TPH2 explained

Tryptophan hydroxylase 2 (TPH2) is an isozyme of tryptophan hydroxylase found in vertebrates. In humans, TPH2 is primarily expressed in the serotonergic neurons of the brain, with the highest expression in the raphe nucleus of the midbrain. Until the discovery of TPH2 in 2003,^[1] 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.^[2]

Function

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]^[3]

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^[4]). 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.^[5] Drugs such as MDMA^[6] and methamphetamine^[7] 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".^[8]

See also

• Tryptophan hydroxylase
• TPH1

Further reading

• Walther DJ, Peter JU, Bashammakh S, Hörtnagl H, Voits M, Fink H, Bader M . Synthesis of serotonin by a second tryptophan hydroxylase isoform . Science . 299 . 5603 . 76 . January 2003 . 12511643 . 10.1126/science.1078197 . 7095712 .
• Walther DJ, Bader M . A unique central tryptophan hydroxylase isoform . Biochemical Pharmacology . 66 . 9 . 1673–1680 . November 2003 . 14563478 . 10.1016/S0006-2952(03)00556-2 .
• Zill P, Baghai TC, Zwanzger P, Schüle C, Eser D, Rupprecht R, Möller HJ, Bondy B, Ackenheil M . 6 . SNP and haplotype analysis of a novel tryptophan hydroxylase isoform (TPH2) gene provide evidence for association with major depression . Molecular Psychiatry . 9 . 11 . 1030–1036 . November 2004 . 15124006 . 10.1038/sj.mp.4001525 . free .
• Breidenthal SE, White DJ, Glatt CE . Identification of genetic variants in the neuronal form of tryptophan hydroxylase (TPH2) . Psychiatric Genetics . 14 . 2 . 69–72 . June 2004 . 15167691 . 10.1097/01.ypg.0000107929.32051.58 . 21842482 .
• De Luca V, Mueller DJ, Tharmalingam S, King N, Kennedy JL . Analysis of the novel TPH2 gene in bipolar disorder and suicidality . Molecular Psychiatry . 9 . 10 . 896–897 . October 2004 . 15197398 . 10.1038/sj.mp.4001531 . free .
• Harvey M, Shink E, Tremblay M, Gagné B, Raymond C, Labbé M, Walther DJ, Bader M, Barden N . 6 . Support for the involvement of TPH2 gene in affective disorders . Molecular Psychiatry . 9 . 11 . 980–981 . November 2004 . 15263906 . 10.1038/sj.mp.4001557 . free .
• Zill P, Büttner A, Eisenmenger W, Möller HJ, Bondy B, Ackenheil M . Single nucleotide polymorphism and haplotype analysis of a novel tryptophan hydroxylase isoform (TPH2) gene in suicide victims . Biological Psychiatry . 56 . 8 . 581–586 . October 2004 . 15476687 . 10.1016/j.biopsych.2004.07.015 . 24630985 .
• Zhang X, Gainetdinov RR, Beaulieu JM, Sotnikova TD, Burch LH, Williams RB, Schwartz DA, Krishnan KR, Caron MG . 6 . Loss-of-function mutation in tryptophan hydroxylase-2 identified in unipolar major depression . Neuron . 45 . 1 . 11–16 . January 2005 . 15629698 . 10.1016/j.neuron.2004.12.014 . 15865069 . free .
• Coon H, Dunn D, Lainhart J, Miller J, Hamil C, Battaglia A, Tancredi R, Leppert MF, Weiss R, McMahon W . 6 . 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 . May 2005 . 15768392 . 10.1002/ajmg.b.30168 . 32184220 .
• Sheehan K, Lowe N, Kirley A, Mullins C, Fitzgerald M, Gill M, Hawi Z . Tryptophan hydroxylase 2 (TPH2) gene variants associated with ADHD . Molecular Psychiatry . 10 . 10 . 944–949 . October 2005 . 15940290 . 10.1038/sj.mp.4001698 . 2460069 .
• Shamir A, Shaltiel G, Levi I, Belmaker RH, Agam G . 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 . 2005 . 15968084 . 10.1385/JMN:26:1:033 . 20701904 .
• Brown SM, Peet E, Manuck SB, Williamson DE, Dahl RE, Ferrell RE, Hariri AR . A regulatory variant of the human tryptophan hydroxylase-2 gene biases amygdala reactivity . Molecular Psychiatry . 10 . 9 . 884–8, 805 . September 2005 . 16044172 . 10.1038/sj.mp.4001716 . free .
• Walitza S, Renner TJ, Dempfle A, Konrad K, Wewetzer C, Halbach A, Herpertz-Dahlmann B, Remschmidt H, Smidt J, Linder M, Flierl L, Knölker U, Friedel S, Schäfer H, Gross C, Hebebrand J, Warnke A, Lesch KP . 6 . Transmission disequilibrium of polymorphic variants in the tryptophan hydroxylase-2 gene in attention-deficit/hyperactivity disorder . Molecular Psychiatry . 10 . 12 . 1126–1132 . December 2005 . 16116490 . 10.1038/sj.mp.4001734 . free .
• Canli T, Congdon E, Gutknecht L, Constable RT, Lesch KP . Amygdala responsiveness is modulated by tryptophan hydroxylase-2 gene variation . Journal of Neural Transmission . 112 . 11 . 1479–1485 . November 2005 . 16245070 . 10.1007/s00702-005-0391-4 . 24755144 .
• Mössner R, Freitag CM, Gutknecht L, Reif A, Tauber R, Franke P, Fritze J, Wagner G, Peikert G, Wenda B, Sand P, Rietschel M, Garritsen H, Jacob C, Lesch KP, Deckert J . 6 . The novel brain-specific tryptophan hydroxylase-2 gene in panic disorder . Journal of Psychopharmacology . 20 . 4 . 547–552 . July 2006 . 16401665 . 10.1177/0269881106059704 . 20360040 .
• De Luca V, Hlousek D, Likhodi O, Van Tol HH, Kennedy JL, Wong AH . The interaction between TPH2 promoter haplotypes and clinical-demographic risk factors in suicide victims with major psychoses . Genes, Brain and Behavior . 5 . 1 . 107–110 . February 2006 . 16436194 . 10.1111/j.1601-183X.2005.00182.x . 1739158 . free .
• Delorme R, Durand CM, Betancur C, Wagner M, Ruhrmann S, Grabe HJ, Nygren G, Gillberg C, Leboyer M, Bourgeron T, Courtet P, Jollant F, Buresi C, Aubry JM, Baud P, Bondolfi G, Bertschy G, Perroud N, Malafosse A . 6 . No human tryptophan hydroxylase-2 gene R441H mutation in a large cohort of psychiatric patients and control subjects . Biological Psychiatry . 60 . 2 . 202–203 . July 2006 . 16581035 . 10.1016/j.biopsych.2005.12.014 . 221881 .
• Carkaci-Salli N, Flanagan JM, Martz MK, Salli U, Walther DJ, Bader M, Vrana KE . Functional domains of human tryptophan hydroxylase 2 (hTPH2) . The Journal of Biological Chemistry . 281 . 38 . 28105–28112 . September 2006 . 16864580 . 10.1074/jbc.M602817200 . free . Kent Vrana .

Notes and References

1. Walther DJ, Peter JU, Bashammakh S, Hörtnagl H, Voits M, Fink H, Bader M . Synthesis of serotonin by a second tryptophan hydroxylase isoform . Science . 299 . 5603 . 76 . January 2003 . 12511643 . 10.1126/science.1078197 . 7095712 .
2. Zill P, Büttner A, Eisenmenger W, Möller HJ, Ackenheil M, Bondy B . 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 . 2005 . 16023677 . 10.1016/j.jpsychires.2005.05.004 .
3. Web site: Entrez Gene: TPH2 tryptophan hydroxylase 2.
4. Ferguson J, Henriksen S, Cohen H, Mitchell G, Barchas J, Dement W . "Hypersexuality" and behavioral changes in cats caused by administration of p-chlorophenylalanine . Science . 168 . 3930 . 499–501 . April 1970 . 5461688 . 10.1126/science.168.3930.499 . 1970Sci...168..499F . 16691506 .
5. Richard F, Sanne JL, Bourde O, Weissman D, Ehret M, Cash C, Maître M, Pujol JF . 6 . 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 . December 1990 . 2150773 . 10.1016/0006-8993(90)90006-w . 12214077 .
6. Bonkale WL, Austin MC . 3,4-Methylenedioxymethamphetamine induces differential regulation of tryptophan hydroxylase 2 protein and mRNA levels in the rat dorsal raphe nucleus . Neuroscience . 155 . 1 . 270–276 . July 2008 . 18515011 . 2505057 . 10.1016/j.neuroscience.2008.03.086 .
7. Hotchkiss AJ, Gibb JW . 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 . August 1980 . 6104722 .
8. Cremata VY, Koe BK . Clinical and biochemical effects of fenclonine: a serotonin depletor . Diseases of the Nervous System . 29 . 5 . Suppl:147–Suppl:152 . May 1968 . 5673619 . 2 July 2022 .