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Gene Review

HTR3A  -  5-hydroxytryptamine (serotonin) receptor...

Homo sapiens

Synonyms: 5-HT-3, 5-HT3-A, 5-HT3A, 5-HT3R, 5-hydroxytryptamine receptor 3, ...
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Disease relevance of HTR3A


Psychiatry related information on HTR3A


High impact information on HTR3A

  • The neurotransmitter serotonin (5-hydroxytryptamine or 5-HT) mediates rapid excitatory responses through ligand-gated channels (5-HT3 receptors) [11].
  • Transcripts of this subunit are co-expressed with the 5-HT3A subunit in the amygdala, caudate and hippocampus [11].
  • Thus, on the basis of these essential criteria for receptor characterisation and classification, there are at least three main groups or classes of 5-HT receptor: 5-HT1, 5-HT2, and 5-HT3 [12].
  • Serotonin receptor subtypes and neuropsychiatric diseases: focus on 5-HT1D and 5-HT3 receptor agents [13].
  • The fast-acting ligand-gated ion channels (LGICs) constitute a group that encompasses nicotinic ACh, 5-HT3, GABAA and glycine receptors [14].

Chemical compound and disease context of HTR3A

  • These 5-HT3- and 5-HT2C-antagonistic actions of cyamemazine can be involved, at least in part, in its beneficial therapeutic actions in anxiety disorders [9].
  • Antagonism of 5-HT3 receptors attenuated upper airway and cardiopulmonary reflex bradycardias; this is compatible with data showing that 5-HT3 receptors excite DVN and NTS neurones by a glutamate-dependent mechanism [15].
  • Since meal termination and satiety are mainly vagally mediated functions, since binge-eating and vomiting produce intense stimulation of vagal afferent fibres, and since ondansetron and other 5-HT3 antagonists decrease afferent vagal activity, the symptom improvement may result from a pharmacological correction of abnormal vagal neurotransmission [16].
  • CONCLUSIONS: Selective antagonism of 5-HT3 receptors suppresses the gastric component of phase-3 motor activity and simultaneously suppresses plasma motilin peaks [10].
  • Interactions between dopamine and 5-HT3 receptors suggest new treatments for psychosis and drug addiction [17].

Biological context of HTR3A

  • RESULTS: Two haplotype blocks each were revealed for HTR3A and HTR3B in Japanese samples [6].
  • BACKGROUND: Genetic variations in the serotonin receptor 3A (HTR3A) and 3B (HTR3B) genes, positioned in tandem on chromosome 11q23.2, have been shown to be associated with psychiatric disorders in samples of European ancestry [6].
  • CONCLUSIONS: Our results suggest an important role for HTR3B in major depression in women and also raise the possibility that previously proposed disease-associated SNPs in the HTR3A/B region in Caucasians are in linkage disequilibrium with haplotype block 2 of HTR3B in the Japanese [6].
  • A variant C178T in the regulatory region of the serotonin receptor gene HTR3A modulates neural activation in the human amygdala [18].
  • Association analysis showed similar allele and genotype distributions among clozapine responders and nonresponders.These results make unlikely the possibility that 5-HT3A and 5-HT3B receptor genes underlie variation in clinical response to clozapine [19].

Anatomical context of HTR3A


Associations of HTR3A with chemical compounds

  • A polymorphism in the serotonin receptor 3A (HTR3A) gene and its association with harm avoidance in women [23].
  • Paradoxically, from the results of studies performed on the closely related nicotinic acetylcholine receptor, the channel-lining M2 domain of the 5-HT3A subunit is predicted to enhance cation conduction, whereas that of the 5-HT3B subunit would not [24].
  • 5-HT3 (5-hydroxytryptamine type 3) receptors are cation-selective ion channels of the Cys-loop transmitter-gated ion channel superfamily [24].
  • Replacement of three arginine residues (R432, R436 and R440) unique to the HA stretch of the 5-HT3A subunit with the aligned residues (Q395, D399 and A403) of the 5-HT3B subunit increased the single-channel conductance 28-fold [24].
  • The 178C/C genotype of the HTR3A was associated with an antidepressant response (p = 0.022-0.042), and more significantly in paroxetine-treated patients (p = 0.002-0.042) [25].

Regulatory relationships of HTR3A

  • Acute and chronic role of 5-HT3 neuronal system on behavioral and neuroendocrine changes induced by intravenous cholecystokinin tetrapeptide administration in humans [26].
  • The present study was undertaken in order to establish the possible involvement of 5-HT3 serotonergic receptors in the control of basal and/or hypoglycemia-stimulated arginine vasopressin (AVP) and/or oxytocin (OT) secretion [27].
  • The 5-HT3-receptor antagonist ondansetron inhibited the plasma CGRP and adrenalin response to central hypovolaemia without influencing cardiovascular tolerance [28].
  • Using a saporin-substance P conjugate to produce site-specific neuronal ablation, we demonstrate that NK1-R expressing cells in the superficial dorsal horn are crucial for the generation of LTP-like changes in neuronal excitability in deep dorsal horn neurons and this is modulated by descending 5HT3-R-mediated facilitatory controls [29].
  • In conclusion, neither 5-HT3 nor 5-HT4 receptors tonically regulate ferret gut motility except that 5-HT3 receptors have a key role in the occurrence of migrating motor complex specifically in the stomach [30].

Other interactions of HTR3A

  • Serotonin receptor type 3 is a ligand-gated channel encoded by 2 different subunit genes, HTR3A and HTR3B [23].
  • We additionally found that HTR2A and HTR3A polymorphisms are associated with the efficacy, and the HTR2A polymorphism is also associated with adverse drug reactions [25].
  • The roles of 5-HT2C and 5-HT3 receptors in psychiatric disorders are less clear [31].
  • Moreover, hric3 totally abolished currents evoked by 5-HT3 serotonin receptors, whereas it barely modified alpha1 glycine receptor currents [32].
  • The gene structure of the human 5-HT3A receptor gene was analyzed by exon to exon polymerase chain reaction and subsequent sequencing [33].

Analytical, diagnostic and therapeutic context of HTR3A


  1. Mutational analysis of serotonin receptor genes: HTR3A and HTR3B in fibromyalgia patients. Frank, B., Niesler, B., Bondy, B., Späth, M., Pongratz, D.E., Ackenheil, M., Fischer, C., Rappold, G. Clin. Rheumatol. (2004) [Pubmed]
  2. Modulation of 5-HT3 receptor-mediated response and trafficking by activation of protein kinase C. Sun, H., Hu, X.Q., Moradel, E.M., Weight, F.F., Zhang, L. J. Biol. Chem. (2003) [Pubmed]
  3. Investigation of the association between 5-HT3A receptor gene polymorphisms and efficiency of antiemetic treatment with 5-HT3 receptor antagonists. Kaiser, R., Tremblay, P.B., Sezer, O., Possinger, K., Roots, I., Brockmöller, J. Pharmacogenetics (2004) [Pubmed]
  4. Serotonin receptor physiology: relation to emesis. Hasler, W.L. Dig. Dis. Sci. (1999) [Pubmed]
  5. The medical benefit of 5-HT research. Jones, B.J., Blackburn, T.P. Pharmacol. Biochem. Behav. (2002) [Pubmed]
  6. Distinguishable haplotype blocks in the HTR3A and HTR3B region in the Japanese reveal evidence of association of HTR3B with female major depression. Yamada, K., Hattori, E., Iwayama, Y., Ohnishi, T., Ohba, H., Toyota, T., Takao, H., Minabe, Y., Nakatani, N., Higuchi, T., Detera-Wadleigh, S.D., Yoshikawa, T. Biol. Psychiatry (2006) [Pubmed]
  7. Serotonin receptor genes HTR3A and HTR3B are not involved in Gilles de la Tourette syndrome. Niesler, B., Frank, B., Hebebrand, J., Rappold, G. Psychiatr. Genet. (2005) [Pubmed]
  8. Association between the 5' UTR variant C178T of the serotonin receptor gene HTR3A and bipolar affective disorder. Niesler, B., Flohr, T., Nöthen, M.M., Fischer, C., Rietschel, M., Franzek, E., Albus, M., Propping, P., Rappold, G.A. Pharmacogenetics (2001) [Pubmed]
  9. 5-HT3- and 5-HT2C-antagonist properties of cyamemazine: significance for its clinical anxiolytic activity. Alvarez-Guerra, M., d'Alché-Birée, F., Wolf, W.A., Vargas, F., Dib, M., Garay, R.P. Psychopharmacology (Berl.) (2000) [Pubmed]
  10. 5-hydroxytryptamine-3 receptors are involved in the initiation of gastric phase-3 motor activity in humans. Wilmer, A., Tack, J., Coremans, G., Janssens, J., Peeters, T., Vantrappen, G. Gastroenterology (1993) [Pubmed]
  11. The 5-HT3B subunit is a major determinant of serotonin-receptor function. Davies, P.A., Pistis, M., Hanna, M.C., Peters, J.A., Lambert, J.J., Hales, T.G., Kirkness, E.F. Nature (1999) [Pubmed]
  12. International Union of Pharmacology classification of receptors for 5-hydroxytryptamine (Serotonin). Hoyer, D., Clarke, D.E., Fozard, J.R., Hartig, P.R., Martin, G.R., Mylecharane, E.J., Saxena, P.R., Humphrey, P.P. Pharmacol. Rev. (1994) [Pubmed]
  13. Serotonin receptor subtypes and neuropsychiatric diseases: focus on 5-HT1D and 5-HT3 receptor agents. Peroutka, S.J. Pharmacol. Rev. (1991) [Pubmed]
  14. Evolutionary history of the ligand-gated ion-channel superfamily of receptors. Ortells, M.O., Lunt, G.G. Trends Neurosci. (1995) [Pubmed]
  15. Vagal control of the heart: central serotonergic (5-HT) mechanisms. Jordan, D. Exp. Physiol. (2005) [Pubmed]
  16. Effect of decreasing afferent vagal activity with ondansetron on symptoms of bulimia nervosa: a randomised, double-blind trial. Faris, P.L., Kim, S.W., Meller, W.H., Goodale, R.L., Oakman, S.A., Hofbauer, R.D., Marshall, A.M., Daughters, R.S., Banerjee-Stevens, D., Eckert, E.D., Hartman, B.K. Lancet (2000) [Pubmed]
  17. Interactions between dopamine and 5-HT3 receptors suggest new treatments for psychosis and drug addiction. Tricklebank, M.D. Trends Pharmacol. Sci. (1989) [Pubmed]
  18. A variant C178T in the regulatory region of the serotonin receptor gene HTR3A modulates neural activation in the human amygdala. Iidaka, T., Ozaki, N., Matsumoto, A., Nogawa, J., Kinoshita, Y., Suzuki, T., Iwata, N., Yamamoto, Y., Okada, T., Sadato, N. J. Neurosci. (2005) [Pubmed]
  19. Novel mutations in 5-HT3A and 5-HT3B receptor genes not associated with clozapine response. Gutiérrez, B., Arranz, M.J., Huezo-Diaz, P., Dempster, D., Matthiasson, P., Travis, M., Munro, J., Osborne, S., Kerwin, R.W. Schizophr. Res. (2002) [Pubmed]
  20. Monoamine related functional gene variants and relationships to monoamine metabolite concentrations in CSF of healthy volunteers. Jönsson, E.G., Bah, J., Melke, J., Abou Jamra, R., Schumacher, J., Westberg, L., Ivo, R., Cichon, S., Propping, P., Nöthen, M.M., Eriksson, E., Sedvall, G.C. BMC psychiatry [electronic resource]. (2004) [Pubmed]
  21. Serotonin receptor subtype mRNA expression in human ocular tissues, determined by RT-PCR. Sharif, N.A., Senchyna, M. Mol. Vis. (2006) [Pubmed]
  22. Serotonin excites neurons in the human submucous plexus via 5-HT3 receptors. Michel, K., Zeller, F., Langer, R., Nekarda, H., Kruger, D., Dover, T.J., Brady, C.A., Barnes, N.M., Schemann, M. Gastroenterology (2005) [Pubmed]
  23. A polymorphism in the serotonin receptor 3A (HTR3A) gene and its association with harm avoidance in women. Melke, J., Westberg, L., Nilsson, S., Landen, M., Soderstrom, H., Baghaei, F., Rosmond, R., Holm, G., Björntorp, P., Nilsson, L.G., Adolfsson, R., Eriksson, E. Arch. Gen. Psychiatry (2003) [Pubmed]
  24. The 5-hydroxytryptamine type 3 (5-HT3) receptor reveals a novel determinant of single-channel conductance. Peters, J.A., Kelley, S.P., Dunlop, J.I., Kirkness, E.F., Hales, T.G., Lambert, J.J. Biochem. Soc. Trans. (2004) [Pubmed]
  25. Effects of the serotonin type 2A, 3A and 3B receptor and the serotonin transporter genes on paroxetine and fluvoxamine efficacy and adverse drug reactions in depressed Japanese patients. Kato, M., Fukuda, T., Wakeno, M., Fukuda, K., Okugawa, G., Ikenaga, Y., Yamashita, M., Takekita, Y., Nobuhara, K., Azuma, J., Kinoshita, T. Neuropsychobiology (2006) [Pubmed]
  26. Acute and chronic role of 5-HT3 neuronal system on behavioral and neuroendocrine changes induced by intravenous cholecystokinin tetrapeptide administration in humans. Dépôt, M., Caillé, G., Mukherjee, J., Katzman, M.A., Cadieux, A., Bradwejn, J. Neuropsychopharmacology (1999) [Pubmed]
  27. 5-HT3 serotonergic receptor mediation of hypoglycemia-induced arginine-vasopressin but not oxytocin secretion in normal men. Volpi, R., Chiodera, P., Giuliani, N., Capretti, L., Caffarri, G., Magotti, M.G., Coiro, V. J. Endocrinol. Invest. (1998) [Pubmed]
  28. Neuroendocrine mechanisms during reversible hypovolaemic shock in humans with emphasis on the histaminergic and serotonergic system. Matzen, S.H. Acta physiologica Scandinavica. Supplementum. (1995) [Pubmed]
  29. Local and descending circuits regulate long-term potentiation and zif268 expression in spinal neurons. Rygh, L.J., Suzuki, R., Rahman, W., Wong, Y., Vonsy, J.L., Sandhu, H., Webber, M., Hunt, S., Dickenson, A.H. Eur. J. Neurosci. (2006) [Pubmed]
  30. The role of 5-hydroxytryptamine3 and 5-hydroxytryptamine4 receptors in the regulation of gut motility in the ferret. Nagakura, Y., Kiso, T., Ito, H., Miyata, K., Yamaguchi, T. Life Sci. (2000) [Pubmed]
  31. Phosphoinositide system-linked serotonin receptor subtypes and their pharmacological properties and clinical correlates. Pandey, S.C., Davis, J.M., Pandey, G.N. Journal of psychiatry & neuroscience : JPN. (1995) [Pubmed]
  32. Conservation within the RIC-3 gene family. Effectors of mammalian nicotinic acetylcholine receptor expression. Halevi, S., Yassin, L., Eshel, M., Sala, F., Sala, S., Criado, M., Treinin, M. J. Biol. Chem. (2003) [Pubmed]
  33. Exon-intron organization of the human 5-HT3A receptor gene. Brüss, M., Eucker, T., Göthert, M., Bönisch, H. Neuropharmacology (2000) [Pubmed]
  34. Cell surface expression of 5-hydroxytryptamine type 3 receptors is controlled by an endoplasmic reticulum retention signal. Boyd, G.W., Doward, A.I., Kirkness, E.F., Millar, N.S., Connolly, C.N. J. Biol. Chem. (2003) [Pubmed]
  35. Molecular cloning of human 5-hydroxytryptamine3 receptor: heterogeneity in distribution and function among species. Miyake, A., Mochizuki, S., Takemoto, Y., Akuzawa, S. Mol. Pharmacol. (1995) [Pubmed]
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