Alternative titles; symbols
HGNC Approved Gene Symbol: HTR2B
Cytogenetic location: 2q37.1 Genomic coordinates (GRCh38): 2:231,108,230-231,125,042 (from NCBI)
Multiple receptor subtypes of serotonin neurotransmitters with multiple physiologic functions have been recognized. The 5-HT-2 receptors mediate many of the central and peripheral physiologic functions of serotonin. Cardiovascular effects include contraction of blood vessels and shape changes in platelets; central nervous system effects include neuronal sensitization to tactile stimuli and mediation of hallucinogenic effects of phenylisopropylamine hallucinogens.
Several lines of evidence suggest that serotonin regulates cardiovascular functions during embryogenesis as well as adulthood. However, none of the 5-HT receptor disruptions in mice had resulted in embryonic defects until Nebigil et al. (2000) found that inactivation of the Htr2b gene led to embryonic and neonatal death caused by heart defects. The mutant embryos exhibited a lack of trabeculae in the heart and a specific reduction in the expression levels of a tyrosine kinase receptor, ERBB2 (164870), leading to midgestation lethality. These in vivo data suggested that the Gq-coupled receptor 5-HT-2B uses a signaling pathway of tyrosine kinase receptor ERBB2 for cardiac differentiation. All surviving newborn mice displayed a severe ventricular hypoplasia caused by impaired proliferative capacity of myocytes. In adult mutant mice, cardiac histopathologic changes including myocyte disarray and ventricular dilation were consistently observed.
The liver can regenerate its volume after major tissue loss. Lesurtel et al. (2006) showed that in a mouse model of liver regeneration, thrombocytopenia resulted in the failure to initiate cellular proliferation in the liver. Platelets are major carriers of serotonin in the blood. In thrombocytopenic mice, a serotonin agonist reconstituted liver proliferation. The expression of 5-HT2A (182135) and 2B subtype serotonin receptors in the liver increased after hepatectomy. Antagonists of 5-HT2A and 2B receptors inhibited liver regeneration. Liver regeneration was also blunted in mice lacking tryptophan hydroxylase-1 (191060), which is the rate-limiting enzyme for the synthesis of peripheral serotonin. This failure of regeneration was rescued by reloading serotonin-free platelets with a serotonin precursor molecule. Lesurtel et al. (2006) concluded that platelet-derived serotonin is involved in the initiation of liver regeneration.
Dexfenfluramine increases the risk of pulmonary hypertension in humans, and its active metabolite is a selective serotonin 5-HT-2B receptor agonist. This led Launay et al. (2002) to investigate the contribution of the 5-HT-2B receptor to the pathogenesis of pulmonary hypertension. Using the chronic-hypoxic-mouse model of pulmonary hypertension, Launay et al. (2002) found that the hypoxia-dependent increase in pulmonary blood pressure and lung remodeling are associated with an increase in vascular proliferation, elastase activity, and TGF-beta (190180) levels, and that these parameters are potentiated by dexfenfluramine treatment. In contrast, hypoxic mice with genetically or pharmacologically inactive 5-HT-2B receptors manifested no change in any of those parameters. In both humans and mice, pulmonary hypertension is associated with a substantial increase in 5-HT-2B receptor expression in pulmonary arteries. Launay et al. (2002) concluded that activation of 5-HT-2B may be a limiting step in the development of pulmonary hypertension.
Crystal Structure
Wang et al. (2013) reported the crystal structures of human HTR1B (182131) 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, 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.
Le Coniat et al. (1996) mapped the human serotonin 5-HT-2B receptor to 2q36.3-q37.1 by fluorescence in situ hybridization. The gene has sequence homologies and a structural organization similar to those of the HTR2A (182135) and HTR2C (312861) receptor genes. However, they are located on separate chromosomes.
Association with Antisocial Personality Disorder with Severe Impulsivity
Impulsivity, describing action without foresight, is an important feature of several psychiatric diseases including attention deficit-hyperactivity disorder (see 143465), suicide, addictions, and violent criminality, as well as antisocial personality disorder (ASPD), borderline personality disorder (BPD), and intermittent explosive disorder (IED) (summary by Bevilacqua et al., 2010). For discussions of genetic contributions to similar phenotypes, see also COMT (116790.0001) and MAOA (309850.0001).
Bevilacqua et al. (2010) conducted sequencing on 96 unrelated Finnish males with impulsive behavior and an equal number of unrelated Finnish males free of psychiatric diagnoses. Probands had ASPD, BPD, or IED and were all violent offenders or arsonists who, because of the extreme nature of the crimes, underwent inpatient forensic psychiatric examination at the time of their initial incarceration. Exon-centric sequencing was performed on 14 genes involved in dopamine or serotonin function. Dysregulated activity of the monoamine neurotransmitters has been implicated in impulsivity both on a neuropharmacologic basis and a genetic basis. Bevilacqua et al. (2010) identified a glutamine-to-stop substitution, which they designated Q20*, in the HTR2B gene. Bevilacqua et al. (2010) found that Q20* led to variable nonsense-mediated RNA decay and blocked expression of the 5-HT2B receptor protein. HTR2B is widely expressed in the adult human brain, with high expression in frontal lobe. This mutation had been identified by Blanpain et al. (2003) as R393X.
In a larger sample of Finnish cases and controls, Bevilacqua et al. (2010) found that 17 of 228 cases were heterozygous for HTR2B Q20* compared to 7 of 295 controls (chi squared = 7.26, P = 0.007), with an allele frequency in controls of 0.012. Eighty-nine pedigrees comprising family members of the violent offenders were collected and all were genotyped without preselection for phenotype or genotype, identifying 8 HTR2B Q20* carrier families. Affected status was defined as presence of ASPD, BPD, or IED. The transmission disequilibrium test detected overtransmission of Q20* to affected offspring. Similarly, among affected individuals, 6 of 7 had Q20* transmitted, and among unaffected individuals, 10 of 14 did not have Q20* transmitted. From the cumulative binomial distribution, previously proposed for linkage of functional loci in families, the likelihood of 16 of 21 or more linked outcomes was 0.013. Bevilacqua et al. (2010) showed that HTR2BQ 20* cosegregates with impulsivity including antisocial personality disorder and alcohol use disorder in many of the families.
Bevilacqua et al. (2010) found that in the 17 violent offenders from the case-control group who carried Q20*, impulsivity had a strong role in their crimes. Although convicted for a variety of offenses, 94% of their crimes were committed under the influence of alcohol. The crimes of the Q20* carrier probands occurred as disproportionate reactions to minor irritations and were unpremeditated, without potential for financial gain, and recurrent. From court records up to an average age of 43, Q20* carriers had committed an average of 5 violent crimes (range 2 to 12). The cases tended to fulfill the criteria for ASPD (82%) and IED (57% meeting 3 out of 4 criteria), except that alcoholism, ASPD, and BPD are exclusionary for intermittent explosive disorder. Overall, Q20X carriers were cognitively normal (mean IQ, 98; range 75 to 124; 2 were less than 87). Testosterone measured in the cerebrospinal fluid of 9 heterozygous violent offenders was elevated.
Bevilacqua et al. (2010) assessed Htr2b knockout mice for 5 separate measures of impulsivity and novelty seeking and found that the knockout mice were more impulsive and more responsive to novelty in all of these tests. In rats, both impulsivity and response to novelty are predictors for the development of addiction-like behaviors. In addition to their differences in behaviors, Htr2b-null males had 3-fold elevations in plasma testosterone.
Bevilacqua, L., Doly, S., Kaprio, J., Yuan, Q., Tikkanen, R., Paunio, T., Zhou, Z., Wedenoja, J., Maroteaux, L., Diaz, S., Belmer, A., Hodgkinson, C. A., Dell'Osso, L., Suvisaari, J., Coccaro, E., Rose, R. J., Peltonen, L., Virkkunen, M., Goldman, D. A population-specific HTR2B stop codon predisposes to severe impulsivity. Nature 468: 1061-1066, 2010. Note: Erratum: Nature 470: 424 only, 2011. [PubMed: 21179162] [Full Text: https://doi.org/10.1038/nature09629]
Blanpain, C., Le Poul, E., Parma, J., Knoop, C., Detheux, M., Parmentier, M., Vassart, G., Abramowicz, M. J. Serotonin 5-HT(2B) receptor loss of function mutation in a patient with fenfluramine-associated primary pulmonary hypertension. Cardiovasc. Res. 60: 518-528, 2003. [PubMed: 14659797] [Full Text: https://doi.org/10.1016/j.cardiores.2003.09.015]
Launay, J.-M., Herve, P., Peoc'h, K., Tournois, C., Callebert, J., Nebigil, C. G., Etienne, N., Drouet, L., Humbert, M., Simonneau, G., Maroteaux, L. Function of the serotonin 5-hydroxytryptamine 2B receptor in pulmonary hypertension. Nature Med. 8: 1129-1135, 2002. [PubMed: 12244304] [Full Text: https://doi.org/10.1038/nm764]
Le Coniat, M., Choi, D.-S., Maroteaux, L., Launay, J.-M., Berger, R. The 5-HT2B receptor gene maps to 2q36.3-2q37.1. Genomics 32: 172-173, 1996. [PubMed: 8786115] [Full Text: https://doi.org/10.1006/geno.1996.0101]
Lesurtel, M., Graf, R., Aleil, B., Walther, D. J., Tian, Y., Jochum, W., Gachet, C., Bader, M., Clavien, P.-A. Platelet-derived serotonin mediates liver regeneration. Science 312: 104-107, 2006. [PubMed: 16601191] [Full Text: https://doi.org/10.1126/science.1123842]
Nebigil, C. G., Choi, D.-S., Dierich, A., Hickel, P., Le Meur, M., Messaddeq, N., Launay, J.-M., Maroteaux, L. Serotonin 2B receptor is required for heart development. Proc. Nat. Acad. Sci. 97: 9508-9513, 2000. [PubMed: 10944220] [Full Text: https://doi.org/10.1073/pnas.97.17.9508]
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]