Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 292, Issue 15, Pages 6352-6368Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M117.779041
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Funding
- Centre National de la Recherche Scientifique
- Institut National de la Sante et de la Recherche Medicale
- Universite Pierre et Marie Curie
- Universite Paris Descartes
- Fondation de France
- Fondation pour la Recherche Medicale Equipe [FRM DEQ2014039529]
- French Ministry of Research [ANR-12-BSV1-0015-01]
- Investissements d'Avenir Programme [ANR-11-IDEX-0004-02]
- French state funds
- ANR within the Investissements d'Avenir programme [ANR-11-IDEX-0004-02]
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The serotonin receptor subtypes 2 comprise 5-HT2A,5-HT2B, and 5-HT2C, which are G alpha(q)-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-HT2 receptors 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-HT2C receptors interact with either 5-HT2A or 5-HT2B receptors. Although heterodimerization with 5-HT2C receptors does not alter 5-HT2C G alpha(q)-dependent inositol phosphate signaling, 5-HT2A or 5-HT2B receptor-mediated signaling was totally blunted. This feature can be explained by a dominance of 5-HT2C on 5-HT2A and 5-HT2B receptor binding; in 5-HT2C-containing heterodimers, ligands bind and activate the 5-HT2C protomer exclusively. This dominant effect on the associated protomer was also observed in neurons, supporting the physiological relevance of 5-HT2 receptor heterodimerization in vivo. Accordingly, exogenous expression of an inactive form of the 5-HT2C receptor in the locus ceruleus is associated with decreased 5-HT2A-dependent noradrenergic transmission. These data demonstrate that 5-HT2 receptors can form functionally asymmetric heterodimers in vitro and in vivo that must be considered when analyzing the physiological or pathophysiological roles of serotonin in tissues where 5-HT2 receptors are co-expressed.
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