TY - JOUR T1 - Evidence for a Direct and Functional Interaction between the Regulators of G Protein Signaling-2 and Phosphorylated C Terminus of Cholecystokinin-2 Receptor JF - Molecular Pharmacology JO - Mol Pharmacol SP - 502 LP - 513 DO - 10.1124/mol.108.051607 VL - 75 IS - 3 AU - Ingrid Langer AU - Irina G. Tikhonova AU - Cyril Boulègue AU - Jean-Pierre Estève AU - Sébastien Vatinel AU - Audrey Ferrand AU - Luis Moroder AU - Patrick Robberecht AU - Daniel Fourmy Y1 - 2009/03/01 UR - http://molpharm.aspetjournals.org/content/75/3/502.abstract N2 - 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 Gα 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 Gq-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. The American Society for Pharmacology and Experimental Therapeutics ER -