Tryptophan hydroxylase 2 (TPH2) is an isozyme of tryptophan hydroxylase found in vertebrates. In humans, TPH2 is primarily expressed in the serotonergicneurons of the brain, with the highest expression in the raphe nucleus of the midbrain. Until the discovery of TPH2 in 2003,[5]serotonin levels in the central nervous system were believed to be regulated by serotonin synthesis in peripheral tissues, in which tryptophan hydroxylase is the dominant form.[6]
Tryptophan hydroxylase (TPH; EC 1.14.16.4) is the rate-limiting enzyme in the synthesis of serotonin (5-hydroxytryptamine, or 5HT). 5HT is causally involved in numerous central nervous activities, and it has several functions in peripheral tissues, including the maintenance of vascular tone and gut motility.[supplied by OMIM][7]
Disabling this enzyme with drugs (especially p-chlorophenylalanine aka PCPA and Fenclonine) has allowed researchers to investigate the effects of very low serotonin levels on humans and others animals, and by extension, gain insights into the functions of serotonin systems more broadly (such as hypersexuality in rodents as well as increased aggression and hypersexuality cats following PCPA administration[8]). In rat brain, administration of a single PCPA injection resulted in the lowest level of serotonin production occurring on day 2 and returning to control values on day 7.[9] Drugs such as MDMA[10] and methamphetamine[11] have been shown to lower levels of this enzyme which may result in periods of low serotonin levels following drug use. In a study investigating the effects of Fenclonine on humans, the greatly lowered serotonin levels were associated with "fatigue, dizziness, nausea, uneasiness [anxiety], fullness in the head [a feeling of pressure in the head] paresthesias [a pricking, pins-and-needles, burning, and/or aching sensation--typically the limbs], headache, and constipation".[12]
^"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^Walther DJ, Peter JU, Bashammakh S, Hörtnagl H, Voits M, Fink H, Bader M (January 2003). "Synthesis of serotonin by a second tryptophan hydroxylase isoform". Science. 299 (5603): 76. doi:10.1126/science.1078197. PMID12511643. S2CID7095712.
^Zill P, Büttner A, Eisenmenger W, Möller HJ, Ackenheil M, Bondy B (2005). "Analysis of tryptophan hydroxylase I and II mRNA expression in the human brain: a post-mortem study". Journal of Psychiatric Research. 41 (1–2): 168–173. doi:10.1016/j.jpsychires.2005.05.004. PMID16023677.
^Richard F, Sanne JL, Bourde O, Weissman D, Ehret M, Cash C, et al. (December 1990). "Variation of tryptophan-5-hydroxylase concentration in the rat raphe dorsalis nucleus after p-chlorophenylalanine administration. I. A model to study the turnover of the enzymatic protein". Brain Research. 536 (1–2): 41–45. doi:10.1016/0006-8993(90)90006-w. PMID2150773. S2CID12214077.
^Hotchkiss AJ, Gibb JW (August 1980). "Long-term effects of multiple doses of methamphetamine on tryptophan hydroxylase and tyrosine hydroxylase activity in rat brain". The Journal of Pharmacology and Experimental Therapeutics. 214 (2): 257–262. PMID6104722.
Walther DJ, Peter JU, Bashammakh S, Hörtnagl H, Voits M, Fink H, Bader M (January 2003). "Synthesis of serotonin by a second tryptophan hydroxylase isoform". Science. 299 (5603): 76. doi:10.1126/science.1078197. PMID12511643. S2CID7095712.
Walther DJ, Bader M (November 2003). "A unique central tryptophan hydroxylase isoform". Biochemical Pharmacology. 66 (9): 1673–1680. doi:10.1016/S0006-2952(03)00556-2. PMID14563478.
Coon H, Dunn D, Lainhart J, Miller J, Hamil C, Battaglia A, et al. (May 2005). "Possible association between autism and variants in the brain-expressed tryptophan hydroxylase gene (TPH2)". American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics. 135B (1): 42–46. doi:10.1002/ajmg.b.30168. PMID15768392. S2CID32184220.
Sheehan K, Lowe N, Kirley A, Mullins C, Fitzgerald M, Gill M, Hawi Z (October 2005). "Tryptophan hydroxylase 2 (TPH2) gene variants associated with ADHD". Molecular Psychiatry. 10 (10): 944–949. doi:10.1038/sj.mp.4001698. PMID15940290. S2CID2460069.
Shamir A, Shaltiel G, Levi I, Belmaker RH, Agam G (2005). "Postmortem parietal cortex TPH2 expression is not altered in schizophrenic, unipolar-depressed, and bipolar patients vs control subjects". Journal of Molecular Neuroscience. 26 (1): 33–37. doi:10.1385/JMN:26:1:033. PMID15968084. S2CID20701904.
