Editing Serotonin (section)

===Outside the nervous system===

====Digestive tract (emetic)====
Serotonin regulates gastrointestinal (GI) function. The gut is surrounded by [[enterochromaffin cell]]s, which release serotonin in response to food in the [[Lumen (anatomy)|lumen]]. This makes the gut contract around the food. Platelets in the [[Hepatic portal system|veins draining the gut]] collect excess serotonin. There are often serotonin abnormalities in gastrointestinal disorders such as constipation and irritable bowel syndrome.<ref name="ReferenceA">{{cite journal | vauthors = Beattie DT, Smith JA | title = Serotonin pharmacology in the gastrointestinal tract: a review | journal = Naunyn-Schmiedeberg's Archives of Pharmacology | volume = 377 | issue = 3 | pages = 181–203 | date = May 2008 | pmid = 18398601 | doi = 10.1007/s00210-008-0276-9 | s2cid = 32820765 }}</ref>

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 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 [[5-HT3 receptor]]s in the [[chemoreceptor trigger zone]] that stimulate [[vomiting]].<ref>{{cite book | vauthors = Rang HP |title=Pharmacology |publisher=Churchill Livingstone |location=Edinburgh |year=2003 |page=187 |isbn=978-0-443-07145-4}}</ref> Thus, drugs and toxins stimulate serotonin release from enterochromaffin cells in the gut wall can induce emesis. The enterochromaffin cells not only react to bad food but are also very sensitive to [[Radiation therapy|irradiation]] and [[chemotherapy|cancer chemotherapy]]. Drugs that [[5-HT antagonist|block 5HT3]] are very effective in controlling the nausea and vomiting produced by cancer treatment, and are considered the gold standard for this purpose.<ref>{{cite journal | vauthors = de Wit R, Aapro M, Blower PR | title = Is there a pharmacological basis for differences in 5-HT3-receptor antagonist efficacy in refractory patients? | journal = Cancer Chemotherapy and Pharmacology | volume = 56 | issue = 3 | pages = 231–238 | date = September 2005 | pmid = 15838653 | doi = 10.1007/s00280-005-1033-0 | s2cid = 27576150 }}</ref>

====Lungs====
The [[lung]],<ref name="Lauweryns_1973">{{cite journal | vauthors = Lauweryns JM, Cokelaere J, Theunynck P | title = Serotonin producing neuroepithelial bodies in rabbit respiratory mucosa | journal = Science | volume = 180 | issue = 4084 | pages = 410–413 | date = April 1973 | pmid = 4121716 | doi = 10.1126/science.180.4084.410 | s2cid = 2809307 | bibcode = 1973Sci...180..410L }}</ref> including that of reptiles,<ref name="Pastor Ballesta Perez-Tomas Marin 1987 pp. 713–715">{{cite journal | vauthors = Pastor LM, Ballesta J, Perez-Tomas R, Marin JA, Hernandez F, Madrid JF | title = Immunocytochemical localization of serotonin in the reptilian lung | journal = Cell and Tissue Research | volume = 248 | issue = 3 | pages = 713–715 | date = June 1987 | pmid = 3301000 | doi = 10.1007/bf00216504 | publisher = Springer Science and Business Media LLC | s2cid = 9871728 }}</ref> contains specialized [[epithelial cells]] that occur as solitary cells or as clusters called neuroepithelial bodies or bronchial Kulchitsky cells or alternatively ''K cells''.<ref name="Sonstegard_1982">{{cite journal | vauthors = Sonstegard KS, Mailman RB, Cheek JM, Tomlin TE, DiAugustine RP | title = Morphological and cytochemical characterization of neuroepithelial bodies in fetal rabbit lung. I. Studies of isolated neuroepithelial bodies | journal = Experimental Lung Research | volume = 3 | issue = 3–4 | pages = 349–377 | date = November 1982 | pmid = 6132813 | doi = 10.3109/01902148209069663 }}</ref> These are enterochromaffin cells that like those in the gut release serotonin.<ref name="Sonstegard_1982" /> Their function is probably [[Hypoxic pulmonary vasoconstriction|vasoconstriction during hypoxia]].<ref name="Lauweryns_1973" />

====Skin====
Serotonin is also produced by [[Merkel cell]]s which are part of the [[somatosensory]] system.<ref>{{cite journal | vauthors = Chang W, Kanda H, Ikeda R, Ling J, DeBerry JJ, Gu JG | title = Merkel disc is a serotonergic synapse in the epidermis for transmitting tactile signals in mammals | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 113 | issue = 37 | pages = E5491–E5500 | date = September 2016 | pmid = 27573850 | pmc = 5027443 | doi = 10.1073/pnas.1610176113 | bibcode = 2016PNAS..113E5491C | doi-access = free }}</ref>

====Bone metabolism====
In mice and humans, alterations in serotonin levels and signalling have been shown to regulate bone mass.<ref name="pmid20200960">{{cite journal | vauthors = Frost M, Andersen TE, Yadav V, Brixen K, Karsenty G, Kassem M | title = Patients with high-bone-mass phenotype owing to Lrp5-T253I mutation have low plasma levels of serotonin | journal = Journal of Bone and Mineral Research | volume = 25 | issue = 3 | pages = 673–675 | date = March 2010 | pmid = 20200960 | doi = 10.1002/jbmr.44 | s2cid = 24280062 | doi-access = free }}</ref><ref name="pmid19197289">{{cite journal | vauthors = Rosen CJ | title = Breaking into bone biology: serotonin's secrets | journal = Nature Medicine | volume = 15 | issue = 2 | pages = 145–146 | date = February 2009 | pmid = 19197289 | doi = 10.1038/nm0209-145 | s2cid = 5489589 }}</ref><ref name="pmid19594297">{{cite journal | vauthors = Mödder UI, Achenbach SJ, Amin S, Riggs BL, Melton LJ, Khosla S | title = Relation of serum serotonin levels to bone density and structural parameters in women | journal = Journal of Bone and Mineral Research | volume = 25 | issue = 2 | pages = 415–422 | date = February 2010 | pmid = 19594297 | pmc = 3153390 | doi = 10.1359/jbmr.090721 }}</ref><ref name="pmid21351148">{{cite journal | vauthors = Frost M, Andersen T, Gossiel F, Hansen S, Bollerslev J, van Hul W, Eastell R, Kassem M, Brixen K | title = Levels of serotonin, sclerostin, bone turnover markers as well as bone density and microarchitecture in patients with high-bone-mass phenotype due to a mutation in Lrp5 | journal = Journal of Bone and Mineral Research | volume = 26 | issue = 8 | pages = 1721–1728 | date = August 2011 | pmid = 21351148 | doi = 10.1002/jbmr.376 | doi-access = free }}</ref> Mice that lack brain serotonin have [[osteopenia]], while mice that lack gut serotonin have high bone density. In humans, increased blood serotonin levels have been shown to be a significant negative predictor of low bone density. Serotonin can also be synthesized, albeit at very low levels, in the bone cells. It mediates its actions on bone cells using three different receptors. Through [[5-HT1B receptor|5-HT<sub>1B</sub> receptors]], it negatively regulates bone mass, while it does so positively through [[5-HT2B receptor|5-HT<sub>2B</sub> receptors]] and [[5-HT2C receptor|5-HT<sub>2C</sub> receptors]]. There is very delicate balance between physiological role of gut serotonin and its pathology. Increase in the extracellular content of serotonin results in a complex relay of signals in the osteoblasts culminating in FoxO1/ Creb and ATF4 dependent transcriptional events.<ref name="pmid22945629">{{cite journal | vauthors = Kode A, Mosialou I, Silva BC, Rached MT, Zhou B, Wang J, Townes TM, Hen R, DePinho RA, Guo XE, Kousteni S | title = FOXO1 orchestrates the bone-suppressing function of gut-derived serotonin | journal = The Journal of Clinical Investigation | volume = 122 | issue = 10 | pages = 3490–3503 | date = October 2012 | pmid = 22945629 | pmc = 3461930 | doi = 10.1172/JCI64906 }}</ref> Following the 2008 findings that gut serotonin regulates bone mass, the mechanistic investigations into what regulates serotonin synthesis from the gut in the regulation of bone mass have started. [[PIEZO1|Piezo1]] has been shown to sense RNA in the gut and relay this information through serotonin synthesis to the bone by acting as a sensor of single-stranded RNA (ssRNA) governing 5-HT production. Intestinal epithelium-specific deletion of mouse ''Piezo1'' profoundly disturbed gut peristalsis, impeded experimental colitis, and suppressed serum 5-HT levels. Because of systemic 5-HT deficiency, conditional knockout of ''Piezo1'' increased bone formation. Notably, fecal ssRNA was identified as a natural Piezo1 ligand, and ssRNA-stimulated 5-HT synthesis from the gut was evoked in a MyD88/TRIF-independent manner. Colonic infusion of RNase A suppressed gut motility and increased bone mass. These findings suggest gut ssRNA as a master determinant of systemic 5-HT levels, indicating the ssRNA-Piezo1 axis as a potential prophylactic target for treatment of bone and gut disorders. Studies in 2008, 2010 and 2019 have opened the potential for serotonin research to treat bone mass disorders.<ref name="pmid20139991">{{cite journal | vauthors = Yadav VK, Balaji S, Suresh PS, Liu XS, Lu X, Li Z, Guo XE, Mann JJ, Balapure AK, Gershon MD, Medhamurthy R, Vidal M, Karsenty G, Ducy P | title = Pharmacological inhibition of gut-derived serotonin synthesis is a potential bone anabolic treatment for osteoporosis | journal = Nature Medicine | volume = 16 | issue = 3 | pages = 308–312 | date = March 2010 | pmid = 20139991 | pmc = 2836724 | doi = 10.1038/nm.2098 }}</ref><ref name="pmid32640190">{{cite journal | vauthors = Sugisawa E, Takayama Y, Takemura N, Kondo T, Hatakeyama S, Kumagai Y, Sunagawa M, Tominaga M, Maruyama K | title = RNA Sensing by Gut Piezo1 Is Essential for Systemic Serotonin Synthesis | journal = Cell | volume = 182 | issue = 3 | pages = 609–624.e21 | date = August 2020 | pmid = 32640190 | doi = 10.1016/j.cell.2020.06.022 | doi-access = free }}</ref>

====Organ development====
Since serotonin signals resource availability it is not surprising that it affects organ development. Many human and animal studies have shown that nutrition in early life can influence, in adulthood, such things as body fatness, blood lipids, blood pressure, [[atherosclerosis]], behavior, learning, and longevity.<ref>{{cite journal | vauthors = Ozanne SE, Hales CN | title = Lifespan: catch-up growth and obesity in male mice | journal = Nature | volume = 427 | issue = 6973 | pages = 411–412 | date = January 2004 | pmid = 14749819 | doi = 10.1038/427411b | s2cid = 40256021 | bibcode = 2004Natur.427..411O }}</ref><ref>{{cite journal | vauthors = Lewis DS, Bertrand HA, McMahan CA, McGill HC, Carey KD, Masoro EJ | title = Preweaning food intake influences the adiposity of young adult baboons | journal = The Journal of Clinical Investigation | volume = 78 | issue = 4 | pages = 899–905 | date = October 1986 | pmid = 3760191 | pmc = 423712 | doi = 10.1172/JCI112678 }}</ref><ref name="Hahn1984">{{cite journal | vauthors = Hahn P | title = Effect of litter size on plasma cholesterol and insulin and some liver and adipose tissue enzymes in adult rodents | journal = The Journal of Nutrition | volume = 114 | issue = 7 | pages = 1231–1234 | date = July 1984 | pmid = 6376732 | doi = 10.1093/jn/114.7.1231 }}</ref> Rodent experiment shows that neonatal exposure to SSRIs makes persistent changes in the serotonergic transmission of the brain resulting in behavioral changes,<ref name="pmid18385313">{{cite journal | vauthors = Popa D, Léna C, Alexandre C, Adrien J | title = Lasting syndrome of depression produced by reduction in serotonin uptake during postnatal development: evidence from sleep, stress, and behavior | journal = The Journal of Neuroscience | volume = 28 | issue = 14 | pages = 3546–3554 | date = April 2008 | pmid = 18385313 | pmc = 6671102 | doi = 10.1523/JNEUROSCI.4006-07.2008 }}</ref><ref name="pmid16012532">{{cite journal | vauthors = Maciag D, Simpson KL, Coppinger D, Lu Y, Wang Y, Lin RC, Paul IA | title = Neonatal antidepressant exposure has lasting effects on behavior and serotonin circuitry | journal = Neuropsychopharmacology | volume = 31 | issue = 1 | pages = 47–57 | date = January 2006 | pmid = 16012532 | pmc = 3118509 | doi = 10.1038/sj.npp.1300823 }}</ref> which are reversed by treatment with antidepressants.<ref name="pmid16483567">{{cite journal | vauthors = Maciag D, Williams L, Coppinger D, Paul IA | title = Neonatal citalopram exposure produces lasting changes in behavior which are reversed by adult imipramine treatment | journal = European Journal of Pharmacology | volume = 532 | issue = 3 | pages = 265–269 | date = February 2006 | pmid = 16483567 | pmc = 2921633 | doi = 10.1016/j.ejphar.2005.12.081 }}</ref> By treating normal and [[Knockout mouse|knockout mice]] lacking the serotonin transporter with fluoxetine scientists showed that normal emotional reactions in adulthood, like a short latency to escape foot shocks and inclination to explore new environments were dependent on active serotonin transporters during the neonatal period.<ref>{{cite journal | vauthors = Holden C | title = Neuroscience. Prozac treatment of newborn mice raises anxiety | journal = Science | volume = 306 | issue = 5697 | pages = 792 | date = October 2004 | pmid = 15514122 | doi = 10.1126/science.306.5697.792 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Ansorge MS, Zhou M, Lira A, Hen R, Gingrich JA | title = Early-life blockade of the 5-HT transporter alters emotional behavior in adult mice | journal = Science | volume = 306 | issue = 5697 | pages = 879–881 | date = October 2004 | pmid = 15514160 | doi = 10.1126/science.1101678 | doi-access = free | bibcode = 2004Sci...306..879A }}</ref>

Human serotonin can also act as a [[growth factor]] directly. Liver damage increases cellular expression of [[5-HT2A receptor|5-HT<sub>2A</sub>]] and [[5-HT2B receptor|5-HT<sub>2B</sub> receptor]]s, mediating liver compensatory regrowth (see {{section link|Liver|Regeneration and transplantation}})<ref name="pmid16601191">{{cite journal | vauthors = Lesurtel M, Graf R, Aleil B, Walther DJ, Tian Y, Jochum W, Gachet C, Bader M, Clavien PA | title = Platelet-derived serotonin mediates liver regeneration | journal = Science | volume = 312 | issue = 5770 | pages = 104–107 | date = April 2006 | pmid = 16601191 | doi = 10.1126/science.1123842 | s2cid = 43189753 | bibcode = 2006Sci...312..104L }}</ref> Serotonin present in the blood then stimulates cellular growth to repair liver damage.<ref name="pmid19246633">{{cite journal | vauthors = Matondo RB, Punt C, Homberg J, Toussaint MJ, Kisjes R, Korporaal SJ, Akkerman JW, Cuppen E, de Bruin A | title = Deletion of the serotonin transporter in rats disturbs serotonin homeostasis without impairing liver regeneration | journal = American Journal of Physiology. Gastrointestinal and Liver Physiology | volume = 296 | issue = 4 | pages = G963–G968 | date = April 2009 | pmid = 19246633 | doi = 10.1152/ajpgi.90709.2008 | url = http://www.suaire.suanet.ac.tz:8080/xmlui/handle/123456789/2619 | access-date = 5 December 2019 | url-status = dead | archive-url = https://web.archive.org/web/20191228005416/http://www.suaire.suanet.ac.tz:8080/xmlui/handle/123456789/2619 | archive-date = 28 December 2019 }}</ref>

5-HT<sub>2B</sub> receptors also activate [[osteocyte]]s, which build up bone<ref name="pmid17846081">{{cite journal | vauthors = Collet C, Schiltz C, Geoffroy V, Maroteaux L, Launay JM, de Vernejoul MC | title = The serotonin 5-HT2B receptor controls bone mass via osteoblast recruitment and proliferation | journal = FASEB Journal | volume = 22 | issue = 2 | pages = 418–427 | date = February 2008 | pmid = 17846081 | pmc = 5409955 | doi = 10.1096/fj.07-9209com | doi-access = free }}</ref> However, serotonin also inhibits [[osteoblast]]s, through 5-HT<sub>1B</sub> receptors.<ref name="pmid19041748">{{cite journal | vauthors = 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 | title = Lrp5 controls bone formation by inhibiting serotonin synthesis in the duodenum | journal = Cell | volume = 135 | issue = 5 | pages = 825–837 | date = November 2008 | pmid = 19041748 | pmc = 2614332 | doi = 10.1016/j.cell.2008.09.059 }}
* {{cite press release |date=December 1, 2008 |title=It Takes Guts To Build Bone, Scientists Discover |website=ScienceDaily |url=https://www.sciencedaily.com/releases/2008/11/081126122209.htm}}</ref>

====Cardiovascular growth factor====
{{Main|Cardiac fibrosis}}

Serotonin, in addition, evokes [[endothelium|endothelial]] [[nitric oxide synthase]] activation and stimulates, through a [[5-HT1B receptor]]-mediated mechanism, the phosphorylation of p44/p42 mitogen-activated protein kinase activation in bovine aortic endothelial cell cultures.{{clarify|incomprehensible to lay readers|date=December 2018}}<ref name="pmid10710124">{{cite journal | vauthors = McDuffie JE, Motley ED, Limbird LE, Maleque MA | title = 5-hydroxytryptamine stimulates phosphorylation of p44/p42 mitogen-activated protein kinase activation in bovine aortic endothelial cell cultures | journal = Journal of Cardiovascular Pharmacology | volume = 35 | issue = 3 | pages = 398–402 | date = March 2000 | pmid = 10710124 | doi = 10.1097/00005344-200003000-00008 | doi-access = free }}</ref> 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.<ref>{{cite journal | vauthors = Noguchi M, Furukawa KT, Morimoto M | title = Pulmonary neuroendocrine cells: physiology, tissue homeostasis and disease | journal = Disease Models & Mechanisms | volume = 13 | issue = 12 | pages = dmm046920 | date = December 2020 | pmid = 33355253 | pmc = 7774893 | doi = 10.1242/dmm.046920 }}</ref>

====Adipose tissue====
Serotonin also regulates white and brown adipose tissue function, and adipocytes are capable of producing 5-HT separately from the gut. Serotonin increases lipogenesis through [[5-HT2A receptor|HTR2A]] in white adipose tissue, and suppressed thermogenesis in brown adipose tissue via Htr3.<ref>{{cite journal | vauthors = Oh CM, Namkung J, Go Y, Shong KE, Kim K, Kim H, Park BY, Lee HW, Jeon YH, Song J, Shong M, Yadav VK, Karsenty G, Kajimura S, Lee IK, Park S, Kim H | title = Regulation of systemic energy homeostasis by serotonin in adipose tissues | journal = Nature Communications | volume = 6 | pages = 6794 | date = April 2015 | pmid = 25864946 | doi = 10.1038/ncomms7794 | pmc = 4403443 | bibcode = 2015NatCo...6.6794O }}</ref>