5-HT2C receptor

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5-hydroxytryptamine (serotonin) receptor 2C
SymbolsHTR2C; 5-HT2C; HTR1C
External IDsOMIM312861 MGI96281 HomoloGene20242 IUPHAR: 5-HT2C GeneCards: HTR2C Gene
RNA expression pattern
More reference expression data
RefSeq (mRNA)NM_000868XM_978183
RefSeq (protein)NP_000859XP_983277
Location (UCSC)Chr X:
113.72 - 114.05 Mb
Chr X:
142.21 - 142.44 Mb
PubMed search[1][2]

The 5-HT2C receptor is a subtype of 5-HT receptor that binds the endogenous neurotransmitter serotonin (5-hydroxytryptamine, 5-HT). It is a G protein-coupled receptor (GPCR) that is coupled to Gq/G11 and mediates excitatory neurotransmission. HTR2C denotes the human gene encoding for the receptor,[1][2] that in humans is located at the X chromosome. As only females have two copies of the gene, it can act as a significant contributor to the human gender differences in the brain and to psychological traits.[3]


5-HT2C receptors are widely distributed across the peripheral and brain CNS. 5-HT2C is expressed in the striatum, prefrontal cortex, nucleus accumbens, hippocampus, hypothalamus, amygdala, and many other areas.


The 5-HT2C receptor is one of the many binding sites for serotonin. Activation of this receptor by serotonin inhibits dopamine and norepinephrine release in certain areas of the brain.[4]

5-HT2C receptors significantly regulate mood, anxiety, feeding, and reproductive behavior.[5] 5-HT2C receptors regulate dopamine release in the striatum, prefrontal cortex, nucleus accumbens, hippocampus, hypothalamus, and amygdala, among others.

Research indicates that some suicide victims have an abnormally high number of 5-HT2C receptors in the prefrontal cortex.[6] There is some mixed evidence that agomelatine, a 5-HT2C antagonist, is an effective antidepressant.[7] Antagonism of 5-HT2C receptors by agomelatine results in an increase of dopamine and norepinephrine activity in the frontal cortex. Conversely, fluoxetine and other SSRIs indirectly stimulate 5-HT2C activity by increasing levels of serotonin in the synapse. Many atypical antipsychotics block 5-HT2C receptors, but their clinical use is limited by multiple undesirable actions on various neurotransmitters and receptors. Fluoxetine acts as a direct 5-HT2C antagonist in addition to inhibiting serotonin reuptake, however, the clinical significance of this action is variable.[8]

An overactivity of 5-HT2C receptors may contribute to depressive and anxiety symptoms in a certain population of patients. Activation of 5-HT2C by serotonin is responsible for many of the negative side effects of SSRI and SNRI medications, such as sertraline, paroxetine, venlafaxine, and others. Some of the initial anxiety caused by SSRIs is due to excessive signalling at 5-HT2C. Over a period of 1–2 weeks, the receptor begins to downregulate, along with the downregulation of 5-HT2A, 5-HT1A, and other serotonin receptors. This downregulation parallels the onset of the clinical benefits of SSRIs. 5-HT2C receptors exhibit constitutive activity in vivo, and may retain the ability to influence neurotransmission in the absence of ligand occupancy. Thus, 5-HT2C receptors do not require binding by a ligand (serotonin) in order to exhibit influence on neurotransmission. Inverse agonists may be required to fully extinguish 5-HT2C constitutive activity, and may prove useful in the treatment of 5-HT2C-mediated conditions in the absence of typical serotonin activity.[9]

5-HT2C receptors mediate the release and increase of extracellular dopamine in response to many drugs,[10][11] including caffeine, nicotine, amphetamine, morphine, cocaine, and others. 5-HT2C antagonism increases dopamine release in response to reinforcing drugs, and many dopaminergic stimuli. Feeding, social interaction, and sexual activity all release dopamine subject to inhibition by 5-HT2C. Increased 5-HT2C expression reduces dopamine release in both the presence and absence of stimuli.

Many GPCRs downregulate in response to agonists for the receptor, and upregulate in response to antagonists. The 5-HT2A and 5-HT2C receptors appear to downregulate in response to both antagonists and agonists. Chronic treatment with antipsychotic drugs, which possess 5-HT2 antagonist activity, results in downregulation of both 5-HT2A and 5-HT2C, as does chronic treatment with SSRIs and other 5-HT agonists.[12] However, chronic SSRI treatment may increase 5-HT2C expression, specifically in the choroid plexus.[13]

Conditions that increase cytokine levels in the human body may have potential to raise 5-HT2C gene expression in the brain. This could possibly comprise a link between viral infections and associated depression. Cytokine therapy has been shown to increase 5-HT2C gene expression, resulting in increased activity of 5-HT2C receptors in the brain.


Serotonin is involved in basal and stress-induced regulation of hypothalamus and pituitary gland hormones such as prolactin, adrenocorticotropic hormone (ACTH), vasopressin and oxytocin, mainly via actions of receptor subtypes 5-HT2A and 5-HT2C.[14] As such, the 5-HT2C receptor is a significant modulator of Hypothalamic–pituitary–adrenal axis (HPA axis).[3] The HPA axis is the main controller of acute sympathetic stress responses related to fight-or-flight response. Prolonged activation and disturbances of the HPA axis contribute to depressive and anxiety symptoms seen in many psychopathological conditions.

Stimulation of 5-HT2C receptors leads to increase of corticotropin releasing hormone (CRH) and vasopressin mRNA in the paraventricular nucleus and proopiomelanocortin in the anterior pituitary lobe. In rats, restraint stress (which can produces depressive symptoms if being chronic) induces secretion of prolactin, ACTH, vasopressin and oxytocin which is partially mediated via 5-HT2C receptor. Responses during such conditions as dehydration or haemorrhage causes the release oxytocin via serotonergic response that is partly mediated via 5-HT2C. In addition, peripheral release of vasopressin involves serotonergic response which is partially mediated via 5-HT2C.

Expression of the 5-HT2C receptor in the CNS is modulated by female sex hormones estradiol and progesterone. Combination of the hormones decrease the receptor concentration in the ventral hippocampus in rats and could thus affect mood.[15]


As only females have two copies of the gene, it can act as a significant contributor to the human gender differences in the brain and to psychological traits such as proneness to anxiety and depression.[3]

Many human polymorphisms have been identified influencing the expression of 5-HT2C. Significant correlations are suggested, specifically in relation to psychiatric disorders such as depression, OCD, and anxiety-related conditions. Polymorphisms influencing such also correlate to susceptibility and influence conditions including drug abuse and obesity. There are indications that the alternative splicing of the 5-HT2C receptor is regulated by a snoRNA called SNORD115, the deletion of which is associated with Prader–Willi syndrome.[16][17] As the human gene is located in the X chromosome, males have only one copy of the gene whereas women have two, meaning that mutations in the gene affect the phenotype of men even when the allele would be recessive in nature. As women have two copies, their receptor densities are higher than in males and could possibly contribute to differences between the genders; for example the corpus callosum which connects the two hemispheres of the brain (and contains 5-HT2C receptors) is larger in females than in males.



The 5-HT2C receptor has been shown to interact with MPDZ.[18][19]

See also


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Further reading

  • Niswender CM, Sanders-Bush E, Emeson RB (1999). "Identification and characterization of RNA editing events within the 5-HT2C receptor". Ann. N. Y. Acad. Sci. 861: 38–48. doi:10.1111/j.1749-6632.1998.tb10171.x. PMID 9928237. 
  • Hoyer D, Hannon JP, Martin GR (2002). "Molecular, pharmacological and functional diversity of 5-HT receptors". Pharmacol. Biochem. Behav. 71 (4): 533–54. doi:10.1016/S0091-3057(01)00746-8. PMID 11888546. 
  • Raymond JR, Mukhin YV, Gelasco A; et al. (2002). "Multiplicity of mechanisms of serotonin receptor signal transduction". Pharmacol. Ther. 92 (2-3): 179–212. doi:10.1016/S0163-7258(01)00169-3. PMID 11916537. 
  • Van Oekelen D, Luyten WH, Leysen JE (2003). "5-HT2A and 5-HT2C receptors and their atypical regulation properties". Life Sci. 72 (22): 2429–49. doi:10.1016/S0024-3205(03)00141-3. PMID 12650852. 
  • Reynolds GP, Templeman LA, Zhang ZJ (2005). "The role of 5-HT2C receptor polymorphisms in the pharmacogenetics of antipsychotic drug treatment". Prog. Neuropsychopharmacol. Biol. Psychiatry. 29 (6): 1021–8. doi:10.1016/j.pnpbp.2005.03.019. PMID 15953671. 
  • Millan MJ (2006). "Serotonin 5-HT2C receptors as a target for the treatment of depressive and anxious states: focus on novel therapeutic strategies". Therapie. 60 (5): 441–60. doi:10.2515/therapie:2005065. PMID 16433010. 
  • Milatovich A, Hsieh CL, Bonaminio G; et al. (1993). "Serotonin receptor 1c gene assigned to X chromosome in human (band q24) and mouse (bands D-F4)". Hum. Mol. Genet. 1 (9): 681–4. doi:10.1093/hmg/1.9.681. PMID 1302605. 
  • Saltzman AG, Morse B, Whitman MM; et al. (1992). "Cloning of the human serotonin 5-HT2 and 5-HT1C receptor subtypes". Biochem. Biophys. Res. Commun. 181 (3): 1469–78. doi:10.1016/0006-291X(91)92105-S. PMID 1722404. 
  • Lappalainen J, Zhang L, Dean M; et al. (1995). "Identification, expression, and pharmacology of a Cys23-Ser23 substitution in the human 5-HT2c receptor gene (HTR2C)". Genomics. 27 (2): 274–9. doi:10.1006/geno.1995.1042. PMID 7557992. 
  • Tecott LH, Sun LM, Akana SF; et al. (1995). "Eating disorder and epilepsy in mice lacking 5-HT2c serotonin receptors". Nature. 374 (6522): 542–6. doi:10.1038/374542a0. PMID 7700379. 
  • Stam NJ, Vanderheyden P, van Alebeek C; et al. (1995). "Genomic organisation and functional expression of the gene encoding the human serotonin 5-HT2C receptor". Eur. J. Pharmacol. 269 (3): 339–48. PMID 7895773. 
  • Xie E, Zhu L, Zhao L, Chang LS (1996). "The human serotonin 5-HT2C receptor: complete cDNA, genomic structure, and alternatively spliced variant". Genomics. 35 (3): 551–61. doi:10.1006/geno.1996.0397. PMID 8812491. 
  • Burns CM, Chu H, Rueter SM; et al. (1997). "Regulation of serotonin-2C receptor G-protein coupling by RNA editing". Nature. 387 (6630): 303–8. doi:10.1038/387303a0. PMID 9153397. 
  • Brennan TJ, Seeley WW, Kilgard M; et al. (1997). "Sound-induced seizures in serotonin 5-HT2c receptor mutant mice". Nat. Genet. 16 (4): 387–90. doi:10.1038/ng0897-387. PMID 9241279. 
  • Ullmer C, Schmuck K, Figge A, Lübbert H (1998). "Cloning and characterization of MUPP1, a novel PDZ domain protein". FEBS Lett. 424 (1-2): 63–8. doi:10.1016/S0014-5793(98)00141-0. PMID 9537516. 
  • Samochowiec J, Smolka M, Winterer G; et al. (1999). "Association analysis between a Cys23Ser substitution polymorphism of the human 5-HT2c receptor gene and neuronal hyperexcitability". Am. J. Med. Genet. 88 (2): 126–30. doi:10.1002/(SICI)1096-8628(19990416)88:2<126::AID-AJMG6>3.0.CO;2-M. PMID 10206230. 
  • Cargill M, Altshuler D, Ireland J; et al. (1999). "Characterization of single-nucleotide polymorphisms in coding regions of human genes". Nat. Genet. 22 (3): 231–8. doi:10.1038/10290. PMID 10391209. 
  • Marshall SE, Bird TG, Hart K, Welsh KI (2000). "Unified approach to the analysis of genetic variation in serotonergic pathways". Am. J. Med. Genet. 88 (6): 621–7. doi:10.1002/(SICI)1096-8628(19991215)88:6<621::AID-AJMG9>3.0.CO;2-H. PMID 10581480. 
  • Backstrom JR, Price RD, Reasoner DT, Sanders-Bush E (2000). "Deletion of the serotonin 5-HT2C receptor PDZ recognition motif prevents receptor phosphorylation and delays resensitization of receptor responses". J. Biol. Chem. 275 (31): 23620–6. doi:10.1074/jbc.M000922200. PMID 10816555. 

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

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