Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

5-Hydroxytryptamine Receptor 2C

  • Carine BécamelEmail author
  • Philippe Marin
  • Joël Bockaert
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_55


Historical Background

The 5-hydroxytryptamine-type 2C receptor (5-HT2C, previously 5-HT1C) is one of the 14 G protein-coupled receptor subtypes activated by serotonin. 5-HT2C receptors are involved in a large variety of physiological functions such as nociception, motor behavior, endocrine secretion, thermoregulation, modulation of appetite, and the control of exchanges between the central nervous system and the cerebrospinal fluid. They have also been implicated in numerous pathologies such as schizophrenia, anxiety, depression, Parkinson’s disease, drug addiction, and obesity (Berg et al. 2008; Chagraoui et al. 2016). In line with their implication in various pathological situations, 5-HT2C receptors are considered as a major pharmacological target for the development of new treatments (see  “Ligand-Dependent Nuclear Receptor Corepressor (LCoR)”) (Di Giovanni and De Deurwaerdere 2016).


This is a preview of subscription content, log in to check access.


  1. Abbas AI, Yadav PN, Yao WD, Arbuckle MI, Grant SG, Caron MG, Roth BL. PSD-95 is essential for hallucinogen and atypical antipsychotic drug actions at serotonin receptors. J Neurosci. 2009;29:7124–36.PubMedPubMedCentralCrossRefGoogle Scholar
  2. Applegate CD, Tecott LH. Global increases in seizure susceptibility in mice lacking 5-HT2C receptors: a behavioral analysis. Exp Neurol. 1998;154:522–30.PubMedPubMedCentralCrossRefGoogle Scholar
  3. Becamel C, Figge A, Poliak S, Dumuis A, Peles E, Bockaert J, Lubbert H, Ullmer C. Interaction of serotonin 5-hydroxytryptamine type 2C receptors with PDZ10 of the multi-PDZ domain protein MUPP1. J Biol Chem. 2001;276:12974–82.PubMedPubMedCentralCrossRefGoogle Scholar
  4. Becamel C, Alonso G, Galeotti N, Demey E, Jouin P, Ullmer C, Dumuis A, Bockaert J, Marin P. Synaptic multiprotein complexes associated with 5-HT(2C) receptors: a proteomic approach. EMBO J. 2002;21:2332–42.PubMedPubMedCentralCrossRefGoogle Scholar
  5. Becamel C, Gavarini S, Chanrion B, Alonso G, Galeotti N, Dumuis A, Bockaert J, Marin P. The serotonin 5-HT2A and 5-HT2C receptors interact with specific sets of PDZ proteins. J Biol Chem. 2004;279:20257–66.PubMedPubMedCentralCrossRefGoogle Scholar
  6. Berg KA, Clarke WP, Cunningham KA, Spampinato U. Fine-tuning serotonin2c receptor function in the brain: molecular and functional implications. Neuropharmacology. 2008;55:969–76.PubMedPubMedCentralCrossRefGoogle Scholar
  7. Bigford GE, Chaudhry NS, Keane RW, Holohean AM. 5-Hydroxytryptamine 5HT2C receptors form a protein complex with N-methyl-D-aspartate GluN2A subunits and activate phosphorylation of Src protein to modulate motoneuronal depolarization. J Biol Chem. 2012;287:11049–59.PubMedPubMedCentralCrossRefGoogle Scholar
  8. Bockaert J, Claeysen S, Becamel C, Dumuis A, Marin P. Neuronal 5-HT metabotropic receptors: fine-tuning of their structure, signaling, and roles in synaptic modulation. Cell Tissue Res. 2006;326:553–72.PubMedPubMedCentralCrossRefGoogle Scholar
  9. Bonn M, Schmitt A, Lesch KP, Van Bockstaele EJ, Asan E. Serotonergic innervation and serotonin receptor expression of NPY-producing neurons in the rat lateral and basolateral amygdaloid nuclei. Brain Struct Funct. 2013;218:421–35.PubMedPubMedCentralCrossRefGoogle Scholar
  10. Brennan TJ, Seeley WW, Kilgard M, Schreiner CE, Tecott LH. Sound-induced seizures in serotonin 5-HT2c receptor mutant mice. Nat Genet. 1997;16:387–90.PubMedPubMedCentralCrossRefGoogle Scholar
  11. Bubar MJ, Cunningham KA. Prospects for serotonin 5-HT2R pharmacotherapy in psychostimulant abuse. Prog Brain Res. 2008;172:319–46.PubMedPubMedCentralCrossRefGoogle Scholar
  12. Bubar MJ, Stutz SJ, Cunningham KA. 5-HT(2C) receptors localize to dopamine and GABA neurons in the rat mesoaccumbens pathway. PLoS One. 2011;6:e20508.PubMedPubMedCentralCrossRefGoogle Scholar
  13. Buckland PR, Hoogendoorn B, Guy CA, Smith SK, Coleman SL, O’Donovan MC. Low gene expression conferred by association of an allele of the 5-HT2C receptor gene with antipsychotic-induced weight gain. Am J Psychiatry. 2005;162:613–5.CrossRefPubMedGoogle Scholar
  14. Canal CE, Olaghere da Silva UB, Gresch PJ, Watt EE, Sanders-Bush E, Airey DC. The serotonin 2C receptor potently modulates the head-twitch response in mice induced by a phenethylamine hallucinogen. Psychopharmacology. 2010;209:163–74.PubMedPubMedCentralCrossRefGoogle Scholar
  15. Canal CE, Booth RG, Morgan D. Support for 5-HT2C receptor functional selectivity in vivo utilizing structurally diverse, selective 5-HT2C receptor ligands and the 2,5-dimethoxy-4-iodoamphetamine elicited head-twitch response model. Neuropharmacology. 2013;70:112–21.PubMedPubMedCentralCrossRefGoogle Scholar
  16. Cassier E, Gallay N, Bourquard T, Claeysen S, Bockaert J, Crepieux P, Poupon A, Reiter E, Marin P, Vandermoere F. Phosphorylation of beta-arrestin2 at Thr383 by MEK underlies beta-arrestin-dependent activation of Erk1/2 by GPCRs. ELife. 2017;6:e23777.Google Scholar
  17. Chagraoui A, Thibaut F, Skiba M, Thuillez C, Bourin M. 5-HT2C receptors in psychiatric disorders: a review. Prog Neuro-Psychopharmacol Biol Psychiatry. 2016;66:120–35.CrossRefGoogle Scholar
  18. Chanrion B, Mannoury la Cour C, Gavarini S, Seimandi M, Vincent L, Pujol JF, Bockaert J, Marin P, Millan MJ. Inverse agonist and neutral antagonist actions of antidepressants at recombinant and native 5-hydroxytryptamine2C receptors: differential modulation of cell surface expression and signal transduction. Mol Pharmacol. 2008;73:748–57.CrossRefPubMedGoogle Scholar
  19. de Bodinat C, Guardiola-Lemaitre B, Mocaer E, Renard P, Munoz C, Millan MJ. Agomelatine, the first melatonergic antidepressant: discovery, characterization and development. Nat Rev Drug Discov. 2010;9:628–42.CrossRefPubMedGoogle Scholar
  20. De Deurwaerdere P, Navailles S, Berg KA, Clarke WP, Spampinato U. Constitutive activity of the serotonin2C receptor inhibits in vivo dopamine release in the rat striatum and nucleus accumbens. J Neurosci. 2004;24:3235–41.CrossRefPubMedGoogle Scholar
  21. Deckert J, Meyer J, Catalano M, Bosi M, Sand P, DiBella D, Ortega G, Stober G, Franke P, Nothen MM, et al. Novel 5′-regulatory region polymorphisms of the 5-HT2C receptor gene: association study with panic disorder. Int J Neuropsychopharmacol. 2000;3:321–5.CrossRefPubMedGoogle Scholar
  22. Del’Guidice T, Lemay F, Lemasson M, Levasseur-Moreau J, Manta S, Etievant A, Escoffier G, Dore FY, Roman FS, Beaulieu JM. Stimulation of 5-HT2C receptors improves cognitive deficits induced by human tryptophan hydroxylase 2 loss of function mutation. Neuropsychopharmacology. 2014;39:1125–34.PubMedPubMedCentralCrossRefGoogle Scholar
  23. Di Giovanni G, De Deurwaerdere P. New therapeutic opportunities for 5-HT2C receptor ligands in neuropsychiatric disorders. Pharmacol Ther. 2016;157:125–62.CrossRefPubMedGoogle Scholar
  24. Fentress HM, Grinde E, Mazurkiewicz JE, Backstrom JR, Herrick-Davis K, Sanders-Bush E. Pharmacological properties of the Cys23Ser single nucleotide polymorphism in human 5-HT2C receptor isoforms. Pharmacogenomics J. 2005;5:244–54.CrossRefPubMedGoogle Scholar
  25. Fossat P, Bacque-Cazenave J, De Deurwaerdere P, Cattaert D, Delbecque JP. Serotonin, but not dopamine, controls the stress response and anxiety-like behavior in the crayfish Procambarus clarkii. J Exp Biol. 2015;218:2745–52.CrossRefPubMedGoogle Scholar
  26. Garfield AS, Davies JR, Burke LK, Furby HV, Wilkinson LS, Heisler LK, Isles AR. Increased alternate splicing of Htr2c in a mouse model for Prader-Willi syndrome leads disruption of 5HT2C receptor mediated appetite. Mol Brain. 2016;9:95.PubMedPubMedCentralCrossRefGoogle Scholar
  27. Gavarini S, Becamel C, Altier C, Lory P, Poncet J, Wijnholds J, Bockaert J, Marin P. Opposite effects of PSD-95 and MPP3 PDZ proteins on serotonin 5-hydroxytryptamine2C receptor desensitization and membrane stability. Mol Biol Cell. 2006;17:4619–31.PubMedPubMedCentralCrossRefGoogle Scholar
  28. Graves SM, Napier TC. SB 206553, a putative 5-HT2C inverse agonist, attenuates methamphetamine-seeking in rats. BMC Neurosci. 2012;13:65.PubMedPubMedCentralCrossRefGoogle Scholar
  29. Heisler LK, Cowley MA, Kishi T, Tecott LH, Fan W, Low MJ, Smart JL, Rubinstein M, Tatro JB, Zigman JM, et al. Central serotonin and melanocortin pathways regulating energy homeostasis. Ann N Y Acad Sci. 2003;994:169–74.CrossRefPubMedGoogle Scholar
  30. Heisler LK, Zhou L, Bajwa P, Hsu J, Tecott LH. Serotonin 5-HT(2C) receptors regulate anxiety-like behavior. Genes Brain Behav. 2007;6:491–6.CrossRefPubMedGoogle Scholar
  31. Herrick-Davis K, Grinde E, Weaver BA. Serotonin 5-HT(2C) receptor homodimerization is not regulated by agonist or inverse agonist treatment. Eur J Pharmacol. 2007;568:45–53.PubMedPubMedCentralCrossRefGoogle Scholar
  32. Herrick-Davis K, Grinde E, Lindsley T, Teitler M, Mancia F, Cowan A, Mazurkiewicz JE. Native serotonin 5-HT2C receptors are expressed as homodimers on the apical surface of choroid plexus epithelial cells. Mol Pharmacol. 2015;87:660–73.PubMedPubMedCentralCrossRefGoogle Scholar
  33. Higgins GA, Fletcher PJ. Therapeutic potential of 5-HT2C receptor agonists for addictive disorders. ACS Chem Neurosci. 2015;6:1071–88.CrossRefPubMedGoogle Scholar
  34. Howell LL, Cunningham KA. Serotonin 5-HT2 receptor interactions with dopamine function: implications for therapeutics in cocaine use disorder. Pharmacol Rev. 2015;67:176–97.PubMedPubMedCentralCrossRefGoogle Scholar
  35. Jensen NH, Cremers TI, Sotty F. Therapeutic potential of 5-HT2C receptor ligands. ScientificWorldJournal. 2010;10:1870–85.CrossRefPubMedPubMedCentralGoogle Scholar
  36. Ji SP, Zhang Y, Van Cleemput J, Jiang W, Liao M, Li L, Wan Q, Backstrom JR, Zhang X. Disruption of PTEN coupling with 5-HT2C receptors suppresses behavioral responses induced by drugs of abuse. Nat Med. 2006;12:324–9.CrossRefPubMedGoogle Scholar
  37. Ji G, Zhang W, Mahimainathan L, Narasimhan M, Kiritoshi T, Fan X, Wang J, Green TA, Neugebauer V. 5-HT2C receptor knockdown in the amygdala inhibits neuropathic-pain-related plasticity and behaviors. J Neurosci. 2017;37:1378–93.PubMedPubMedCentralCrossRefGoogle Scholar
  38. Labasque M, Reiter E, Becamel C, Bockaert J, Marin P. Physical interaction of calmodulin with the 5-hydroxytryptamine2C receptor C-terminus is essential for G protein-independent, arrestin-dependent receptor signaling. Mol Biol Cell. 2008;19:4640–50.PubMedPubMedCentralCrossRefGoogle Scholar
  39. Labasque M, Meffre J, Carrat G, Becamel C, Bockaert J, Marin P. Constitutive activity of Serotonin2C receptors at G protein-independent signaling: modulation by RNA editing and antidepressants. Mol Pharmacol. 2010;78:818–26.CrossRefPubMedGoogle Scholar
  40. Lappalainen J, Zhang L, Dean M, Oz M, Ozaki N, Yu DH, Virkkunen M, Weight F, Linnoila M, Goldman D. Identification, expression, and pharmacology of a Cys23-Ser23 substitution in the human 5-HT2c receptor gene (HTR2C). Genomics. 1995;27:274–9.CrossRefPubMedGoogle Scholar
  41. Mancia F, Assur Z, Herman AG, Siegel R, Hendrickson WA. Ligand sensitivity in dimeric associations of the serotonin 5HT2c receptor. EMBO Rep. 2008;9:363–9.PubMedPubMedCentralCrossRefGoogle Scholar
  42. Marcinkiewcz CA, Mazzone CM, D’Agostino G, Halladay LR, Hardaway JA, DiBerto JF, Navarro M, Burnham N, Cristiano C, Dorrier CE, et al. Serotonin engages an anxiety and fear-promoting circuit in the extended amygdala. Nature. 2016;537:97–101.PubMedPubMedCentralCrossRefGoogle Scholar
  43. Marion S, Weiner DM, Caron MG. RNA editing induces variation in desensitization and trafficking of 5-hydroxytryptamine 2c receptor isoforms. J Biol Chem. 2004;279:2945–54.CrossRefPubMedGoogle Scholar
  44. McMahon LR, Filip M, Cunningham KA. Differential regulation of the mesoaccumbens circuit by serotonin 5-hydroxytryptamine (5-HT)2A and 5-HT2C receptors. J Neurosci. 2001;21:7781–7.CrossRefPubMedGoogle Scholar
  45. Meyer J, Saam W, Mossner R, Cangir O, Ortega GR, Tatschner T, Riederer P, Wienker TF, Lesch KP. Evolutionary conserved microsatellites in the promoter region of the 5-hydroxytryptamine receptor 2C gene (HTR2C) are not associated with bipolar disorder in females. J Neural Transm. 2002;109:939–46.CrossRefPubMedGoogle Scholar
  46. Millan MJ. Serotonin 5-HT2C receptors as a target for the treatment of depressive and anxious states: focus on novel therapeutic strategies. Therapie. 2005;60:441–60.CrossRefPubMedGoogle Scholar
  47. Miller KJ. Serotonin 5-ht2c receptor agonists: potential for the treatment of obesity. Mol Interv. 2005;5:282–91.CrossRefPubMedGoogle Scholar
  48. Morabito MV, Abbas AI, Hood JL, Kesterson RA, Jacobs MM, Kump DS, Hachey DL, Roth BL, Emeson RB. Mice with altered serotonin 2C receptor RNA editing display characteristics of Prader-Willi syndrome. Neurobiol Dis. 2010;39:169–80.PubMedPubMedCentralCrossRefGoogle Scholar
  49. Moutkine I, Quentin E, Guiard BP, Maroteaux L, Doly S. Heterodimers of serotonin receptor subtypes 2 are driven by 5-HT2C protomers. J Biol Chem. 2017;292:6352–68.PubMedPubMedCentralCrossRefGoogle Scholar
  50. Neelakantan H, Holliday ED, Fox RG, Stutz SJ, Comer SD, Haney M, Anastasio NC, Moeller FG, Cunningham KA. Lorcaserin suppresses oxycodone self-administration and relapse vulnerability in rats. ACS chem Neurosci. 2017;6b00413.Google Scholar
  51. Nocjar C, Alex KD, Sonneborn A, Abbas AI, Roth BL, Pehek EA. Serotonin-2C and -2a receptor co-expression on cells in the rat medial prefrontal cortex. Neuroscience. 2015;297:22–37.PubMedPubMedCentralCrossRefGoogle Scholar
  52. Nonogaki K, Strack AM, Dallman MF, Tecott LH. Leptin-independent hyperphagia and type 2 diabetes in mice with a mutated serotonin 5-HT2C receptor gene. Nat Med. 1998;4:1152–6.CrossRefPubMedGoogle Scholar
  53. Nonogaki K, Abdallah L, Goulding EH, Bonasera SJ, Tecott LH. Hyperactivity and reduced energy cost of physical activity in serotonin 5-HT(2C) receptor mutant mice. Diabetes. 2003;52:315–20.CrossRefPubMedGoogle Scholar
  54. Olaghere da Silva UB, Morabito MV, Canal CE, Airey DC, Emeson RB, Sanders-Bush E. Impact of RNA editing on functions of the serotonin 2C receptor in vivo. Front Neurosci. 2010;4:26.PubMedPubMedCentralGoogle Scholar
  55. Parker LL, Backstrom JR, Sanders-Bush E, Shieh BH. Agonist-induced phosphorylation of the serotonin 5-HT2C receptor regulates its interaction with multiple PDZ protein 1. J Biol Chem. 2003;278:21576–83.CrossRefPubMedGoogle Scholar
  56. Risselada AJ, Vehof J, Bruggeman R, Wilffert B, Cohen D, Al Hadithy AF, Arends J, Mulder H. Association between HTR2C gene polymorphisms and the metabolic syndrome in patients using antipsychotics: a replication study. Pharmacogenomics J. 2012;12:62–7.CrossRefPubMedGoogle Scholar
  57. Sanders-Bush E, Fentress H, Hazelwood L. Serotonin 5-ht2 receptors: molecular and genomic diversity. Mol Interv. 2003;3:319–30.CrossRefPubMedGoogle Scholar
  58. Song HR, Gu A, Schanen NC. Identification of a new polymorphism in the 3′-untranslated region of the human serotonin receptor 2C (5-HT2C) gene. Mol Genet Metab. 1999;66:224–7.CrossRefPubMedGoogle Scholar
  59. Sullivan LC, Clarke WP, Berg KA. Atypical antipsychotics and inverse agonism at 5-HT2 receptors. Curr Pharm Des. 2015;21:3732–8.PubMedPubMedCentralCrossRefGoogle Scholar
  60. Thomsen WJ, Grottick AJ, Menzaghi F, Reyes-Saldana H, Espitia S, Yuskin D, Whelan K, Martin M, Morgan M, Chen W, et al. Lorcaserin, a novel selective human 5-hydroxytryptamine2C agonist: in vitro and in vivo pharmacological characterization. J Pharmacol Exp Ther. 2008;325:577–87.CrossRefPubMedGoogle Scholar
  61. Ullmer C, Schmuck K, Figge A, Lubbert H. Cloning and characterization of MUPP1, a novel PDZ domain protein. FEBS Lett. 1998;424:63–8.CrossRefPubMedGoogle Scholar
  62. Werry TD, Loiacono R, Sexton PM, Christopoulos A. RNA editing of the serotonin 5HT2C receptor and its effects on cell signalling, pharmacology and brain function. Pharmacol Ther. 2008;119:7–23.CrossRefPubMedGoogle Scholar
  63. Xiao H, Hapiak VM, Smith KA, Lin L, Hobson RJ, Plenefisch J, Komuniecki R. SER-1, a Caenorhabditis elegans 5-HT2-like receptor, and a multi-PDZ domain containing protein (MPZ-1) interact in vulval muscle to facilitate serotonin-stimulated egg-laying. Dev Biol. 2006;298:379–91.CrossRefPubMedGoogle Scholar
  64. Xu Y, Berglund ED, Sohn JW, Holland WL, Chuang JC, Fukuda M, Rossi J, Williams KW, Jones JE, Zigman JM, et al. 5-HT(2C)Rs expressed by pro-opiomelanocortin neurons regulate insulin sensitivity in liver. Nat Neurosci. 2010;13:1457–9.PubMedPubMedCentralCrossRefGoogle Scholar
  65. Yuan X, Yamada K, Ishiyama-Shigemoto S, Koyama W, Nonaka K. Identification of polymorphic loci in the promoter region of the serotonin 5-HT2C receptor gene and their association with obesity and type II diabetes. Diabetologia. 2000;43:373–6.CrossRefPubMedGoogle Scholar
  66. Zayara AE, McIver G, Valdivia PN, Lominac KD, McCreary AC, Szumlinski KK. Blockade of nucleus accumbens 5-HT2A and 5-HT2C receptors prevents the expression of cocaine-induced behavioral and neurochemical sensitization in rats. Psychopharmacology. 2011;213:321–35.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Carine Bécamel
    • 1
    Email author
  • Philippe Marin
    • 1
  • Joël Bockaert
    • 1
  1. 1.Dépt. de NeurobiologieInstitut de Génomique Fonctionnelle, Université de Montpellier, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche MédicaleMontpellier Cedex 5France