Synephrine · Thyronamine · Tryptamine · Tyramine
Others

1,4-BD · Acetylcholine · GBL · GHB · Histamine
See also Template:Neuropeptides
PNS

anat(h,r,t,,b,l,s)/phys/devp///nttm/

noco/auto/cong/tumr, sysi/, injr

proc, drug(N1B)
Tryptamines

2-Methyl-5-HT • 4-Acetoxy-DET • 4-Acetoxy-DIPT • 4-Acetoxy-DMT • 4-HO-αMT • 4-HO-DIPT • 4-HO-MET • 4-MeO-DMT • 4-Methyl-αET • 4-Methyl-αMT • 5-Benzyloxytryptamine • 5-Bromo-DMT • 5-Carboxamidotryptamine • 5-Fluoro-αMT • 5-HO-αMT • 5-HTP • 5-Fluoro-DMT • 5-Methyl-DMT • 5-Methoxytryptamine • 5-MeO-7,N,N-TMT • 5-MeO-αET  • 5-MeO-αMT • 5-MeO-DALT • 5-MeO-DET • 5-MeO-DIPT • 5-MeO-DMT • 5-MeO-DPT • 5-MeO-MIPT • 5,7-Dihydroxytryptamine • 7-Methyl-αET • 7-Methyl-DMT • αET • αMT • Aeruginascin • AL-37350A • BW-723C86 • Baeocystin • Bufotenidine • Bufotenin • DALT • Desformylflustrabromine • DET • DiPT • DMT • DPT • Ethocybin • EiPT • EMDT • Ethocin • FGIN-127 • FGIN-143 • Ibogaine • Iprocin • MET • MiPT • Miprocin • Melatonin • MS-245 • NAS • NMT • Norbaeocystin • Normelatonin • Oxypertine • PiPT • Psilocin • Psilocybin • Rizatriptan • Serotonin • Sumatriptan • Tryptamine • Tryptophan • Yohimbine • Yuremamine • Zolmitriptan
Autacoids
Kinins
Kininogen (HMWK, LMWK) • Bradykinin • Kallidin • Tachykinins • Urotensin-II
Others
Angiotensin • Eicosanoid • Histamine • Platelet-activating factor • Serotonin
trdu: iter (nrpl/grfl/cytl/horl), csrc (lgic, enzr, gprc, nrpr/grfr/), (, , ), , ; path (, , +, , , fsap, , )