Alternative titles; symbols
HGNC Approved Gene Symbol: HTR2C
Cytogenetic location: Xq23 Genomic coordinates (GRCh38): X:114,584,086-114,910,061 (from NCBI)
In the mammalian nervous system, serotonin (5-hydroxytryptamine; 5-HT) binds to distinct cell surface receptor subtypes that are defined by their ligand-binding and effector-coupling properties. The 5HT1C receptor is a G protein-coupled receptor that stimulates phospholipase C (PLC)-catalyzed hydrolysis of phosphatidylinositol bisphosphate, leading to the mobilization of intracellular calcium and to the activation of protein kinase C (summary by Milatovich et al., 1992).
The 5HT1A (HTR1A; 109760), 5HT1B (HTR1B; 182131), 5HT1D (HTR1D; 182133), and 5HT4 (HTR4; 602164) receptors regulate adenylate cyclase activity, whereas the 5HT1C and 5HT2 receptors activate phospholipase C. Whereas the HTR1C and HTR2 (182135) genes contain multiple introns within the coding regions, the HTR1A, HTR1B, HTR1D, and HTR1E (182132) genes are intronless, as are many of the adrenergic receptor genes, and show greater sequence similarity to the family of adrenergic receptor genes than to HTR1C and HTR2 (summary by Milatovich et al., 1992).
The 5-HT-2C receptor undergoes pre-mRNA editing by deaminating enzymes (ADAR1, 146920 and ADAR2, 601218) at sites designated A, B, C-prime, E, C, and D, which may alter the ability of the receptor to activate phospholipase C. Gurevich et al. (2002) found that in suicide victims with a history of major depression, C-prime site editing was significantly increased, D site editing was significantly decreased, and the C site showed a trend toward increased editing, which may indicate an overall decreased 5-HT-2C receptor activity in these patients. Treatment of mice with the antidepressant drug fluoxetine caused changes in C, C-prime, and D site editing that were opposite to those seen in suicide victims. Thus, posttranslational regulation of gene expression may play a role in modulation of neurotransmitter receptors.
Editing of HTR2C mRNA generates up to 24 different receptor isoforms. The extent of editing correlates with functional activity of the receptor such that more highly edited isoforms exhibit the least function. In a comparative analysis of gene expression and DNA methylation in the prefrontal cortex of 32 patients who committed suicide and controls, Di Narzo et al. (2014) found an overrepresentation of highly edited mRNA variants, which encode hypoactive HTR2C receptors, in the brains of suicide victims. A large set of genes for which the expression level is associated with editing was detected, including genes that are involved in synaptic transmission, genes that are preferentially expressed in neurons, and genes whose expression is correlated with the level of DNA methylation. The link between HTR2C editing and gene expression was disrupted in suicide victims. Di Narzo et al. (2014) suggested that the postulated homeostatic function of HTR2C mRNA editing is dysregulated in individuals who commit suicide.
Heisler et al. (2002) hypothesized that 5-HT receptors are expressed in POMC (176830) neurons and that action at these receptors mediates a component of the anorexic effect of d-FEN (D-fenfluramine). Heisler et al. (2002) found that up to 80% of alpha-MSH neurons express HTR2C mRNA and that the pattern of coexpression is greatest in the caudal arcuate nucleus of the hypothalamus. Heisler et al. (2002) demonstrated that direct activation of HTR2C by agonist in rats decreased their food intake and showed increased induction of FOS-like immunoreactivity in a pattern consistent with d-FEN-induced FOS-like immunoreactivity expression in the arcuate nucleus and paraventricular nucleus of the hypothalamus. Heisler et al. (2002) demonstrated that d-FEN directly activates POMC neurons, indicating that central 5-HT systems directly activate POMC neurons.
The small nucleolar RNA (snoRNA) HBII-52 (SNORD115-1; 609837), which exhibits sequence complementarity to the alternatively spliced exon Vb of the serotonin receptor HTR2C, is contained within the Prader-Willi deleted region on chromosome 15q11 (PWS; 176270). Kishore and Stamm (2006) found that HBII-52 regulates alternative splicing of HTR2C by binding to a silencing element in exon Vb. Prader-Willi syndrome patients do not express HBII-52 and have different HTR2C mRNA isoforms than healthy individuals. Kishore and Stamm (2006) concluded that a snoRNA regulates the processing of an mRNA expressed from a gene located on a different chromosome, and the results indicate that a defect in pre-mRNA processing contributes to the Prader-Willi syndrome.
Using in vitro studies of rat PC12 cells, Ji et al. (2006) found that Pten (601728) regulated phosphorylation of Htr2c. Immunoprecipitation studies showed that Pten interacts with the 3L4F region (amino acids 283 to 297) of the third intracellular loop of Htr2c. Pten limited agonist-induced phosphorylation of Htr2C through its protein phosphatase activity. In vivo studies localized the Pten/Htr2C complex in dopaminergic neurons of the nucleus accumbens in the rat ventral tegmental area. Htr2c appeared to tonically inhibit the activity of dopaminergic neurons, and disruption of the Pten/Htr2c complex also resulted in inhibition of this dopaminergic pathway.
By somatic cell hybrid analysis and fluorescence in situ hybridization, Milatovich et al. (1992) mapped the HTR1C locus to human Xq24 and to the mouse X chromosome region D-F4.
Lappalainen et al. (1995) identified a cys-to-ser polymorphism at amino acid 23 in the first hydrophobic region of the human 5-HT-2C receptor (312861.0001). Allele frequencies in unrelated Caucasians were 0.13 and 0.87 for ser and cys, respectively. DNAs from informative CEPH families were typed for polymorphism and analyzed with respect to 20 linked markers on the X chromosome. By linkage analysis, Lappalainen et al. (1995) placed the HTR2C gene on Xq24, where it had been assigned by other methods. To evaluate whether this amino acid substitution causes a variant function of this receptor, Lappalainen et al. (1995) expressed recombinant receptors of the 2 amino acid types in Xenopus oocytes and tested for responses to serotonin using electrophysiologic techniques. Concentration-response curves were not significantly different in oocytes expressing either form of the receptor, suggesting that the 2 receptor proteins do not differ in their responses to serotonin under baseline physiologic conditions.
Holmes et al. (1998) hypothesized that common genetic polymorphisms in neurotransmitter systems are risk factors for the development of behavioral and psychologic symptoms in the course of Alzheimer disease. A total of 211 subjects from a population-based prospective study of psychopathology within late-onset AD were genotyped for the cys23-to-ser polymorphism of the HTR2C gene (312861.0001) and for the 102T-C polymorphism of the HTR2A gene (182135.0001). Association was found between the presence of the ser23 allele and visual hallucinations. In addition, there was an association between the cys23-to-ser polymorphism and hyperphagia.
A side effect of treatment of schizophrenia (see 181500) with antipsychotic drugs is increased body weight, which leads to further morbidity and poor adherence to treatment. The underlying mechanisms of weight gain are probably multifactorial. The 5-HT-2C receptor has been implicated in particular, since knockout of this receptor in mice can result in obesity and increased feeding. Clozapine and several other antipsychotics are 5-HT-2C antagonists, which could contribute to their propensity to induce weight gain. Reynolds et al. (2002) demonstrated a genetic polymorphism of the promoter region of the HTR2C gene, -759C-T, which was associated with weight gain after drug treatment in patients presenting with a first episode of schizophrenia.
Miller et al. (2005) examined the association between clozapine-induced weight gain and the 5-HT-2C receptor -759C/T polymorphism in 41 patients with treatment-refractory schizophrenia who were followed prospectively during treatment with the drug. Weight and height measurements were obtained prior to starting clozapine and after 6 months of treatment. The -759T allele had significant effects on body mass index in that subjects without the T allele were at greater risk for weight gain from clozapine over 6 months compared to those with the T allele.
Tecott et al. (1995) generated mice lacking 5-HT-2C receptors by introducing a nonsense mutation into exon 5 of the cognate gene, thereby placing a stop codon within the fifth putative transmembrane segment of the receptor and eliminating the carboxyl-terminal half of the protein. The HTR2C gene is X-linked in the mouse as well, and Tecott et al. (1995) observed disruption of a single allele in targeted male embryonic stem cells. They also showed that the 5-HT-2C receptor-deficient mice were overweight as a result of abnormal control of feeding behavior, thus establishing a role for this receptor in the serotonergic control of appetite. Mutant animals were also prone to spontaneous death from seizures, suggesting that receptors of this type mediate tonic inhibition of neuronal network excitability.
Hall (1947) found that DBA/2 mice exhibited genetic susceptibility to audiogenic seizures (AGSs) stimulated by a doorbell mounted in an iron tub. Thereafter, audiogenic seizures were among the intensively studied phenotypes in behavioral genetics. Brennan et al. (1997) found that null mutant mice lacking serotonin 5-HT-2C receptors are extremely susceptible to AGSs. The onset of susceptibility was between 2 and 3 months of age, with complete penetrance in adult animals.
In mice, Ji et al. (2006) found that pharmacologic disruption of the Pten/Htr2c complex with an interfering peptide (Tat-3L4F) suppressed the increased firing rate of ventral tegmental dopaminergic neurons and suppressed behavioral responses induced by THC, the psychoactive ingredient in marijuana. Treatment with Tat-3L4F resulted in no apparent side effects compared to treatment with the direct Htr2c agonist Ro600175.
In a mouse model for Prader-Willi syndrome (PWS; 176270) lacking expression of Mbii-52, the mouse homolog of HBII-52, Doe et al. (2009) showed an increase in editing, but not alternative splicing, of the Htr2c pre-RNA. This change in posttranscriptional modification was associated with alterations in a number of brain serotonin-related behaviors, including impulsive responding, locomotor activity and reactivity to palatable foodstuffs. For marble burying, a behavior not related to brain serotonin, loss of Mbii-52 was without effect. The specificity of the behavioral effects to changes in Htr2c function was further confirmed using drug challenges. These data illustrated the physiologic consequences of altered RNA editing of Htr2c linked to Mbii-52 loss that may underlie specific aspects of the complex PWS phenotype and point to an important functional role for this imprinted snoRNA.
Tecott et al. (1995) pointed out that the receptor previously called 5-HT-1C had been redesignated as 5-HT-2C.
By use of SSCP analysis, Lappalainen et al. (1995) identified a nonconservative cys23-to-ser (C23S) substitution in the HTR2C gene.
Brennan, T. J., Seeley, W. W., Kilgard, M., Schreiner, C. E., Tecott, L. H. Sound-induced seizures in serotonin 5-HT-2C receptor mutant mice. Nature Genet. 16: 387-390, 1997. [PubMed: 9241279] [Full Text: https://doi.org/10.1038/ng0897-387]
Di Narzo, A. F., Kozlenkov, A., Roussos, P., Hao, K., Hurd, Y., Lewis, D. A., Sibille, E., Siever, L. J., Koonin, E., Dracheva, S. A unique gene expression signature associated with serotonin 2C receptor RNA editing in the prefrontal cortex and altered in suicide. Hum. Molec. Genet. 23: 4801-4813, 2014. [PubMed: 24781207] [Full Text: https://doi.org/10.1093/hmg/ddu195]
Doe, C. M., Relkovic, D., Garfield, A. S., Dalley, J. W., Theobald, D. E. H., Humby, T., Wilkinson, L. S., Isles, A. R. Loss of imprinted snoRNA mbii-52 leads to increased 5htr2c pre-RNA editing and altered 5HT(2C)R-mediated behaviour. Hum. Molec. Genet. 18: 2140-2148, 2009. [PubMed: 19304781] [Full Text: https://doi.org/10.1093/hmg/ddp137]
Gurevich, I., Tamir, H., Arango, V., Dwork, A. J., Mann, J. J., Schmauss, C. Altered editing of serotonin 2C receptor pre-mRNA in the prefrontal cortex of depressed suicide victims. Neuron 34: 349-356, 2002. [PubMed: 11988167] [Full Text: https://doi.org/10.1016/s0896-6273(02)00660-8]
Hall, C. S. Genetic differences in fatal audiogenic seizures: between two inbred strains of house mice. J. Hered. 38: 3-6, 1947.
Heisler, L. K., Cowley, M. A., Tecott, L. H., Fan, W., Low, M. J., Smart, J. L., Rubinstein, M., Tatro, J. B., Marcus, J. N., Holstege, H., Lee, C. E., Cone, R. D., Elmquist, J. K. Activation of central melanocortin pathways by fenfluramine. Science 297: 609-611, 2002. [PubMed: 12142539] [Full Text: https://doi.org/10.1126/science.1072327]
Holmes, C., Arranz, M. J., Powell, J. F., Collier, D. A., Lovestone, S. 5-HT-2A and 5-HT-2C receptor polymorphisms and psychopathology in late onset Alzheimer's disease. Hum. Molec. Genet. 7: 1507-1509, 1998. [PubMed: 9700207] [Full Text: https://doi.org/10.1093/hmg/7.9.1507]
Ji, S.-P., Zhang, Y., Van Cleemput, J., Jiang, W., Liao, M., Li, L., Wan, Q., Backstrom, J. R., Zhang, X. Disruption of PTEN coupling with 5-HT2C receptors suppresses behavioral responses induced by drugs of abuse. (Letter) Nature Med. 12: 324-329, 2006. [PubMed: 16474401] [Full Text: https://doi.org/10.1038/nm1349]
Kishore, S., Stamm, S. The snoRNA HBII-52 regulates alternative splicing of the serotonin receptor 2C. Science 311: 230-232, 2006. [PubMed: 16357227] [Full Text: https://doi.org/10.1126/science.1118265]
Lappalainen, J., Zhang, L., Dean, M., Oz, M., Ozaki, N., Yu, D., Virkkunen, M., Weight, F., Linnoila, M., Goldman, D. Identification, expression, and pharmacology of a cys(23)-ser(23) substitution in the human 5-HT(2C) receptor gene (HTR2C). Genomics 27: 274-279, 1995. [PubMed: 7557992] [Full Text: https://doi.org/10.1006/geno.1995.1042]
Milatovich, A., Hsieh, C.-L., Bonaminio, G., Tecott, L., Julius, D., Francke, U. Serotonin receptor 1c gene assigned to X chromosome in human (band q24) and mouse (bands D-F4). Hum. Molec. Genet. 1: 681-684, 1992. [PubMed: 1302605] [Full Text: https://doi.org/10.1093/hmg/1.9.681]
Miller, D. D., Ellingrod, V. L., Holman, T. L., Buckley, P. F., Arndt, S. Clozapine-induced weight gain associated with the 5HT2C receptor -759C/T polymorphism. Am. J. Med. Genet. 133B: 97-100, 2005. [PubMed: 15635667] [Full Text: https://doi.org/10.1002/ajmg.b.30115]
Reynolds, G. P., Zhang, Z.-J., Zhang, X.-B. Association of antipsychotic drug-induced weight gain with a 5-HT2C receptor gene polymorphism. Lancet 359: 2086-2087, 2002. [PubMed: 12086765] [Full Text: https://doi.org/10.1016/S0140-6736(02)08913-4]
Tecott, L. H., Sun, L. M., Akana, S. F., Strack, A. M., Lowenstein, D. H., Dallman, M. F., Julius, D. Eating disorder and epilepsy in mice lacking 5-HT2C serotonin receptors. Nature 374: 542-546, 1995. [PubMed: 7700379] [Full Text: https://doi.org/10.1038/374542a0]