Editing Serotonin (section)

===Cellular effects===
Serotonin primarily acts through its receptors and its effects depend on which cells and tissues express these receptors.<ref name="Zifa_1992" />

Metabolism involves first [[oxidation]] by [[monoamine oxidase]] to [[5-Hydroxyindoleacetaldehyde|5-hydroxyindoleacetaldehyde]] (5-HIAL).<ref name="BortolatoChenShih2010">{{cite book | vauthors = Bortolato M, Chen K, Shih JC | title=Handbook of Behavioral Neuroscience | chapter=The Degradation of Serotonin: Role of MAO | publisher=Elsevier | volume=21 | date=2010 | isbn=978-0-12-374634-4 | doi=10.1016/s1569-7339(10)70079-5 | pages=203–218}}</ref><ref name="MatthesMosienkoBashammakh2010">{{cite journal | vauthors = Matthes S, Mosienko V, Bashammakh S, Alenina N, Bader M | title = Tryptophan hydroxylase as novel target for the treatment of depressive disorders | journal = Pharmacology | volume = 85 | issue = 2 | pages = 95–109 | date = 2010 | pmid = 20130443 | doi = 10.1159/000279322 | url = }}</ref> The rate-limiting step is hydride transfer from serotonin to the flavin cofactor.<ref>{{cite journal | vauthors = Prah A, Purg M, Stare J, Vianello R, Mavri J | title = How Monoamine Oxidase A Decomposes Serotonin: An Empirical Valence Bond Simulation of the Reactive Step | journal = The Journal of Physical Chemistry B | volume = 124 | issue = 38 | pages = 8259–8265 | date = September 2020 | pmid = 32845149 | pmc = 7520887 | doi = 10.1021/acs.jpcb.0c06502 }}</ref> There follows oxidation by [[aldehyde dehydrogenase]] (ALDH) to [[5-hydroxyindoleacetic acid]] ({{nowrap|5-HIAA}}), the [[indole]] acetic-acid derivative. The latter is then excreted by the kidneys.

====Receptors====
{{Main|Serotonin receptor}}

The [[serotonin receptor]]s are located on the [[cell membrane]] of [[Neuron|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 [[Psychedelics|psychedelic drug]]s. There are currently 14{{nbsp}}known serotonin receptors, including the serotonin [[5-HT1 receptor|5-HT<sub>1</sub>]] (<sub>[[5-HT1A receptor|1A]]</sub>, <sub>[[5-HT1B receptor|1B]]</sub>, <sub>[[5-HT1D receptor|1D]]</sub>, <sub>[[5-HT1E receptor|1E]]</sub>, <sub>[[5-HT1F receptor|1F]]</sub>), [[5-HT2 receptor|5-HT<sub>2</sub>]] (<sub>[[5-HT2A receptor|2A]]</sub>, <sub>[[5-HT2B receptor|2B]]</sub>, <sub>[[5-HT2C receptor|2C]]</sub>), [[5-HT3 receptor|5-HT<sub>3</sub>]], [[5-HT4 receptor|5-HT<sub>4</sub>]], [[5-HT5 receptor|5-HT<sub>5</sub>]] (<sub>[[5-HT5A receptor|5A]]</sub>, <sub>[[5-HT5B receptor|5B]]</sub>), [[5-HT6 receptor|5-HT<sub>6</sub>]], and [[5-HT7 receptor|5-HT<sub>7</sub> receptor]]s. Except for the serotonin [[5-HT3|5-HT<sub>3</sub> receptor]], a ligand-gated [[ion channel]], all other 5-HT receptors are [[G-protein-coupled receptors]] (also called seven-transmembrane, or heptahelical receptors) that activate an [[intracellular]] [[second messenger]] cascade.<ref name="pmid18571247">{{cite journal | vauthors = Hannon J, Hoyer D | title = Molecular biology of 5-HT receptors | journal = Behavioural Brain Research | volume = 195 | issue = 1 | pages = 198–213 | date = December 2008 | pmid = 18571247 | doi = 10.1016/j.bbr.2008.03.020 | s2cid = 46043982 }}</ref> The 5-HT<sub>5B</sub> receptor is present in rodents but not in humans.

In addition to the serotonin receptors, serotonin is an [[agonist]] of the [[trace amine-associated receptor 1]] (TAAR1) in some species.<ref name="GainetdinovHoenerBerry2018">{{cite journal | vauthors = Gainetdinov RR, Hoener MC, Berry MD | title = Trace Amines and Their Receptors | journal = Pharmacol Rev | volume = 70 | issue = 3 | pages = 549–620 | date = July 2018 | pmid = 29941461 | doi = 10.1124/pr.117.015305 | url = | doi-access = free }}</ref><ref name="SimmlerBuchyChaboz2016">{{cite journal | vauthors = Simmler LD, Buchy D, Chaboz S, Hoener MC, Liechti ME | title = In Vitro Characterization of Psychoactive Substances at Rat, Mouse, and Human Trace Amine-Associated Receptor 1 | journal = J Pharmacol Exp Ther | volume = 357 | issue = 1 | pages = 134–144 | date = April 2016 | pmid = 26791601 | doi = 10.1124/jpet.115.229765 | url = https://d1wqtxts1xzle7.cloudfront.net/74120533/eae6c6e62565b82d46b4d111bbea0f77b9c2-libre.pdf?1635931703=&response-content-disposition=inline%3B+filename%3DIn_Vitro_Characterization_of_Psychoactiv.pdf&Expires=1746838268&Signature=Sy4fJ90yUhxs68314NxYsW5PAaNrBGePRu35WRR4PIF-3YC7Z~sLdnCn5wfqqbLg9bDEGdt~oW55ugMP3D3jgA0BoRI~~GOb0NQOwrtfUEQK1PQs1uuN9qg5Y1ct8z5NsABm44RgtukkwRMdU6fO7OlfIsQ68hOiFk129Ll7UYqldxD2f1xhE2fTTfsxSpb8cMCJzHn7-ItqLdwnAUPFK7WggDIjmY1kCnaHLwIxMwdJCAq8L6DYzSTg7pZkbR8qlou~GXbTPQt~gYpyZTJp5hgW-7V6K5wLlQ7Z2xE7B0f9wEfuc1W1QNafg125Tr-vvAe4LEGKXV58bnn1bpfWKw__&Key-Pair-Id=APKAJLOHF5GGSLRBV4ZA| archive-url = https://web.archive.org/web/20250509235235/https://d1wqtxts1xzle7.cloudfront.net/74120533/eae6c6e62565b82d46b4d111bbea0f77b9c2-libre.pdf?1635931703=&response-content-disposition=inline%3B+filename%3DIn_Vitro_Characterization_of_Psychoactiv.pdf&Expires=1746838268&Signature=Sy4fJ90yUhxs68314NxYsW5PAaNrBGePRu35WRR4PIF-3YC7Z~sLdnCn5wfqqbLg9bDEGdt~oW55ugMP3D3jgA0BoRI~~GOb0NQOwrtfUEQK1PQs1uuN9qg5Y1ct8z5NsABm44RgtukkwRMdU6fO7OlfIsQ68hOiFk129Ll7UYqldxD2f1xhE2fTTfsxSpb8cMCJzHn7-ItqLdwnAUPFK7WggDIjmY1kCnaHLwIxMwdJCAq8L6DYzSTg7pZkbR8qlou~GXbTPQt~gYpyZTJp5hgW-7V6K5wLlQ7Z2xE7B0f9wEfuc1W1QNafg125Tr-vvAe4LEGKXV58bnn1bpfWKw__&Key-Pair-Id=APKAJLOHF5GGSLRBV4ZA | archive-date = 9 May 2025 }}</ref> It is a weak TAAR1 [[partial agonist]] in rats, but is inactive at the TAAR1 in mice and humans.<ref name="GainetdinovHoenerBerry2018" /><ref name="SimmlerBuchyChaboz2016" />

The [[cryo-EM]] [[protein–ligand complex|structure]]s of the serotonin 5-HT<sub>2A</sub> receptor with serotonin, as well as with various [[serotonergic psychedelic]]s, have been solved and published by [[Bryan L. Roth]] and colleagues.<ref name="GumpperJainKim2025">{{cite journal | vauthors = Gumpper RH, Jain MK, Kim K, Sun R, Sun N, Xu Z, DiBerto JF, Krumm BE, Kapolka NJ, Kaniskan HÜ, Nichols DE, Jin J, Fay JF, Roth BL | title = The structural diversity of psychedelic drug actions revealed | journal = Nature Communications | volume = 16 | issue = 1 | pages = 2734 | date = March 2025 | pmid = 40108183 | doi = 10.1038/s41467-025-57956-7 | pmc = 11923220 | bibcode = 2025NatCo..16.2734G }}</ref><ref name="GumpperDiBertoJain2022">{{cite conference | vauthors = Gumpper RH, DiBerto J, Jain M, Kim K, Fay J, Roth BL | title = Structures of Hallucinogenic and Non-Hallucinogenic Analogues of the 5-HT2A Receptor Reveals Molecular Insights into Signaling Bias | conference = University of North Carolina at Chapel Hill Department of Pharmacology Research Retreat September 16th, 2022 – William and Ida Friday Center | date = September 2022 | url = https://www.med.unc.edu/pharm/wp-content/uploads/sites/930/2022/07/COMPLETE-PHARM-RETREAT-PROGRAM-2022-UPDATE.pdf#page=37}}</ref>

====Termination====
Serotonergic action is terminated primarily via [[reuptake|uptake]] of 5-HT from the synapse. This is accomplished through the specific [[monoamine transporter]] for 5-HT, [[Serotonin transporter|SERT]], on the presynaptic neuron. Various agents can inhibit 5-HT reuptake, including [[cocaine]], [[dextromethorphan]] (an [[antitussive]]), [[tricyclic antidepressants]] and [[selective serotonin reuptake inhibitor]]s (SSRIs). A 2006 study found that a significant portion of 5-HT's synaptic clearance is due to the selective activity of the [[plasma membrane monoamine transporter]] (PMAT) which actively transports the molecule across the membrane and back into the presynaptic cell.<ref name="pmid 1828907">{{cite journal | vauthors = Zhou M, Engel K, Wang J | title = Evidence for significant contribution of a newly identified monoamine transporter (PMAT) to serotonin uptake in the human brain | journal = Biochemical Pharmacology | volume = 73 | issue = 1 | pages = 147–154 | date = January 2007 | pmid = 17046718 | pmc = 1828907 | doi = 10.1016/j.bcp.2006.09.008 }}</ref>

In contrast to the high affinity of SERT, the PMAT has been identified as a low-affinity transporter, with an apparent ''K''<sub>m</sub> of 114 micromoles/l for serotonin, which is 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."<ref name="pmid 1828907" /> The study also suggests that the administration of SSRIs such as [[fluoxetine]] and [[sertraline]] may be associated with an inhibitory effect on PMAT activity when used at higher than normal dosages ([[IC50|IC<sub>50</sub>]] test values used in trials were 3–4 fold higher than typical prescriptive dosage).

====Serotonylation====
{{Main|Serotonylation}}

Serotonin can also signal through a nonreceptor mechanism called serotonylation, in which serotonin modifies proteins.<ref name="pmid19859528"/> This process underlies serotonin's effects upon platelet-forming cells ([[thrombocyte]]s) in which it links to the modification of signaling enzymes called [[GTPase]]s that then trigger the release of vesicle contents by [[exocytosis]].<ref name="pmid14697203">{{cite journal | vauthors = Walther DJ, Peter JU, Winter S, Höltje M, Paulmann N, Grohmann M, Vowinckel J, Alamo-Bethencourt V, Wilhelm CS, Ahnert-Hilger G, Bader M | title = Serotonylation of small GTPases is a signal transduction pathway that triggers platelet alpha-granule release | journal = Cell | volume = 115 | issue = 7 | pages = 851–862 | date = December 2003 | pmid = 14697203 | doi = 10.1016/S0092-8674(03)01014-6 | s2cid = 16847296 | doi-access = free }}</ref> A similar process underlies the pancreatic release of insulin.<ref name="pmid19859528"/>

The effects of serotonin upon vascular smooth [[muscle tone]]{{snd}}the biological function after which serotonin was originally named{{snd}}depend upon the serotonylation of proteins involved in the contractile apparatus of muscle cells.<ref name="pmid19479059">{{cite journal | vauthors = Watts SW, Priestley JR, Thompson JM | title = Serotonylation of vascular proteins important to contraction | journal = PLOS ONE | volume = 4 | issue = 5 | pages = e5682 | date = May 2009 | pmid = 19479059 | pmc = 2682564 | doi = 10.1371/journal.pone.0005682 | doi-access = free | bibcode = 2009PLoSO...4.5682W }}</ref>

{| class = wikitable
|+ <big>Binding profile of serotonin</big>
! Receptor !! K<sub>i</sub> (nM)<ref>{{cite web | title = PDSP K<sub>i</sub> Database | work = Psychoactive Drug Screening Program (PDSP) | vauthors = Roth BL, Driscol J | url = http://pdsp.med.unc.edu/pdsp.php | publisher = University of North Carolina at Chapel Hill and the United States National Institute of Mental Health | access-date = 17 December 2013 | date = 12 January 2011 | url-status = dead | archive-url = https://web.archive.org/web/20131108013656/http://pdsp.med.unc.edu/pdsp.php | archive-date = 8 November 2013 | df = dmy-all }}</ref> !! Receptor function<ref group = Note>References for the functions of these receptors are available on the wikipedia pages for the specific receptor in question</ref>
|-
| colspan ="3" align="center" | 5-HT<sub>1</sub> receptor family signals via [[Gi alpha subunit|G<sub>i/o</sub>]] inhibition of [[adenylyl cyclase]].
|-
| [[5-HT1A receptor|5-HT<sub>1A</sub>]] || 3.17 || Memory{{Vague|date=March 2014}} (agonists ↓); learning{{Vague|date=March 2014}} (agonists ↓); anxiety (agonists ↓); depression (agonists ↓); positive, negative, and cognitive symptoms of schizophrenia (partial agonists ↓); analgesia (agonists ↑); [[aggression]] (agonists ↓); dopamine release in the prefrontal cortex (agonists ↑); serotonin release and synthesis (agonists ↓)
|-
| [[5-HT1B receptor|5-HT<sub>1B</sub>]] || 4.32 || Vasoconstriction (agonists ↑); aggression (agonists ↓); bone mass (↓). Serotonin autoreceptor.
|-
| [[5-HT1D receptor|5-HT<sub>1D</sub>]] || 5.03 || Vasoconstriction (agonists ↑)
|-
| [[5-HT1E receptor|5-HT<sub>1E</sub>]] || 7.53 ||
|-
| [[5-HT1F receptor|5-HT<sub>1F</sub>]] || 10 ||
|-
| colspan ="3" align="center" | 5-HT<sub>2</sub> receptor family signals via [[Gq alpha subunit|G<sub>q</sub>]] activation of [[phospholipase C]].
|-
| [[5-HT2A receptor|5-HT<sub>2A</sub>]] || 11.55 || Psychedelia (agonists ↑); depression (agonists & antagonists ↓); anxiety (antagonists ↓); positive and negative symptoms of schizophrenia (antagonists ↓); norepinephrine release from the [[locus coeruleus]] (antagonists ↑); glutamate release in the [[prefrontal cortex]] (agonists ↑); dopamine in the prefrontal cortex (agonists ↑);<ref>{{cite journal | vauthors = Bortolozzi A, Díaz-Mataix L, Scorza MC, Celada P, Artigas F | title = The activation of 5-HT receptors in prefrontal cortex enhances dopaminergic activity | journal = Journal of Neurochemistry | volume = 95 | issue = 6 | pages = 1597–1607 | date = December 2005 | pmid = 16277612 | doi = 10.1111/j.1471-4159.2005.03485.x | hdl-access = free | s2cid = 18350703 | hdl = 10261/33026 }}</ref> urinary bladder contractions (agonists ↑)<ref name="MoroEdwards2016">{{cite journal | vauthors = Moro C, Edwards L, Chess-Williams R | title = 5-HT<sub>2A</sub> receptor enhancement of contractile activity of the porcine urothelium and lamina propria | journal = International Journal of Urology | volume = 23 | issue = 11 | pages = 946–951 | date = November 2016 | pmid = 27531585 | doi = 10.1111/iju.13172 | doi-access = free }}</ref>
|-
| [[5-HT2B receptor|5-HT<sub>2B</sub>]] || 8.71 || Cardiovascular functioning (agonists increase risk of pulmonary hypertension), empathy (via [[von Economo neurons]]<ref>{{cite web|url=http://neuronbank.org/wiki/index.php/Von_Economo_neuron|title=Von Economo neuron – NeuronBank|website=neuronbank.org}}{{MEDRS|date=October 2017}}</ref>)
|-
| [[5-HT2C receptor|5-HT<sub>2C</sub>]] || 5.02 || Dopamine release into the mesocorticolimbic pathway (agonists ↓); acetylcholine release in the prefrontal cortex (agonists ↑); dopaminergic and noradrenergic activity in the [[frontal cortex]] (antagonists ↑);<ref>{{cite journal | vauthors = Millan MJ, Gobert A, Lejeune F, Dekeyne A, Newman-Tancredi A, Pasteau V, Rivet JM, Cussac D | title = The novel melatonin agonist agomelatine (S20098) is an antagonist at 5-hydroxytryptamine2C receptors, blockade of which enhances the activity of frontocortical dopaminergic and adrenergic pathways | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 306 | issue = 3 | pages = 954–964 | date = September 2003 | pmid = 12750432 | doi = 10.1124/jpet.103.051797 | s2cid = 18753440 }}</ref> appetite (agonists ↓); antipsychotic effects (agonists ↑); antidepressant effects (agonists & antagonists ↑)
|-
| colspan =3 align = center | Other 5-HT receptors
|-
| [[5-HT3 receptor|5-HT<sub>3</sub>]] || 593 || Emesis (agonists ↑); anxiolysis (antagonists ↑).
|-
| [[5-HT4 receptor|5-HT<sub>4</sub>]] || 125.89 || Movement of food across the GI tract (agonists ↑); memory & learning (agonists ↑); antidepressant effects (agonists ↑). Signalling via [[Gs alpha subunit|G<sub>αs</sub>]] activation of adenylyl cyclase.
|-
| [[5-HT5A receptor|5-HT<sub>5A</sub>]] || 251.2 || Memory consolidation.<ref>{{cite journal | vauthors = Gonzalez R, Chávez-Pascacio K, Meneses A | title = Role of 5-HT5A receptors in the consolidation of memory | journal = Behavioural Brain Research | volume = 252 | pages = 246–251 | date = September 2013 | pmid = 23735322 | doi = 10.1016/j.bbr.2013.05.051 | s2cid = 140204585 }}</ref> Signals via [[Gi alpha subunit|G<sub>i/o</sub>]] inhibition of [[adenylyl cyclase]].
|-
| [[5-HT6 receptor|5-HT<sub>6</sub>]] || 98.41 || Cognition (antagonists ↑); antidepressant effects (agonists & antagonists ↑); [[anxiogenic]] effects (antagonists ↑<ref>{{cite journal | vauthors = Nautiyal KM, Hen R | title = Serotonin receptors in depression: from A to B | journal = F1000Research | volume = 6 | pages = 123 | year = 2017 | pmid = 28232871 | pmc = 5302148 | doi = 10.12688/f1000research.9736.1 | doi-access = free }}</ref>). [[Gs alpha subunit|G<sub>s</sub>]] signalling via activating [[adenylyl cyclase]].
|-
| [[5-HT7 receptor|5-HT<sub>7</sub>]] || 8.11 || Cognition (antagonists ↑); antidepressant effects (antagonists ↑). Acts by [[Gs alpha subunit|G<sub>s</sub>]] signalling via activating [[adenylyl cyclase]].
|}