Alternative titles; symbols
HGNC Approved Gene Symbol: HTR1B
Cytogenetic location: 6q14.1 Genomic coordinates (GRCh38): 6:77,460,924-77,463,491 (from NCBI)
The neurotransmitter serotonin (5-hydroxytryptamine; 5-HT) exerts a wide variety of physiologic functions through a multiplicity of receptors and may be involved in human neuropsychiatric disorders such as anxiety, depression, or migraine. These receptors consist of several main groups subdivided into several distinct subtypes on the basis of their pharmacologic characteristics, coupling to intracellular second messengers, and distribution within the nervous system (Zifa and Fillion, 1992). The serotonergic receptors belong to the multigene family of receptors coupled to guanine nucleotide-binding proteins.
Hamblin et al. (1992) and Jin et al. (1992) isolated genomic clones for the gene encoding the 5-hydroxytryptamine-1B receptor. They found that it has the characteristics of a G protein-linked receptor and is most homologous to the human 5-HT-1D receptor (182133). The gene was most abundantly expressed in the striatum. Mochizuki et al. (1992) also cloned the gene from human genomic DNA.
Some investigators (e.g., Demchyshyn et al., 1992) refer to the 5HT1B receptor as the 5HT1DB receptor. Weinshank et al. (1992) isolated genomic clones for two 5HT1D receptor genes, alpha (HTR1DA; 182133) and beta. Demchyshyn et al. (1992) cloned the intronless gene encoding 5HT1D-beta (HTR1DB) and functionally expressed it in mammalian fibroblast cultures. They concluded on the basis of the deduced amino acid sequence that the gene encodes a 390-amino acid protein displaying about 75% identity within putative transmembrane domains to the canine and human 5HT1D receptors. Demchyshyn et al. (1992) stated: 'Although the rat 5HT1B and human 5HT1D-beta receptor share an amino acid sequence homology of more than 93%, we concur with arguments based on both molecular and pharmacologic grounds, that the human receptor be classified as a member of the 5HT1D-like family.'
The HTR1B gene consists of a single exon (Demchyshyn et al., 1992).
Svenningsson et al. (2006) found that the 5HT1B receptor interacts with p11 (114085). p11 increased localization of 5HT1B receptors at the cell surface. p11 was increased in rodent brains by antidepressants or electroconvulsive therapy, but decreased in an animal model of depression and in brain tissue from depressed patients. Overexpression of p11 increases 5HT1B receptor function in cells and recapitulated certain behaviors seen after antidepressant treatment in mice. p11 knockout mice exhibited a depression-like phenotype and had reduced responsiveness to 5HT1B receptor agonists and reduced behavioral reactions to antidepressants.
Crystal Structure
Wang et al. (2013) reported the crystal structures of human HTR1B bound to the agonist antimigraine medications ergotamine and dihydroergotamine. The structures reveal similar binding modes for these ligands, which occupy the orthosteric pocket and an extended binding pocket close to the extracellular loops. The orthosteric pocket is formed by residues conserved in the 5-HT receptor family, clarifying the familywide agonist activity of 5-HT. Compared with the structure of HTR2B (601122), HTR1B displays a 3-angstrom outward shift at the extracellular end of helix V, resulting in a more open extended pocket that explains subtype selectivity. Together with docking and mutagenesis studies, Wang et al. (2013) concluded that these structures provide a comprehensive structural basis for understanding receptor-ligand interactions and designing subtype-selective serotonergic drugs.
Wacker et al. (2013) reported biochemical studies showing that the hallucinogen lysergic acid diethylamide (LSD), its precursor ergotamine (ERG), and related ergolines display strong functional selectivity for beta-arrestin (see ARRB1, 107940) signaling at HTR2B, whereas they are relatively unbiased at HTR1B. To investigate the structural basis for biased signaling, Wacker et al. (2013) determined the crystal structure of human HTR2B bound to ERG and compared it with the HTR1B/ERG structure.
Cryoelectron Microscopy
Garcia-Nafria et al. (2018) presented the cryoelectron microscopy structure of the serotonin 5-HT1B receptor bound to the agonist donitriptan and coupled to an engineered G(o) heterotrimer. In this complex, 5-HT1BR is in an active state; the intracellular domain of the receptor is in a similar conformation to that observed for the beta-2-adrenoceptor (ADRB2; 109690) or the adenosine A2A receptor (ADORA2A; 102776) in complex with G(s). In contrast to the complexes with G(s), the gap between the receptor and the G-beta subunit in the G(o)-5-HT1BR complex precludes molecular contacts, and the interface between the G-alpha subunit of G(o) and the receptor is considerably smaller.
By Southern blot analysis of a hybrid cell panel, Jin et al. (1992) assigned the HTR1B gene to chromosome 6 and regionalized it to 6q13 by chromosomal in situ hybridization. Simon-Chazottes et al. (1993) mapped the Htr1b gene to mouse chromosome 9. Demchyshyn et al. (1992) suggested that the presence of a RFLP related to the 5HT1B gene can be used for linkage mapping.
Smoller et al. (2006) sought to examine haplotype structure of the 5HTR1B gene in reference to ADHD (143465) by genotyping 21 SNPs in and around the gene in 12 multigenerational CEPH pedigrees. A haplotype block encompassing the gene was identified and single-marker association analyses for 8 SNPs within this block was performed in 229 families of ADHD probands to include association with inattentive and combined ADHD subtypes. Although Hawi et al. (2002) and Quist et al. (2003) had reported association of the G861 variant (861G-C) with ADHD, Smoller et al. (2006) observed only nonsignificant overtransmission of the G861 allele to ADHD offspring (one-tailed p = 0.07). Single-marker and haplotype tests of a haplotype block encompassing 5HTR1B revealed no other associations with ADHD. However, the haplotype block was associated with the inattentive subtype (global p less than 0.01). Additionally, 3 polymorphisms in this block were nominally associated with the inattentive subtype, but the associations did not remain significant after correction for multiple testing (p less than 0.05). Paternal overtransmission of G861 alleles to offspring with ADHD was observed and was largely attributable to inattentive cases.
Serotonin, acting through many receptors, can modulate the activity of neural reward pathways and thus the effects of various drugs of abuse. Rocha et al. (1998) examined the effects of cocaine in mice lacking one of the serotonin receptor subtypes, the 5-HT1B-receptor. They showed that mice lacking this receptor displayed increased locomotor responses to cocaine and were more motivated to self-administer cocaine. Rocha et al. (1998) proposed that even drug-naive 5-HT1B knockout mice are in a behavioral and biochemical state that resembles that of wildtype mice sensitized to cocaine by repeated exposure to the drug. This altered state may be responsible for their increased vulnerability to cocaine.
The triptans are an established class of antimigraine drugs that act selectively via 5-HT1B/1D receptors, particularly in the trigeminal system. In rats, Bartsch et al. (2004) found that infusion of naratriptan into the ventrolateral periaqueductal gray matter activated descending pain-modulating pathways that inhibited dural nociceptive input; however, similar effects were not observed for facial or corneal input. The findings implicated a novel mode of action of triptans.
Bartsch, T., Knight, Y. E., Goadsby, P. J. Activation of 5-HT(1B/1D) receptor in the periaqueductal gray inhibits nociception. Ann. Neurol. 56: 371-381, 2004. [PubMed: 15349864] [Full Text: https://doi.org/10.1002/ana.20193]
Demchyshyn, L., Sunahara, R. K., Miller, K., Teitler, M., Hoffman, B. J., Kennedy, J. L., Seeman, P., Van Tol, H. H. M., Niznik, H. B. A human serotonin 1D receptor variant (5HT1D-beta) encoded by an intronless gene on chromosome 6. Proc. Nat. Acad. Sci. 89: 5522-5526, 1992. [PubMed: 1351684] [Full Text: https://doi.org/10.1073/pnas.89.12.5522]
Garcia-Nafria, J., Nehme, R., Edwards, P. C., Tate, C. G. Cryo-EM structure of the serotonin 5-HT(1B) receptor coupled to heterotrimeric G(o). Nature 558: 620-623, 2018. [PubMed: 29925951] [Full Text: https://doi.org/10.1038/s41586-018-0241-9]
Hamblin, M. W., Metcalf, M. A., McGuffin, R. W., Karpells, S. Molecular cloning and functional characterization of a human 5-HT(1B) serotonin receptor: a homologue of the rat 5-HT(1B) receptor with 5-HT(1D)-like pharmacological specificity. Biochem. Biophys. Res. Commun. 184: 752-759, 1992. [PubMed: 1315531] [Full Text: https://doi.org/10.1016/0006-291x(92)90654-4]
Hawi, Z., Dring, M., Kirley, A., Foley, D., Kent, L., Craddock, N., Asherson, P., Curran, S., Gould, A., Richards, S., Lawson, D., Pay, H., Turic, D., Langley, K., Owen, M., O'Donovan, M., Thapar, A., Fitzgerald, M., Gill, M. Serotonergic system and attention deficit hyperactivity disorder (ADHD): a potential susceptibility locus at the 5-HT(1B) receptor gene in 273 nuclear families from a multi-centre sample. Molec. Psychiat. 7: 718-725, 2002. [PubMed: 12192616] [Full Text: https://doi.org/10.1038/sj.mp.4001048]
Jin, H., Oksenberg, D., Ashkenazi, A., Peroutka, S. J., Duncan, A. M. V., Rozmahel, R., Yang, Y., Mengod, G., Palacios, J. M., O'Dowd, B. F. Characterization of the human 5-hydroxytryptamine(1B) receptor. J. Biol. Chem. 267: 5735-5738, 1992. [PubMed: 1348246]
Mochizuki, D., Yuyama, Y., Tsujita, R., Komaki, H., Sagai, H. Cloning and expression of the human 5-HT1B-type receptor gene. Biochem. Biophys. Res. Commun. 185: 517-523, 1992. [PubMed: 1610347] [Full Text: https://doi.org/10.1016/0006-291x(92)91655-a]
Quist, J. F., Barr, C. L., Schachar, R., Roberts, W., Malone, M., Tannock, R., Basile, V. S., Beitchman, J., Kennedy, J. L. The serotonin 5-HT1B receptor gene and attention deficit hyperactivity disorder. Molec. Psychiat. 8: 98-102, 2003. [PubMed: 12556913] [Full Text: https://doi.org/10.1038/sj.mp.4001244]
Rocha, B. A., Scearce-Levie, K., Lucas, J. J., Hiroi, N., Castanon, N., Crabbe, J. C., Nestler, E. J., Hen, R. Increased vulnerability to cocaine in mice lacking the serotonin-1B receptor. Nature 393: 175-178, 1998. [PubMed: 9603521] [Full Text: https://doi.org/10.1038/30259]
Simon-Chazottes, D., Cloez-Tayarani, I., Fillion, M.-P., Guenet, J.-L., Fillion, G. The serotonin 5-HT(1B) receptor subtype (Htr1b) gene maps to mouse chromosome 9. Mammalian Genome 4: 397-398, 1993. [PubMed: 8358175] [Full Text: https://doi.org/10.1007/BF00360593]
Smoller, J. W., Biederman, J., Arbeitman, L., Doyle, A. E., Fagerness, J., Perlis, R. H., Sklar, P., Faraone, S. V. Association between the 5HT1B receptor gene (HTR1B) and the inattentive subtype of ADHD. Biol. Psychiat. 59: 460-467, 2006. [PubMed: 16197923] [Full Text: https://doi.org/10.1016/j.biopsych.2005.07.017]
Svenningsson, P., Chergui, K., Rachleff, I., Flajolet, M., Zhang, X., El Yacoubi, M., Vaugeois, J.-M., Nomikos, G. G., Greengard, P. Alterations in 5-HT1B receptor function by p11 in depression-like states. Science 311: 77-80, 2006. [PubMed: 16400147] [Full Text: https://doi.org/10.1126/science.1117571]
Wacker, D., Wang, C., Katritch, V., Han, G. W., Huang, X.-P., Vardy, E., McCorvy, J. D., Jiang, Y., Chu, M., Siu, F. Y., Liu, W., Xu, H. E., Cherezov, V., Roth, B. L., Stevens, R. C. Structural features for functional selectivity at serotonin receptors. Science 340: 615-619, 2013. [PubMed: 23519215] [Full Text: https://doi.org/10.1126/science.1232808]
Wang, C., Jiang, Y., Ma, J., Wu, H., Wacker, D., Katritch, V., Han, G. W., Liu, W., Huang, X.-P., Vardy, E., McCorvy, J. D., Gao, X., and 11 others. Structural basis for molecular recognition at serotonin receptors. Science 340: 610-614, 2013. [PubMed: 23519210] [Full Text: https://doi.org/10.1126/science.1232807]
Weinshank, R. L., Zgombick, J. M., Macchi, M. J., Branchek, T. A., Hartig, P. R. Human serotonin 1D receptor is encoded by a subfamily of two distinct genes: 5-HT-1D-alpha and 5-HT-1D-beta. Proc. Nat. Acad. Sci. 89: 3630-3634, 1992. [PubMed: 1565658] [Full Text: https://doi.org/10.1073/pnas.89.8.3630]
Zifa, E., Fillion, G. 5-Hydroxytryptamine receptors. Pharm. Rev. 44: 401-458, 1992. [PubMed: 1359584]