title: Heterodimers of serotonin receptor subtypes 2 are driven by 5-HT2Cprotomers.
abstract: The serotonin receptor subtypes 2 comprise 5-HT2A, 5-HT2B, and 5-HT2C, which are Gαq-coupled receptors and display distinct pharmacological properties. Although co-expressed in some brain regions and involved in various neurological disorders, their functional interactions have not yet been studied. We report that 5-HT2receptors can form homo- and heterodimers when expressed alone or co-expressed in transfected cells. Co-immunoprecipitation and bioluminescence resonance energy transfer studies confirmed that 5-HT2Creceptors interact with either 5-HT2Aor 5-HT2Breceptors. Although heterodimerization with 5-HT2Creceptors does not alter 5-HT2CGαq-dependent inositol phosphate signaling, 5-HT2Aor 5-HT2Breceptor-mediated signaling was totally blunted. This feature can be explained by a dominance of 5-HT2Con 5-HT2Aand 5-HT2Breceptor binding; in 5-HT2C-containing heterodimers, ligands bind and activate the 5-HT2Cprotomer exclusively. This dominant effect on the associated protomer was also observed in neurons, supporting the physiological relevance of 5-HT2receptor heterodimerizationin vivoAccordingly, exogenous expression of an inactive form of the 5-HT2Creceptor in the locus ceruleus is associated with decreased 5-HT2A-dependent noradrenergic transmission. These data demonstrate that 5-HT2receptors can form functionally asymmetric heterodimersin vitroandin vivothat must be considered when analyzing the physiological or pathophysiological roles of serotonin in tissues where 5-HT2receptors are co-expressed.
authors.affiliation: From the INSERM UMR-S839, Paris 75005.|the Université Pierre et Marie Curie, Paris 75005.|the Institut du Fer à Moulin, Paris 75005.
authors.forename: Imane
authors.initials: I
authors.lastname: Moutkine
authors.affiliation: From the INSERM UMR-S839, Paris 75005.|the Université Pierre et Marie Curie, Paris 75005.|the Institut du Fer à Moulin, Paris 75005.
authors.forename: Emily
authors.initials: E
authors.lastname: Quentin
authors.affiliation: the Research Center on Animal Cognition, Center for Integrative Biology, Université Paul Sabatier, UMR5169 CNRS, 118, Route de Narbonne, 31062, Toulouse Cedex 9, France.
authors.forename: Bruno P
authors.initials: BP
authors.lastname: Guiard
authors.affiliation: From the INSERM UMR-S839, Paris 75005, Luc.maroteaux@upmc.fr.|the Université Pierre et Marie Curie, Paris 75005.|the Institut du Fer à Moulin, Paris 75005.
authors.forename: Luc
authors.initials: L
authors.lastname: Maroteaux
authors.affiliation: the Institut Cochin, INSERM U1016, CNRS UMR8104, Paris 75014, stephane.doly@inserm.fr.|the Université Paris Descartes, Sorbonne Paris Cité, Paris 75014.|the Université Clermont Auvergne, INSERM, NEURO-DOL, F-63000 Clermont-Ferrand, and.
authors.forename: Stephane
authors.initials: S
authors.lastname: Doly
mesh_terms: D000818:Animals; D016466:CHO Cells; D019556:COS Cells; D002522:Chlorocebus aethiops; D003412:Cricetulus; D057809:HEK293 Cells; D006801:Humans; D008125:Locus Coeruleus / Q000378:metabolism*; D008297:Male; D051379:Mice; D055503:Protein Multimerization; D044348:Receptors, Serotonin, 5-HT2 / Q000235:genetics / Q000378:metabolism*; D009435:Synaptic Transmission / Q000502:physiology*
chemical_list: D044348:Receptors, Serotonin, 5-HT2
keywords: G protein-coupled receptor (GPCR); cell signaling; cell-surface receptor; dimerization; molecular pharmacology; receptor regulation; serotonin; signal transduction