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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.

par Langer, Ingrid ;Tikhonova, Irina G;Boulègue, Cyril;Estève, Jean-Pierre;Vatinel, Sébastien;Ferrand, Audrey;Moroder, Luis;Robberecht, Patrick ;Fourmy, Daniel
Référence Molecular pharmacology, 75, 3, page (502-513)
Publication Publié, 2009-03

Article révisé par les pairs

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Résumé :

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 Galpha 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.