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5-hydroxytryptamine (serotonin) receptor 2C
Identifiers
Symbols HTR2C; 5-HT2C; HTR1C
External IDs OMIM312861 MGI96281 HomoloGene20242 IUPHAR: 5-HT2C GeneCards: HTR2C Gene
RNA expression pattern
PBB GE HTR2C 211479 s at tn.png
PBB GE HTR2C 207307 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 3358 15560
Ensembl ENSG00000147246 ENSMUSG00000041380
UniProt P28335 Q8BUB1
RefSeq (mRNA) NM_000868 XM_978183
RefSeq (protein) NP_000859 XP_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]

Contents

Function

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.[5]

Clinical significance

Research indicates that some suicide victims have an abnormally high number of 5-HT2C receptors in the prefrontal cortex.[6] 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 repsonse 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.

Ligands

Agonists
Antagonists
Inverse Agonists

Interactions

The 5-HT2C receptor has been shown to interact with MPDZ.[14][15]

See also

References

  1. ^ "Entrez Gene: HTR2C 5-hydroxytryptamine (serotonin) receptor 2C". http://www.ncbi.nlm.nih.gov/gene/3358?ordinalpos=2&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSum. 
  2. ^ Stam NJ, Vanderheyden P, van Alebeek C, Klomp J, de Boer T, van Delft AM, Olijve W (November 1994). "Genomic organisation and functional expression of the gene encoding the human serotonin 5-HT2C receptor". Eur. J. Pharmacol. 269 (3): 339–48. doi:10.1016/0922-4106(94)90042-6. PMID 7895773. 
  3. ^ Heisler LK, Zhou L, Bajwa P, Hsu J, Tecott LH (July 2007). "Serotonin 5-HT2C receptors regulate anxiety-like behavior". Genes, Brain and Behavior 6 (5): 491–6. doi:10.1111/j.1601-183X.2007.00316.x. PMID 17451451. 
  4. ^ Speake T, Kibble JD, Brown PD (March 2004). "Kv1.1 and Kv1.3 channels contribute to the delayed-rectifying K+ conductance in rat choroid plexus epithelial cells". Am. J. Physiol., Cell Physiol. 286 (3): C611–20. doi:10.1152/ajpcell.00292.2003. PMID 14602579. 
  5. ^ Alex KD, Yavanian GJ, McFarlane HG, Pluto CP, Pehek EA (March 2005). "Modulation of dopamine release by striatal 5-HT2C receptors". Synapse 55 (4): 242–51. doi:10.1002/syn.20109. PMID 15668911. 
  6. ^ Niswender CM, Herrick-Davis K, Dilley GE, Meltzer HY, Overholser JC, Stockmeier CA, Emeson RB, Sanders-Bush E (May 2001). "RNA editing of the human serotonin 5-HT2C receptor. alterations in suicide and implications for serotonergic pharmacotherapy". Neuropsychopharmacology 24 (5): 478–91. doi:10.1016/S0893-133X(00)00223-2. PMID 11282248. 
  7. ^ Eser, D.; Baghai, T.C.; Möller, H.J. (2009), "Agomelatine: the evidence for its place in the treatment of depression.", Core Evidence 3: 109–16 
  8. ^ Ni YG, Miledi R (March 1997). "Blockage of 5HT2C serotonin receptors by fluoxetine (Prozac)". Proceedings of the National Academy of Sciences of the United States of America 94 (5): 2036–40. PMID 9050900. PMC 20038. http://www.pnas.org/cgi/pmidlookup?view=long&pmid=9050900. 
  9. ^ Berg KA, Harvey JA, Spampinato U, Clarke WP (December 2005). "Physiological relevance of constitutive activity of 5-HT2A and 5-HT2C receptors". Trends Pharmacol. Sci. 26 (12): 625–30. doi:10.1016/j.tips.2005.10.008. PMID 16269190. 
  10. ^ Esposito E (February 2006). "Serotonin-dopamine interaction as a focus of novel antidepressant drugs". Curr Drug Targets 7 (2): 177–85. doi:10.2174/138945006775515455. PMID 16475959. 
  11. ^ Bubar MJ, Cunningham KA (2006). "Serotonin 5-HT2A and 5-HT2C receptors as potential targets for modulation of psychostimulant use and dependence". Curr Top Med Chem 6 (18): 1971–85. PMID 17017968. 
  12. ^ Gray JA, Roth BL (November 2001). "Paradoxical trafficking and regulation of 5-HT2A receptors by agonists and antagonists". Brain Res. Bull. 56 (5): 441–51. doi:10.1016/S0361-9230(01)00623-2. PMID 11750789. 
  13. ^ Laakso A, Pälvimäki EP, Kuoppamäki M, Syvälahti E, Hietala J (August 1996). "Chronic citalopram and fluoxetine treatments upregulate 5-HT2c receptors in the rat choroid plexus". Neuropsychopharmacology 15 (2): 143–51. doi:10.1016/0893-133X(95)00176-E. PMID 8840350. 
  14. ^ Becamel, C; Figge A, Poliak S, Dumuis A, Peles E, Bockaert J, Lubbert H, Ullmer C (Apr. 2001). "Interaction of serotonin 5-hydroxytryptamine type 2C receptors with PDZ10 of the multi-PDZ domain protein MUPP1". J. Biol. Chem. (United States) 276 (16): 12974–82. doi:10.1074/jbc.M008089200. ISSN 0021-9258. PMID 11150294. 
  15. ^ Ullmer, C; Schmuck K, Figge A, Lübbert H (Mar. 1998). "Cloning and characterization of MUPP1, a novel PDZ domain protein". FEBS Lett. (NETHERLANDS) 424 (1-2): 63–8. ISSN 0014-5793. PMID 9537516. 

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. 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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