While established models suggest that GRKs interact only transiently with GPCRs to phos-phorylate sites that promote arrestin binding, evidence suggests that GRKs may form a stable complex with GPCRs and other proteins. Recent studies indicate that GRKs engage a growing list of binding partners besides GPCRs, supporting the idea that GRKs are multifunctional proteins. Besides GPCRs, GRK isoforms have been shown to directly bind to the Ca++ binding proteins recoverin (GRK1) and calmodulin (GRKs2-6); caveolin (GRK2, others); actin (GRK5), tubulin (GRK2 and GRK5); synucleins (GRK5); and Gqa (GRK2) and G^y (GRK2 and GRK3) (for review see Penn et al. 2000 and references therein).

In many cases, binding of these proteins to GRKs either directly stimulates or inhibits GRK catalytic activity. However, in other cases GRKs may provide a functional link between GPCRs and these signalling proteins. Caveolin is a scaffolding protein that is the principle structural protein of caveolae, that is, subsets of the plasma membrane specializations known as lipid rafts (Brown and London 1998). Caveolin can bind a remarkable variety of signalling proteins that concentrate in caveolae, including certain GPCRs (Okamoto et al. 1998). It is possible that GRKs may contribute to GPCR localization to caveolae by interacting with caveolin (Carman et al. 1999a). The cytoskeletal proteins tubulin, actin, and synucleins also directly interact with GRKs. Both a- and ^-synucleins are phosphorylated by GRK5 (Pronin et al. 2000), whereas tubulin is phosphorylated by both GRK2 and GRK5 (Carman et al. 1998; Pitcher et al. 1998 b). Although actin is not a substrate for GRK phosphorylation, it binds to the N terminus of GRK5 to inhibit its kinase activity (Freeman et al. 1998). Taken together, these observations raise the intriguing possibility that GRKs may physically link GPCRs to proteins of the cytoskeleton and consequently influence GPCR subcellular localization, either at the plasma membrane or during intracellular trafficking following receptor internalization.

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