Characterization of GRK2 RH domain-dependent regulation of GPCR coupling to heterotrimeric G proteins

Abstract

Heterotrimeric guanine nucleotide (G)-coupled receptors (GPCRs) form the largest family of integral membrane proteins. GPCR activation by an agonist promotes the exchange of GDP for GTP on the Galpha subunit of the heterotrimeric G protein. The dissociated Galpha and Gbetagamma subunits subsequently modulate the activity of a diverse assortment of effector systems. GPCR signaling via heterotrimeric G proteins is attenuated rapidly by the engagement of protein kinases. The canonical model for GPCR desensitization involves G protein-coupled receptor kinase (GRK)-dependent receptor phosphorylation to promote the binding of arrestin proteins that function to sterically block receptor:G-protein interactions. GRK2 and GRK3 have been shown to interact with Galphaq via the regulator of G-protein signaling (RGS) homology (RH) domain localized within their amino-terminal domains. It now appears that the G-protein uncoupling of many GPCRs linked to Galphaq, in particularly metabotropic glutamate receptors, may be mediated by the GRK2 RH domain via a phosphorylation-independent mechanism. This article reviews much of the background and methodology required for the characterization of the GRK2 phosphorylation-independent attenuation of GPCR signaling.