title: Serotonin 5-HT2A receptor-mediated hypertrophy is negatively regulated by caveolin-3 in cardiomyoblasts and neonatal cardiomyocytes.
abstract: The serotonin 5-HT(2A) receptor belongs to the G-protein-coupled receptors (GPCRs) superfamily and mediates the hypertrophic response to serotonin (5-HT) in cardiac myocytes. At present the regulatory mechanisms of 5-HT(2A) receptor-induced myocyte hypertrophy are not fully understood. The localization and the compartmentation of GPCRs within specialized membrane microdomains are known to modulate their signalling pathway. Therefore, we hypothesized that caveolae microdomains and caveolin-3, the predominant isoform of cardiac caveolae, might be regulators of 5-HT(2A) receptor signalling. We demonstrate that 5-HT(2A) receptors interact with caveolin-3 upon 5-HT stimulation and traffic into caveolae membrane microdomains. We provide evidence that caveolin-3 knockdown abolishes the redistribution of 5-HT(2A) receptors into caveolae and enhances 5-HT(2A) receptor-induced myocyte hypertrophic markers such as cell size, protein synthesis and ANF gene expression. Importantly, we demonstrate that caveolin-3 and caveolae structures are negative regulators of 5-HT(2A) receptor-induced nuclear factor of activated T cells (NFAT) transcriptional activation. Taken together, our data demonstrate that caveolin-3 and caveolae microdomains are important regulators of the hypertrophic response induced by 5-HT(2A) receptors. These findings thus open new insights to target heart hypertrophy under the enhanced serotonin system. This article is part of a Special Issue entitled "Local Signaling in Myocytes".
authors.affiliation: Inserm, UMR-1048, Institut des Maladies Métaboliques et Cardiovasculaires, F-31342 Toulouse, France.
authors.forename: Jeanne
authors.initials: J
authors.lastname: Mialet-Perez
authors.forename: Romina
authors.initials: R
authors.lastname: D'Angelo
authors.forename: Christelle
authors.initials: C
authors.lastname: Villeneuve
authors.forename: Catherine
authors.initials: C
authors.lastname: Ordener
authors.forename: Anne
authors.initials: A
authors.lastname: Nègre-Salvayre
authors.forename: Angelo
authors.initials: A
authors.lastname: Parini
authors.forename: Cécile
authors.initials: C
authors.lastname: Vindis
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism*; D021941:Caveolae / Q000187:drug effects / Q000378:metabolism; D051244:Caveolin 3 / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D020868:Gene Silencing; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D032386:Myoblasts, Cardiac / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D011485:Protein Binding; D021381:Protein Transport; D051381:Rats; D044402:Receptor, Serotonin, 5-HT2A / Q000235:genetics / Q000378:metabolism*; D012701:Serotonin / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D051244:Caveolin 3; D044402:Receptor, Serotonin, 5-HT2A; D012701:Serotonin