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Gene Review

HTR1D  -  5-hydroxytryptamine (serotonin) receptor...

Homo sapiens

Synonyms: 5-HT-1D, 5-HT-1D-alpha, 5-HT1D, 5-hydroxytryptamine receptor 1D, HT1DA, ...
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Disease relevance of HTR1D


Psychiatry related information on HTR1D

  • Serotonergic and opioidergic neurotransmitter system alterations have been observed in people with eating disorders; the genes for the serotonin 1D receptor (HTR1D) and the opioid delta receptor (OPRD1) are found on chr1p36.3-34.3, a region identified by our group in a linkage analysis of anorexia nervosa (AN) [6].
  • It is concluded that a functional similarity exists between 5-HT1D and 5-HT1B receptors with regard to the modulation of sensorimotor inhibition and, to a lesser extent, locomotor activity [7].
  • The 5HT1D beta receptor gene had a substitution from GCA276 to GCG276, not only panic disorder but also in controls; however, this substitution does not change the corresponding amino acid, alanine92 [8].
  • To explore the role of serotonergic system in seasonal affective disorder (SAD), we compared growth hormone (GH) responses to a challenge with a novel 5-HT1D receptor agonist sumatriptan between 11 patients with SAD and nine healthy controls [9].
  • We report on 5-HT1A, 5-HT1D, and 5-HT2 binding sites in 23 control subjects and 18 suicide victims subdivided according to the method of death and the previous existence of depressive symptoms [10].

High impact information on HTR1D


Chemical compound and disease context of HTR1D


Biological context of HTR1D


Anatomical context of HTR1D

  • Expression of the human gene product in transfected cell lines results in the appearance of saturable high affinity 5-HT1D-type [3H]5-HT binding [22].
  • The receptor gene was isolated by hybridization to a probe based on a canine thyroid cDNA (called RDC4) previously isolated by others and believed to encode a heretofore undetermined member of the guanine nucleotide-binding protein (G protein)-linked receptor family [22].
  • Subclassification of presynaptic 5-HT autoreceptors in the human cerebral cortex as 5-HT1D receptors [23].
  • Preliminary evidence suggests that the canine basilar artery and saphenous vein, described as models for "5-HT1-like" receptors, could contain 5-HT1D receptors.(ABSTRACT TRUNCATED AT 400 WORDS)[24]
  • The distribution of 5-HT1B and 5-HT1D receptors in all species examined so far, is very similar: high concentrations of sites are found in the nigro-striatal pathway, caudate-putamen, globus pallidus and especially substantia nigra [24].

Associations of HTR1D with chemical compounds

  • These data suggest that polymorphisms in both the serotonin 1D (HTR1D) and opioid delta 1 (OPRD1) receptor genes show a significant association with restricting AN (RAN) [25].
  • Ketanserin at a concentration which should block the 5-HT 1D alpha but not the 5-HT 1D beta receptor failed to antagonize the inhibitory effect of 5-carboxamidotryptamine [23].
  • The K(+)-evoked tritium overflow, which was Ca(2+)-dependent but tetrodotoxin-resistant, was concentration-dependently inhibited by the nonselective 5-HT 1D alpha/1D beta receptor agonist, 5-carboxamidotryptamine [23].
  • 5-HT1D receptors show high to intermediate affinities to compounds such as PAPP, DP-5-CT, 8-OH-DPAT, yohimbine and rauwolscine, whereas 5-HT1B receptors have very low affinities for these compounds [24].
  • Metergoline and the selective 5-HT 1B/D receptor ligands GR 127935 as well as GR 125743 showed significant intrinsic activity (43% to 69%) at the 5-HT 1D receptor subtype, whereas the nonselective ligand 1-naphthylpiperazine yielded less (15% to 19%) intrinsic activity at both receptor subtypes [26].

Physical interactions of HTR1D


Regulatory relationships of HTR1D

  • Variable participation of 5-HT1-like receptors and 5-HT2 receptors in serotonin-induced contraction of human isolated coronary arteries. 5-HT1-like receptors resemble cloned 5-HT1D beta receptors [29].
  • In acute migraine treatment, their mechanisms of action involve constricting the pain-producing intracranial extracerebral blood vessels at the 5-HT1B receptors and inhibiting the trigeminal neurotransmission at the peripheral and central 5-HT1D receptors [30].
  • New developments defining the relationship between 5-hydroxytryptamine (5-HT; serotonin)1B and 5-HT1D receptors are reviewed and a novel pain control system involving spinal 5-HT3 receptors is described [31].

Other interactions of HTR1D

  • Genotype assay development and genotyping of nine SNPs (four at HTR1D and five at OPRD1) was performed on 191 unrelated individuals fulfilling DSM-IV criteria (w/o amenorrhea criterion) for AN, 442 relatives of AN probands and 98 psychiatrically screened controls [6].
  • The results indicate that human RDC1, RDC4, RDC7, and RDC8 are in regions 2q37, 1p34.3-1p36.3, 22q11.2-22q13.1, and 11q11-11q13, respectively [32].
  • 1. In the human temporal artery both 5-HT1-like and 5-HT2A receptors mediate the contractile effects of 5-hydroxytryptamine (5-HT) and we have suggested that the 5-HT1-like receptors resemble more closely recombinant 5-HT1B than 5-HT1D receptors [33].
  • Neural 5-HT1D and/or 5-HT1F receptors localized pre-junctionally on trigeminovascular afferents appear to mediate the triptan-induced inhibition of the neurogenic inflammatory response, with possible additional sites of action for brain penetrant 5-HT1 receptor agonists in inhibiting the transmission of pain centrally [34].
  • Options for acute treatment based on preclinical work and initial clinical studies include: serotonin 5HT1F and 5HT1D receptor agonists, glutamate excitatory amino acid receptor antagonists, nitric oxide synthase inhibitors and adenosine A1 receptor agonists [35].

Analytical, diagnostic and therapeutic context of HTR1D


  1. Expression of mRNA for the serotonin 5-hydroxytryptamine1D beta receptor subtype in human and bovine cerebral arteries. Hamel, E., Fan, E., Linville, D., Ting, V., Villemure, J.G., Chia, L.S. Mol. Pharmacol. (1993) [Pubmed]
  2. The selectivity of MDL 74,721 in models of neurogenic versus vascular components of migraine. Petty, M.A., Elands, J., Johnson, M.P., Linnik, M.D., Hamel, E., Moskowitz, M.A., Lee, W.S., McCarty, D.R., Hibert, M., Baron, B.M. Eur. J. Pharmacol. (1997) [Pubmed]
  3. Decreased sensitivity of 5-HT1D receptors in chronic tension-type headache. Rainero, I., Valfrè, W., Savi, L., Ferrero, M., Del Rizzo, P., Limone, P., Isaia, G.C., Gianotti, L., Pollo, A., Verde, R., Benedetti, F., Pinessi, L. Headache. (2002) [Pubmed]
  4. Is there a relationship between serotonin receptor subtypes and selectivity of response in specific psychiatric illnesses? Montgomery, S.A., Fineberg, N. The British journal of psychiatry. Supplement. (1989) [Pubmed]
  5. Psychoactivity and abuse potential of sumatriptan. Sullivan, J.T., Preston, K.L., Testa, M.P., Busch, M., Jasinski, D.R. Clin. Pharmacol. Ther. (1992) [Pubmed]
  6. Candidate genes for anorexia nervosa in the 1p33-36 linkage region: serotonin 1D and delta opioid receptor loci exhibit significant association to anorexia nervosa. Bergen, A.W., van den Bree, M.B., Yeager, M., Welch, R., Ganjei, J.K., Haque, K., Bacanu, S., Berrettini, W.H., Grice, D.E., Goldman, D., Bulik, C.M., Klump, K., Fichter, M., Halmi, K., Kaplan, A., Strober, M., Treasure, J., Woodside, B., Kaye, W.H. Mol. Psychiatry (2003) [Pubmed]
  7. Functional behavioral homology between rat 5-HT1B and guinea pig 5-HT1D receptors in the modulation of prepulse inhibition of startle. Sipes, T.E., Geyer, M.A. Psychopharmacology (Berl.) (1996) [Pubmed]
  8. The genes encoding the 5HT1D alpha and 5HT1D beta receptors are unchanged in patients with panic disorder. Ohara, K., Xie, D.W., Ishigaki, T., Deng, Z.L., Nakamura, Y., Suzuki, Y., Miyasato, K., Ohara, K. Biol. Psychiatry (1996) [Pubmed]
  9. Growth hormone response to sumatriptan (5-HT1D agonist) challenge in seasonal affective disorder: effects of light therapy. Yatham, L.N., Lam, R.W., Zis, A.P. Biol. Psychiatry (1997) [Pubmed]
  10. Brain 5-HT1A, 5-HT1D, and 5-HT2 receptors in suicide victims. Arranz, B., Eriksson, A., Mellerup, E., Plenge, P., Marcusson, J. Biol. Psychiatry (1994) [Pubmed]
  11. Serotonin receptor subtypes and neuropsychiatric diseases: focus on 5-HT1D and 5-HT3 receptor agents. Peroutka, S.J. Pharmacol. Rev. (1991) [Pubmed]
  12. Treatment of acute migraine with subcutaneous sumatriptan. Cady, R.K., Wendt, J.K., Kirchner, J.R., Sargent, J.D., Rothrock, J.F., Skaggs, H. JAMA (1991) [Pubmed]
  13. Migraine: a research field matured for the basic neurosciences. Olesen, J., Edvinsson, L. Trends Neurosci. (1991) [Pubmed]
  14. Alignment of receptor nomenclature with the human genome: classification of 5-HT1B and 5-HT1D receptor subtypes. Hartig, P.R., Hoyer, D., Humphrey, P.P., Martin, G.R. Trends Pharmacol. Sci. (1996) [Pubmed]
  15. Neurogenic versus vascular mechanisms of sumatriptan and ergot alkaloids in migraine. Moskowitz, M.A. Trends Pharmacol. Sci. (1992) [Pubmed]
  16. Agonistic properties of alniditan, sumatriptan and dihydroergotamine on human 5-HT1B and 5-HT1D receptors expressed in various mammalian cell lines. Lesage, A.S., Wouters, R., Van Gompel, P., Heylen, L., Vanhoenacker, P., Haegeman, G., Luyten, W.H., Leysen, J.E. Br. J. Pharmacol. (1998) [Pubmed]
  17. Rizatriptan, a novel 5-HT1B/1D agonist for migraine: single- and multiple-dose tolerability and pharmacokinetics in healthy subjects. Goldberg, M.R., Lee, Y., Vyas, K.P., Slaughter, D.E., Panebianco, D., Ermlich, S.J., Shadle, C.R., Brucker, M.J., McLoughlin, D.A., Olah, T.V. Journal of clinical pharmacology. (2000) [Pubmed]
  18. Characterisation of the 5-HT receptor binding profile of eletriptan and kinetics of [3H]eletriptan binding at human 5-HT1B and 5-HT1D receptors. Napier, C., Stewart, M., Melrose, H., Hopkins, B., McHarg, A., Wallis, R. Eur. J. Pharmacol. (1999) [Pubmed]
  19. 311C90, a new central and peripherally acting 5-HT1D receptor agonist in the acute oral treatment of migraine: a double-blind, placebo-controlled, dose-range finding study. Visser, W.H., Klein, K.B., Cox, R.C., Jones, D., Ferrari, M.D. Neurology (1996) [Pubmed]
  20. Differences in gene density on chicken macrochromosomes and microchromosomes. Smith, J., Bruley, C.K., Paton, I.R., Dunn, I., Jones, C.T., Windsor, D., Morrice, D.R., Law, A.S., Masabanda, J., Sazanov, A., Waddington, D., Fries, R., Burt, D.W. Anim. Genet. (2000) [Pubmed]
  21. Human serotonin 1D receptor is encoded by a subfamily of two distinct genes: 5-HT1D alpha and 5-HT1D beta. Weinshank, R.L., Zgombick, J.M., Macchi, M.J., Branchek, T.A., Hartig, P.R. Proc. Natl. Acad. Sci. U.S.A. (1992) [Pubmed]
  22. Primary structure and functional characterization of a human 5-HT1D-type serotonin receptor. Hamblin, M.W., Metcalf, M.A. Mol. Pharmacol. (1991) [Pubmed]
  23. Subclassification of presynaptic 5-HT autoreceptors in the human cerebral cortex as 5-HT1D receptors. Fink, K., Zentner, J., Göthert, M. Naunyn Schmiedebergs Arch. Pharmacol. (1995) [Pubmed]
  24. Serotonin 5-HT1D receptors. Hoyer, D., Schoeffter, P., Waeber, C., Palacios, J.M. Ann. N. Y. Acad. Sci. (1990) [Pubmed]
  25. Further Evidence of Association of OPRD1 & HTR1D Polymorphisms with Susceptibility to Anorexia Nervosa. Brown, K.M., Bujac, S.R., Mann, E.T., Campbell, D.A., Stubbins, M.J., Blundell, J.E. Biol. Psychiatry (2007) [Pubmed]
  26. 5-HT 1B/D receptor antagonists. Pauwels, P.J. Gen. Pharmacol. (1997) [Pubmed]
  27. Conversion of the human 5-HT1D beta serotonin receptor to the rat 5-HT1B ligand-binding phenotype by Thr355Asn site directed mutagenesis. Metcalf, M.A., McGuffin, R.W., Hamblin, M.W. Biochem. Pharmacol. (1992) [Pubmed]
  28. Identification of 5-hydroxytryptamine1D binding sites in sheep caudate nucleus membranes. Pauwels, P.J., Palmier, C., Briley, M. Biochem. Pharmacol. (1993) [Pubmed]
  29. Variable participation of 5-HT1-like receptors and 5-HT2 receptors in serotonin-induced contraction of human isolated coronary arteries. 5-HT1-like receptors resemble cloned 5-HT1D beta receptors. Kaumann, A.J., Frenken, M., Posival, H., Brown, A.M. Circulation (1994) [Pubmed]
  30. Ergotamine and dihydroergotamine: history, pharmacology, and efficacy. Silberstein, S.D., McCrory, D.C. Headache. (2003) [Pubmed]
  31. 5-HT in nervous system disease and migraine. Fozard, J.R., Kalkman, H.O. Current opinion in neurology and neurosurgery. (1992) [Pubmed]
  32. Chromosomal mapping of A1 and A2 adenosine receptors, VIP receptor, and a new subtype of serotonin receptor. Libert, F., Passage, E., Parmentier, M., Simons, M.J., Vassart, G., Mattei, M.G. Genomics (1991) [Pubmed]
  33. 5-HT1B receptor-mediated contractions in human temporal artery: evidence from selective antagonists and 5-HT receptor mRNA expression. Verheggen, R., Hundeshagen, A.G., Brown, A.M., Schindler, M., Kaumann, A.J. Br. J. Pharmacol. (1998) [Pubmed]
  34. The biology of serotonin receptors: focus on migraine pathophysiology and treatment. Hamel, E. The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques. (1999) [Pubmed]
  35. New targets in the acute treatment of headache. Goadsby, P.J. Curr. Opin. Neurol. (2005) [Pubmed]
  36. Molecular cloning and functional characterization of a human 5-HT1B serotonin receptor: a homologue of the rat 5-HT1B receptor with 5-HT1D-like pharmacological specificity. Hamblin, M.W., Metcalf, M.A., McGuffin, R.W., Karpells, S. Biochem. Biophys. Res. Commun. (1992) [Pubmed]
  37. Selective 5-HT1D alpha serotonin receptor gene expression in trigeminal ganglia: implications for antimigraine drug development. Rebeck, G.W., Maynard, K.I., Hyman, B.T., Moskowitz, M.A. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  38. Differential pharmacology between the guinea-pig and the gorilla 5-HT1D receptor as probed with isochromans (5-HT1D-selective ligands). Pregenzer, J.F., Alberts, G.L., Im, W.B., Slightom, J.L., Ennis, M.D., Hoffman, R.L., Ghazal, N.B., TenBrink, R.E. Br. J. Pharmacol. (1999) [Pubmed]
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