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Vol. 19, Issue 11, 4640-4650, November 2008

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Physical Interaction of Calmodulin with the 5-Hydroxytryptamine_2C Receptor C-Terminus Is Essential for G Protein-independent, Arrestin-dependent Receptor Signaling

Marilyne Labasque^*,,,, Eric Reiter^||, Carine Becamel^*,,,, Joël Bockaert^*,,,, and Philippe Marin^*,,,

*Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5203, Institut de Génomique Fonctionnelle, Montpellier F-34094, France; Institut National de la Santé et de la Recherche Médicale, U661, Montpellier F-34094, France; Université Montpellier 1, Montpellier F-34094, France; Université Montpellier 2, Montpellier F-34094, France; and ^||Institut National de la Recherche Agronomique, Unité Mixte de Recherche 6175, Centre National de la Recherche Scientifique, Université Tours, Nouzilly F-37380, France

Submitted April 24, 2008; Revised July 28, 2008; Accepted August 21, 2008
Monitoring Editor: Carl-Henrik Heldin

The serotonin (5-hydroxytryptamine; 5-HT)_2C receptor is a G protein-coupled receptor (GPCR) exclusively expressed in CNS that has been implicated in numerous brain disorders, including anxio-depressive states. Like many GPCRs, 5-HT_2C receptors physically interact with a variety of intracellular proteins in addition to G proteins. Here, we show that calmodulin (CaM) binds to a prototypic Ca²⁺-dependent "1-10" CaM-binding motif located in the proximal region of the 5-HT_2C receptor C-terminus upon receptor activation by 5-HT. Mutation of this motif inhibited both β-arrestin recruitment by 5-HT_2C receptor and receptor-operated extracellular signal-regulated kinase (ERK) 1,2 signaling in human embryonic kidney-293 cells, which was independent of G proteins and dependent on β-arrestins. A similar inhibition was observed in cells expressing a dominant-negative CaM or depleted of CaM by RNA interference. Expression of the CaM mutant also prevented receptor-mediated ERK1,2 phosphorylation in cultured cortical neurons and choroid plexus epithelial cells that endogenously express 5-HT_2C receptors. Collectively, these findings demonstrate that physical interaction of CaM with recombinant and native 5-HT_2C receptors is critical for G protein-independent, arrestin-dependent receptor signaling. This signaling pathway might be involved in neurogenesis induced by chronic treatment with 5-HT_2C receptor agonists and their antidepressant-like activity.

Address correspondence to: Philippe Marin (philippe.marin{at}igf.cnrs.fr)

Abbreviations used: CaM, calmodulin; CEC, choroid plexus epithelial cell; ERK, extracellular signal-regulated kinase; GPCR, G protein-coupled receptor; PLC, phospholipase C; PTX, pertussis toxin.

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