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Gene Review

HTR1A  -  5-hydroxytryptamine (serotonin) receptor...

Homo sapiens

Synonyms: 5-HT-1A, 5-HT1A, 5-hydroxytryptamine receptor 1A, 5HT1a, ADRB2RL1, ...
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Disease relevance of HTR1A


Psychiatry related information on HTR1A


High impact information on HTR1A

  • We now report that the protein product of the genomic clone, G21, transiently expressed in monkey kidney cells has all the typical ligand-binding characteristics of the 5-hydroxytryptamine (5-HT1A) receptor [10].
  • We have previously described a genomic clone, G-21, isolated by cross-hybridization at reduced stringency with a full length beta 2-adrenergic receptor probe [10].
  • In addition, two mammalian genes have been identified that code for predicted gene products with sequence similarity to these receptors, but whose ligand specificity is unknown namely, G21 and the mas oncogene [11].
  • The treatment of patients with major depression using an SSRI and pindolol, a 5-HT1A/ beta-adrenoceptor antagonist, markedly reduced the latency of the antidepressant response in previously untreated patients and induced a rapid improvement in treatment-resistant patients [12].
  • At clinically relevant doses, selective serotonin (5-HT) reuptake inhibitors (SSRIs) and MAO inhibitors (MAOIs) increase the extracellular concentration of 5-HT in the midbrain raphé nuclei, thereby activating inhibitory somatodendritic 5-HT1A autoreceptors [12].

Chemical compound and disease context of HTR1A


Biological context of HTR1A

  • Significant haplotype associations were found in all but the HTR1A and HTR2C genes [18].
  • To increase the informativeness of the HTR1A locus we have isolated two new cosmid clones containing the receptor gene [19].
  • The pro16leu HTR1A polymorphism was not observed in our sample; all individuals genotyped were pro/pro 16 homozygotes [20].
  • Patients were genotyped for HTR1A gene and, in addition, for two polymorphisms at the CYP2C19 gene, which together account for the 87% of the Caucasian poor metabolizer phenotype [21].
  • 4. Using a metabolic pathway approach, it can be shown that the best current candidate gene locus for a subtype of schizophrenia located on chromosome 5q11-13 (HGML10 # SCZD1 and OMIM #181510) is in the serotonergic pathway, i.e. a receptor for 5-hydroxytryptamine (subtype 1A; HGML10 #HTR1A) which also maps in the same chromosomal region [22].

Anatomical context of HTR1A

  • Thus it is postulated that one mechanism, among others, through which exogenous thyroid hormones may exert their modulatory effects in affective illness is via an increase in serotonergic neurotransmission, specifically by reducing the sensitivity of 5-HT1A autoreceptors in the raphe area, and by increasing 5-HT2 receptor sensitivity [23].
  • The effects of dopamine (DA) on the function of human 5-HT1A receptors expressed in Xenopus oocytes and CHO-K1 cells were investigated [24].
  • RBI-257 had much lower affinity at D1 and D5 dopamine receptors in transfected cells, as well as dopamine D1-like receptors, alpha1, alpha2 or beta(1,2) adrenoceptors, sigma(1,2) receptors and 5-HT1A or 5-HT2A receptors, and transporters for dopamine, norepinephrine or serotonin in rat forebrain tissue [25].
  • These results are compatible with the hypothesis that the MRN-dorsal hippocampus 5-HT system attenuates stress by facilitation of hippocampal 5-HT1A-mediated neurotransmission [26].
  • NUDR protein was colocalized with 5-HT1A receptors in serotonergic raphe cells, hippocampal and cortical neurons, and adult brain regions including raphe nuclei, indicating a role in regulating 5-HT1A autoreceptor expression [27].

Associations of HTR1A with chemical compounds

  • In the context of a long-term follow-up study, we analysed the possible implication of the 5-HT(1A) receptor gene (HTR1A) -1018C/G polymorphism in the clinical outcome of major depressive patients treated with citalopram [21].
  • Our results demonstrated that the HTR1A -1019C/C carriers (P=0.009) and SERTPR l/l carriers (P<0.001) showed a better response to fluoxetine, while other polymorphisms were not associated with fluoxetine therapeutic response [28].
  • No evidence for cocaine-induced changes in 5-HT1A autoreceptor responsiveness was found [29].
  • 5-carboxamidotryptamine (5-HT1A/B/D) and sumatriptan (5-HT1D selective) were essentially inactive [30].
  • Ziprasidone also exhibits potent interaction with 5-HT2C, 5-HT1D, and 5-HT1A receptors in human brain tissue, characteristics that predict heightened negative symptom relief, enhanced modulation of mood, cognitive improvement, and reduced motor dysfunction [31].

Physical interactions of HTR1A

  • Molecular dynamics (MD) simulations of ligand-receptor complexes were performed for each investigated analogue, docked twice into the central cavity of 5-HT1A/5-HT2A, each time in a different orientation [32].
  • With the exception of the hypoglossal nucleus, where 5-HT1A receptor binding increases while SERT binding remains stable, the medullary 5-HT markers analyzed in the study are essentially "in place" at birth [33].
  • Limbic reductions of 5-HT1A receptor binding in human temporal lobe epilepsy [34].
  • In view of evidence that 5HT2A and 5HT2C sites functionally interact with 5HT1A receptors, we also examined the influence of these agents upon the actions of S 15535, but no significant alteration was seen in its enhancement of rhythms [35].
  • Sequence alignment of several G protein-coupled receptors identified a highly conserved threonine residue in the i2 loop of the 5-hydroxytryptamine 1A (5-HT1A) receptor that is a putative protein kinase C phosphorylation consensus site and is located in a predicted amphipathic alpha-helical domain [36].

Co-localisations of HTR1A

  • We propose that the spectral data following the lower ipsapirone dose reflect a net decrease of neuronal activity at 5-HT2 receptors, mediated through stimulation of somatodendritic autoreceptors in the raphe nuclei (presynaptic) and/or through stimulation of postsynaptic 5-HT1A receptors colocalized with 5-HT2 receptors [37].

Regulatory relationships of HTR1A

  • The 5-HT1A receptor gene is repressed by NUDR/DEAF-1 in raphe cells at the C-, but not at the G-allele of the C(-1019)G polymorphism that is associated with major depression and suicide [38].
  • All mixed serotonin- and 5-HT1A-receptor agonists suppressed GH secretion in 10-day-old pups [39].
  • These data imply that chronic cannabinoid treatment may up-regulate 5-HT2A receptor activity while concurrently down-regulating 5-HT1A receptor activity, a finding similar to that sometimes observed in depression [40].
  • The intrinsic activity of the compounds was evaluated by measuring their effect on VIP-stimulated cAMP production in GH4ZD10 cells stably transfected with the 5-HT1A receptor [41].
  • Based on these findings, we conclude that NMDAR-dependent LTP is specifically inhibited by coactivation of 5-HT1A and 5-HT2 receptors with the increase in 5-HT levels in the rat visual cortex at the end of the critical period [42].

Other interactions of HTR1A

  • Similar studies on human cloned receptors confirmed that xanomeline is an agonist at human cloned 5-HT1A and 5-HT1B receptors [43].
  • This study examined the hypothesis that genetic variation in 5-HT1A, 5-HT6, and 5-HT7 receptor genes is involved in the variability observed in response to clozapine [20].
  • However, a combined genetic effect of HTR1A and SLC6A4 genes was found to influence the clinical outcome of patients [F(4,102) = 2.89, p= 0.02] [21].
  • Aripiprazole, the most recently introduced atypical APD, and a D2 receptor partial agonist, may also owe some of its atypical properties to its net effect of weak D2 antagonism, 5-HT2A antagonism and 5-HT1A agonism [Eur. J. Pharmacol. 441 (2002) 137] [44].
  • The preferential 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetraline (up to 0.3 microM) and the selective 5-HT4 receptor agonist cisapride (up to 1 microM) failed to inhibit tritium overflow [45].

Analytical, diagnostic and therapeutic context of HTR1A


  1. Lack of association between neuroleptic malignant syndrome and polymorphisms in the 5-HT1A and 5-HT2A receptor genes. Kawanishi, C., Hanihara, T., Shimoda, Y., Suzuki, K., Sugiyama, N., Onishi, H., Miyakawa, T., Yamada, Y., Kosaka, K. The American journal of psychiatry. (1998) [Pubmed]
  2. Expression and modulation of 5-hydroxytryptamine1A receptors in P11 cells. Hensler, J.G., Cervera, L.S., Miller, H.A., Corbitt, J. J. Pharmacol. Exp. Ther. (1996) [Pubmed]
  3. Evaluation of the ocular hypotensive response of serotonin 5-HT1A and 5-HT2 receptor ligands in conscious ocular hypertensive cynomolgus monkeys. May, J.A., McLaughlin, M.A., Sharif, N.A., Hellberg, M.R., Dean, T.R. J. Pharmacol. Exp. Ther. (2003) [Pubmed]
  4. Vagal control of the heart: central serotonergic (5-HT) mechanisms. Jordan, D. Exp. Physiol. (2005) [Pubmed]
  5. Comparison of G-protein selectivity of human 5-HT2C and 5-HT1A receptors. Okada, M., Goldman, D., Linnoila, M., Iwata, N., Ozaki, N., Northup, J.K. Ann. N. Y. Acad. Sci. (2004) [Pubmed]
  6. Human 5-HT1A receptor C(-1019)G polymorphism and psychopathology. Huang, Y.Y., Battistuzzi, C., Oquendo, M.A., Harkavy-Friedman, J., Greenhill, L., Zalsman, G., Brodsky, B., Arango, V., Brent, D.A., Mann, J.J. Int. J. Neuropsychopharmacol. (2004) [Pubmed]
  7. Biochemical profile of YM992, a novel selective serotonin reuptake inhibitor with 5-HT2A receptor antagonistic activity. Hatanaka, K., Nomura, T., Hidaka, K., Takeuchi, H., Yatsugi, S., Fujii, M., Yamaguchi, T. Neuropharmacology (1996) [Pubmed]
  8. Putative mechanisms of action of antidepressant drugs in affective and anxiety disorders and pain. Blier, P., Abbott, F.V. Journal of psychiatry & neuroscience : JPN. (2001) [Pubmed]
  9. The C(-1019)G polymorphism of the 5-HT1A gene promoter and antidepressant response in mood disorders: preliminary findings. Serretti, A., Artioli, P., Lorenzi, C., Pirovano, A., Tubazio, V., Zanardi, R. Int. J. Neuropsychopharmacol. (2004) [Pubmed]
  10. The genomic clone G-21 which resembles a beta-adrenergic receptor sequence encodes the 5-HT1A receptor. Fargin, A., Raymond, J.R., Lohse, M.J., Kobilka, B.K., Caron, M.G., Lefkowitz, R.J. Nature (1988) [Pubmed]
  11. The mas oncogene encodes an angiotensin receptor. Jackson, T.R., Blair, L.A., Marshall, J., Goedert, M., Hanley, M.R. Nature (1988) [Pubmed]
  12. Acceleration of the effect of selected antidepressant drugs in major depression by 5-HT1A antagonists. Artigas, F., Romero, L., de Montigny, C., Blier, P. Trends Neurosci. (1996) [Pubmed]
  13. Positive association between panic disorder and polymorphism of the serotonin 2A receptor gene. Inada, Y., Yoneda, H., Koh, J., Sakai, J., Himei, A., Kinoshita, Y., Akabame, K., Hiraoka, Y., Sakai, T. Psychiatry research. (2003) [Pubmed]
  14. Site-selective serotonin agonists as discriminative stimuli. Glennon, R.A. Psychopharmacology series. (1988) [Pubmed]
  15. Effect of ergotamine on serotonin-mediated responses in the rodent and human brain. Haddjeri, N., Seletti, B., Gilbert, F., de Montigny, C., Blier, P. Neuropsychopharmacology (1998) [Pubmed]
  16. Decreased neuroendocrine responses to meta-chlorophenylpiperazine (m-CPP) but normal responses to ipsapirone in marathon runners. Broocks, A., Meyer, T., George, A., Hillmer-Vogel, U., Meyer, D., Bandelow, B., Hajak, G., Bartmann, U., Gleiter, C.H., Rüther, E. Neuropsychopharmacology (1999) [Pubmed]
  17. Serotonin-1A receptor gene HTR1A variation predicts interferon-induced depression in chronic hepatitis C. Kraus, M.R., Al-Taie, O., Schäfer, A., Pfersdorff, M., Lesch, K.P., Scheurlen, M. Gastroenterology (2007) [Pubmed]
  18. Investigation of serotonin-related genes in antidepressant response. Peters, E.J., Slager, S.L., McGrath, P.J., Knowles, J.A., Hamilton, S.P. Mol. Psychiatry (2004) [Pubmed]
  19. A cosmid clone for the 5HT1A receptor (HTR1A) reveals a TaqI RFLP that shows tight linkage to dna loci D5S6, D5S39, and D5S76. Melmer, G., Sherrington, R., Mankoo, B., Kalsi, G., Curtis, D., Gurling, H.M. Genomics (1991) [Pubmed]
  20. Lack of association between the T-->C 267 serotonin 5-HT6 receptor gene (HTR6) polymorphism and prediction of response to clozapine in schizophrenia. Masellis, M., Basile, V.S., Meltzer, H.Y., Lieberman, J.A., Sevy, S., Goldman, D.A., Hamblin, M.W., Macciardi, F.M., Kennedy, J.L. Schizophr. Res. (2001) [Pubmed]
  21. Evidence for a combined genetic effect of the 5-HT(1A) receptor and serotonin transporter genes in the clinical outcome of major depressive patients treated with citalopram. Arias, B., Catalán, R., Gastó, C., Gutiérrez, B., Fañanás, L. J. Psychopharmacol. (Oxford) (2005) [Pubmed]
  22. Integrated genetic databases in the study of neuropsychiatric diseases: inborn errors of cerebral metabolic pathways? Jaworski, M., Edwards, E. Prog. Neuropsychopharmacol. Biol. Psychiatry (1991) [Pubmed]
  23. Thyroid hormones, serotonin and mood: of synergy and significance in the adult brain. Bauer, M., Heinz, A., Whybrow, P.C. Mol. Psychiatry (2002) [Pubmed]
  24. Direct activation by dopamine of recombinant human 5-HT1A receptors: comparison with human 5-HT2C and 5-HT3 receptors. Oz, M., Zhang, L., Rotondo, A., Sun, H., Morales, M. Synapse (2003) [Pubmed]
  25. RBI-257: a highly potent dopamine D4 receptor-selective ligand. Kula, N.S., Baldessarini, R.J., Kebabian, J.W., Bakthavachalam, V., Xu, L. Eur. J. Pharmacol. (1997) [Pubmed]
  26. Role of 5-HT in stress, anxiety, and depression. Graeff, F.G., Guimarães, F.S., De Andrade, T.G., Deakin, J.F. Pharmacol. Biochem. Behav. (1996) [Pubmed]
  27. Impaired repression at a 5-hydroxytryptamine 1A receptor gene polymorphism associated with major depression and suicide. Lemonde, S., Turecki, G., Bakish, D., Du, L., Hrdina, P.D., Bown, C.D., Sequeira, A., Kushwaha, N., Morris, S.J., Basak, A., Ou, X.M., Albert, P.R. J. Neurosci. (2003) [Pubmed]
  28. Response to fluoxetine and serotonin 1A receptor (C-1019G) polymorphism in Taiwan Chinese major depressive disorder. Hong, C.J., Chen, T.J., Yu, Y.W., Tsai, S.J. Pharmacogenomics J. (2006) [Pubmed]
  29. Alterations in serotonergic responsiveness during cocaine withdrawal in rats: similarities to major depression in humans. Baumann, M.H., Rothman, R.B. Biol. Psychiatry (1998) [Pubmed]
  30. 5-Hydroxytryptamine facilitates cholinergic bronchoconstriction in human and guinea pig airways. Takahashi, T., Ward, J.K., Tadjkarimi, S., Yacoub, M.H., Barnes, P.J., Belvisi, M.G. Am. J. Respir. Crit. Care Med. (1995) [Pubmed]
  31. The psychopharmacology of ziprasidone: receptor-binding properties and real-world psychiatric practice. Stahl, S.M., Shayegan, D.K. The Journal of clinical psychiatry. (2003) [Pubmed]
  32. Molecular dynamics of 5-HT1A and 5-HT2A serotonin receptors with methylated buspirone analogues. Bronowska, A., Chilmonczyk, Z., Leś, A., Edvardsen, O., Ostensen, R., Sylte, I. J. Comput. Aided Mol. Des. (2001) [Pubmed]
  33. Differential development of 5-HT receptor and the serotonin transporter binding in the human infant medulla. Paterson, D.S., Belliveau, R.A., Trachtenberg, F., Kinney, H.C. J. Comp. Neurol. (2004) [Pubmed]
  34. Limbic reductions of 5-HT1A receptor binding in human temporal lobe epilepsy. Savic, I., Lindström, P., Gulyás, B., Halldin, C., Andrée, B., Farde, L. Neurology (2004) [Pubmed]
  35. Serotonin1A autoreceptor activation by S 15535 enhances circadian activity rhythms in hamsters: evaluation of potential interactions with serotonin2A and serotonin2C receptors. Gannon, R.L., Millan, M.J. Neuroscience (2006) [Pubmed]
  36. A conserved threonine residue in the second intracellular loop of the 5-hydroxytryptamine 1A receptor directs signaling specificity. Lembo, P.M., Ghahremani, M.H., Morris, S.J., Albert, P.R. Mol. Pharmacol. (1997) [Pubmed]
  37. The 5-HT1A agonist ipsapirone enhances EEG slow wave activity in human sleep and produces a power spectrum similar to 5-HT2 blockade. Seifritz, E., Moore, P., Trachsel, L., Bhatti, T., Stahl, S.M., Gillin, J.C. Neurosci. Lett. (1996) [Pubmed]
  38. Association of the C(-1019)G 5-HT1A functional promoter polymorphism with antidepressant response. Lemonde, S., Du, L., Bakish, D., Hrdina, P., Albert, P.R. Int. J. Neuropsychopharmacol. (2004) [Pubmed]
  39. Inhibition of GH in maternal separation may be mediated through altered serotonergic activity at 5-HT2A and 5-HT2C receptors. Katz, L.M., Nathan, L., Kuhn, C.M., Schanberg, S.M. Psychoneuroendocrinology (1996) [Pubmed]
  40. Altered responsiveness of serotonin receptor subtypes following long-term cannabinoid treatment. Hill, M.N., Sun, J.C., Tse, M.T., Gorzalka, B.B. Int. J. Neuropsychopharmacol. (2006) [Pubmed]
  41. Synthesis of novel 5-substituted 3-amino-3,4-dihydro-2H-1-benzopyran derivatives and their interactions with the 5-HT1A receptor. Hammarberg, E., Nordvall, G., Leideborg, R., Nylöf, M., Hanson, S., Johansson, L., Thorberg, S.O., Tolf, B.R., Jerning, E., Svantesson, G.T., Mohell, N., Ahlgren, C., Westlind-Danielsson, A., Csöregh, I., Johansson, R. J. Med. Chem. (2000) [Pubmed]
  42. Serotonin inhibits the induction of NMDA receptor-dependent long-term potentiation in the rat primary visual cortex. Kim, H.S., Jang, H.J., Cho, K.H., Hahn, S.J., Kim, M.J., Yoon, S.H., Jo, Y.H., Kim, M.S., Rhie, D.J. Brain Res. (2006) [Pubmed]
  43. Functional effects of the muscarinic receptor agonist, xanomeline, at 5-HT1 and 5-HT2 receptors. Watson, J., Brough, S., Coldwell, M.C., Gager, T., Ho, M., Hunter, A.J., Jerman, J., Middlemiss, D.N., Riley, G.J., Brown, A.M. Br. J. Pharmacol. (1998) [Pubmed]
  44. Serotonin receptors: their key role in drugs to treat schizophrenia. Meltzer, H.Y., Li, Z., Kaneda, Y., Ichikawa, J. Prog. Neuropsychopharmacol. Biol. Psychiatry (2003) [Pubmed]
  45. Inhibition of noradrenaline release via presynaptic 5-HT1D alpha receptors in human atrium. Molderings, G.J., Frölich, D., Likungu, J., Göthert, M. Naunyn Schmiedebergs Arch. Pharmacol. (1996) [Pubmed]
  46. 5HT1A receptors and pharmacotherapy. Is serotonin receptor down-regulation linked to the mechanism of action of antidepressant drugs? Stahl, S. Psychopharmacology bulletin. (1994) [Pubmed]
  47. Regional heterogeneity of 5-HT1A receptors in human cerebellum as assessed by positron emission tomography. Parsey, R.V., Arango, V., Olvet, D.M., Oquendo, M.A., Van Heertum, R.L., John Mann, J. J. Cereb. Blood Flow Metab. (2005) [Pubmed]
  48. Identification of serotonin receptors recognized by anti-idiotypic antibodies. Tamir, H., Liu, K.P., Hsiung, S.C., Yu, P.Y., Kirchgessner, A.L., Gershon, M.D. J. Neurochem. (1991) [Pubmed]
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