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Serotonin

Serotonin (/ˌsɛrəˈtnɪn, ˌsɪərə-/)[6][7][8] or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter. Its biological function is complex, touching on diverse functions including mood, cognition, reward, learning, memory, and numerous physiological processes such as vomiting and vasoconstriction.[9]

For other uses, see Serotonin (disambiguation).

Clinical data

5-HT, 5-Hydroxytryptamine, Enteramine, Thrombocytin, 3-(β-Aminoethyl)-5-hydroxyindole, Thrombotonin

system-wide

Indirectly: SSRIs, MAOIs

Serotonin is produced in the central nervous system (CNS), specifically in the brainstem's raphe nuclei, the skin's Merkel cells, pulmonary neuroendocrine cells and the tongue's taste receptor cells. Approximately 90% of the serotonin the human body produces is in the gastrointestinal tract's enterochromaffin cells, where it regulates intestinal movements.[10][11][12] Additionally, it is stored in blood platelets and is released during agitation and vasoconstriction, where it then acts as an agonist to other platelets.[13] About 8% is found in platelets and 1–2% in the CNS.[14]


The serotonin is secreted luminally and basolaterally, which leads to increased serotonin uptake by circulating platelets and activation after stimulation, which gives increased stimulation of myenteric neurons and gastrointestinal motility.[15] The remainder is synthesized in serotonergic neurons of the CNS, where it has various functions, including the regulation of mood, appetite, and sleep.


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 release serotonin, where it can serve as a vasoconstrictor or a vasodilator while regulating hemostasis and blood clotting. In high concentrations, serotonin acts as a vasoconstrictor by contracting endothelial smooth muscle directly or by potentiating the effects of other vasoconstrictors (e.g. angiotensin II and norepinephrine). The vasoconstrictive property is mostly seen in pathologic states affecting the endothelium – such as atherosclerosis or chronic hypertension. In normal physiologic states, vasodilation occurs through the serotonin mediated release of nitric oxide from endothelial cells, and the inhibition of release of norepinephrine from adrenergic nerves.[16] Serotonin is also a growth factor for some types of cells, which may give it a role in wound healing. There are various serotonin receptors.


Biochemically, the indoleamine molecule derives from the amino acid tryptophan. Serotonin is metabolized mainly to 5-hydroxyindoleacetic acid, chiefly by the liver. Several classes of antidepressants, such as selective serotonin reuptake inhibitors (SSRIs) and serotonin–norepinephrine reuptake inhibitors (SNRIs), interfere with the normal reabsorption of serotonin after it is done with the transmission of the signal, therefore augmenting the neurotransmitter levels in the synapses.


Besides mammals, serotonin is found in all bilateral animals including worms and insects,[17] as well as in fungi and in plants.[18] Serotonin's presence in insect venoms and plant spines serves to cause pain, which is a side-effect of serotonin injection.[19][20] Serotonin is produced by pathogenic amoebae, causing diarrhea in the human gut.[21] Its widespread presence in many seeds and fruits may serve to stimulate the digestive tract into expelling the seeds.[22]

Molecular structure[edit]

Biochemically, the indoleamine molecule derives from the amino acid tryptophan, via the (rate-limiting) hydroxylation of the 5 position on the ring (forming the intermediate 5-hydroxytryptophan), and then decarboxylation to produce serotonin.[23] Preferable conformations are defined via ethylamine chain, resulting in six different conformations.[24]

Crystal structure[edit]

Serotonin crystallizes in P212121 chiral space group forming different hydrogen-bonding interactions between serotonin molecules via N-H...O and O-H...N intermolecular bonds.[25] Serotonin also forms several salts, including pharmaceutical formulation of serotonin adipate.[26]

Comparative biology and evolution[edit]

Unicellular organisms[edit]

Serotonin is used by a variety of single-cell organisms for various purposes. SSRIs have been found to be toxic to algae.[116] The gastrointestinal parasite Entamoeba histolytica secretes serotonin, causing a sustained secretory diarrhea in some people.[21][117] Patients infected with E. histolytica have been found to have highly elevated serum serotonin levels, which returned to normal following resolution of the infection.[118] E. histolytica also responds to the presence of serotonin by becoming more virulent.[119] This means serotonin secretion not only serves to increase the spread of enteamoebas by giving the host diarrhea but also serves to coordinate their behaviour according to their population density, a phenomenon known as quorum sensing. Outside the gut of a host, there is nothing that the entoamoebas provoke to release serotonin, hence the serotonin concentration is very low. Low serotonin signals to the entoamoebas they are outside a host and they become less virulent to conserve energy. When they enter a new host, they multiply in the gut, and become more virulent as the enterochromaffine cells get provoked by them and the serotonin concentration increases.

Edible plants and mushrooms[edit]

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.[120]


However, since serotonin is a major gastrointestinal tract modulator, it may be produced in the fruits of plants 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 plantains, pineapples, banana, kiwifruit, plums, and tomatoes. Moderate levels from 0.1–3 mg/kg have been found in a wide range of tested vegetables.[22][18]


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.[20] It is also naturally found in Paramuricea clavata, or the Red Sea Fan.[121]


Serotonin and tryptophan have been found in chocolate with varying cocoa contents. The highest serotonin content (2.93 μg/g) was found in chocolate with 85% cocoa, and the highest tryptophan content (13.27–13.34 μg/g) was found in 70–85% cocoa. The intermediate in the synthesis from tryptophan to serotonin, 5-hydroxytryptophan, was not found.[122]


Root development in Arabidopsis thaliana is stimulated and modulated by serotonin – in various ways at various concentrations.[123]


Serotonin serves as a plant defense chemical against fungi. When infected with Fusarium crown rot (Fusarium pseudograminearum), wheat (Triticum aestivum) greatly increases its production of tryptophan to synthesize new serotonin.[124] The function of this is poorly understood[124] but wheat also produces serotonin when infected by Stagonospora nodorum – in that case to retard spore production.[125] The model cereal Brachypodium distachyon – used as a research substitute for wheat and other production cereals – also produces serotonin, coumaroyl-serotonin, and feruloyl-serotonin in response to F. graminearum. This produces a slight antimicrobial effect. B. distachyon produces more serotonin (and conjugates) in response to deoxynivalenol (DON)-producing F. graminearum than non-DON-producing.[126] Solanum lycopersicum produces many AA conjugates – including several of serotonin – in its leaves, stems, and roots in response to Ralstonia solanacearum infection.[127]

Invertebrates[edit]

Serotonin functions as a neurotransmitter in the nervous systems of most animals.

Analytical chemistry[edit]

Indium tin oxide is recommended for the electrode material in electrochemical investigation of concentrations produced, detected, or consumed by microbes.[170] A mass spectrometry technique was developed in 1994 to measure the molecular weight of both natural and synthetic serotonins.[171]

History and etymology[edit]

It had been known to physiologists for over a century that a vasoconstrictor material appears in serum when blood was allowed to clot.[172] In 1935, Italian Vittorio Erspamer showed an extract from enterochromaffin cells made intestines contract. Some believed it contained adrenaline, but two years later, Erspamer was able to show it was a previously unknown amine, which he named "enteramine".[173][174] 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.[175]


In 1952, enteramine was shown to be the same substance as serotonin, and as the broad range of physiological roles was elucidated, the abbreviation 5-HT of the proper chemical name 5-hydroxytryptamine became the preferred name in the pharmacological field.[176] Synonyms of serotonin include: 5-hydroxytriptamine, thrombotin, enteramin, substance DS, and 3-(β-Aminoethyl)-5-hydroxyindole.[177] In 1953, Betty Twarog and Page discovered serotonin in the central nervous system.[178] Page regarded Erspamer's work on Octopus vulgaris, Discoglossus pictus, Hexaplex trunculus, Bolinus brandaris, Sepia, Mytilus, and Ostrea as valid and fundamental to understanding this newly identified substance, but regarded his earlier results in various models – especially those from rat blood – to be too confounded by the presence of other bioactive chemicals, including some other vasoactives.[179]

HIOC

5-Hydroxytryptamine MS Spectrum

in the PDB

Serotonin bound to proteins

Extensive reviews on serotonergic drugs and Serotonin Syndrome.

PsychoTropicalResearch

at University of Bristol

Molecule of the Month: Serotonin

60-Second Psych: , Scientific American

No Fair! My Serotonin Level Is Low

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Serotonin Test Interpretation on ClinLab Navigator