In addition to their roles in GPCR desensitization and receptor clustering/trafficking, GRKs also bind directly to G protein subunits. GRK2 and GRK3 each contain C-terminal PH domains, which bind Gßy subunits (Pitcher et al. 1992; Carman et al. 2000). While Gßy association is an established mechanism for recruiting GRKs to the plasma membrane to regulate GPCR function, it is possible that GRK2 and GRK3 may also form a stable complex with GPCRs and Gßy to modulate receptor-directed G protein signalling. GRK2 also binds to Gqa through its RGS-like domain (Carman et al. 1999b). RGS domains are present in many proteins and bind directly with activated Ga subunits, and all GRKs contain an RGS-like domain. While the functional consequences of Ga interactions with GRK are unclear at present, it is possible that selective GRK/Ga complex formation could either dictate which receptors GRKs modulate, contribute to desensitization of G protein signalling, and/or propagate as yet unrecognized ligand and GPCR-directed signalling events.
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