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.
Usui
Isao
I
Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla, CA 92093-0673, USA.
Imamura
Takeshi
T
Satoh
Hiroaki
H
Huang
Jie
J
Babendure
Jennie L
JL
Hupfeld
Christopher J
CJ
Olefsky
Jerrold M
JM
D041721:3T3-L1 Cells; D000256:Adenoviridae / Q000235:genetics; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001692:Biological Transport; D002454:Cell Differentiation; D002460:Cell Line; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D003847:Deoxyglucose / Q000378:metabolism; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000378:metabolism; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000187:drug effects; D005947:Glucose / Q000378:metabolism*; D051275:Glucose Transporter Type 4; D007328:Insulin / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D009004:Monosaccharide Transport Proteins / Q000187:drug effects / Q000378:metabolism; D009124:Muscle Proteins / Q000187:drug effects / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000032:analysis / Q000378:metabolism; D010957:Plasmids / Q000378:metabolism; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D051552:beta-Adrenergic Receptor Kinases
D051275:Glucose Transporter Type 4; D007328:Insulin; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C495693:Slc2a4 protein, mouse; D003847:Deoxyglucose; D019869:Phosphatidylinositol 3-Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D051552:beta-Adrenergic Receptor Kinases; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D005947:Glucose