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Evidence for a Direct and Functional Interaction between the Regulators of G Protein Signaling-2 and Phosphorylated C Terminus of Cholecystokinin-2 Receptor

Department of Biological Chemistry and Nutrition, Faculty of Medicine, Université Libre de Bruxelles, Brussels, Belgium (I.L., P.R.); Institut National de la Santé et de la Recherche Médicale, Unit 858, Toulouse, France (I.G.T., J.P.E., S.V., A.F., D.F.); Université de Toulouse 3, Toulouse, France (I.G.T., J.P.E., S.V., A.F., D.F.); and Max Planck Institut für Biochemie, Martinsried, Germany (C.B., L.M.).

Signaling of G protein-coupled receptors (GPCRs) is regulated by different mechanisms. One of these involves regulators of G protein signaling (RGS), which are diverse and multifunctional proteins that bind to active G subunits of G proteins and act as GTPase-activating proteins. Little is known about the molecular mechanisms that govern the selective use of RGS proteins in living cells. We first demonstrated that CCK2R-mediated inositol phosphate production, known to be G_q-dependent, is more sensitive to RGS2 than to RGS4 and is insensitive to RGS8. Both basal and agonist-stimulated activities of the CCK2R are regulated by RGS2. By combining biochemical, functional, and in silico structural approaches, we demonstrate that a direct and functional interaction occurs between RGS2 and agonist-stimulated cholecystokinin receptor-2 (CCK2R) and identified the precise residues involved: phosphorylated Ser434 and Thr439 located in the C-terminal tail of CCK2R and Lys62, Lys63, and Gln67, located in the N-terminal domain of RGS2. These findings confirm previous reports that RGS proteins can interact with GPCRs to modulate their signaling and provide a molecular basis for RGS2 recognition by the CCK2R.

Received for publication August 29, 2008.

Accepted for publication December 5, 2008.

Address correspondence to: Daniel Fourmy, IFR 31, Institut Louis Bugnard, BP 84225, Unité INSERM U858-I2MR, 31432 Toulouse Cedex 4 France. E-mail: fourmyd{at}toulouse.inserm.fr