GRK2 is an endogenous protein inhibitor of the insulin signaling pathway for glucose transport stimulation.
G protein-coupled receptor kinases (GRKs) represent a class of proteins that classically phosphorylate agonist- activated G protein-coupled receptors, leading to uncoupling of the receptor from further G protein activation. Recently, we have reported that the heterotrimeric G protein alpha-subunit, Galphaq/11, can mediate insulin-stimulated glucose transport. GRK2 contains a regulator of G protein signaling (RGS) domain with specificity for Galphaq/11. Therefore, we postulated that GRK2 could be an inhibitor of the insulin signaling cascade leading to glucose transport in 3T3-L1 adipocytes. In this study, we demonstrate that microinjection of anti-GRK2 antibody or siRNA against GRK2 increased insulin-stimulated insulin-responsive glucose transporter 4 (GLUT4) translocation, while adenovirus-mediated overexpression of wild-type or kinase-deficient GRK2 inhibited insulin-stimulated GLUT4 translocation as well as 2-deoxyglucose uptake. Importantly, a mutant GRK2 lacking the RGS domain was without effect. Taken together, these results indicate that through its RGS domain endogenous GRK2 functions as a negative regulator of insulin- stimulated glucose transport by interfering with Galphaq/11 signaling to GLUT4 translocation. Furthermore, inhibitors of GRK2 can lead to enhanced insulin sensitivity.[1]References
- GRK2 is an endogenous protein inhibitor of the insulin signaling pathway for glucose transport stimulation. Usui, I., Imamura, T., Satoh, H., Huang, J., Babendure, J.L., Hupfeld, C.J., Olefsky, J.M. EMBO J. (2004) [Pubmed]
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