Abstract
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 α-subunit, Gαq/11, can mediate insulin-stimulated glucose transport. GRK2 contains a regulator of G protein signaling (RGS) domain with specificity for Gαq/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 Gαq/11 signaling to GLUT4 translocation. Furthermore, inhibitors of GRK2 can lead to enhanced insulin sensitivity.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 2821-2829 |
| Number of pages | 9 |
| Journal | EMBO Journal |
| Volume | 23 |
| Issue number | 14 |
| DOIs | |
| State | Published - Jul 21 2004 |
| Externally published | Yes |
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Keywords
- Gαq/11
- GLUT4 translocation
- GRK2
- Insulin signal transduction
ASJC Scopus subject areas
- Genetics
- Cell Biology
Cite this
GRK2 is an endogenous protein inhibitor of the insulin signaling pathway for glucose transport stimulation. / Usui, Isao; Imamura, Takeshi; Satoh, Hiroaki; Huang, Jie; Bever, Jennie; Hupfeld, Christopher J.; Olefsky, Jerrold M.
In: EMBO Journal, Vol. 23, No. 14, 21.07.2004, p. 2821-2829.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - GRK2 is an endogenous protein inhibitor of the insulin signaling pathway for glucose transport stimulation
AU - Usui, Isao
AU - Imamura, Takeshi
AU - Satoh, Hiroaki
AU - Huang, Jie
AU - Bever, Jennie
AU - Hupfeld, Christopher J.
AU - Olefsky, Jerrold M.
PY - 2004/7/21
Y1 - 2004/7/21
N2 - 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 α-subunit, Gαq/11, can mediate insulin-stimulated glucose transport. GRK2 contains a regulator of G protein signaling (RGS) domain with specificity for Gαq/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 Gαq/11 signaling to GLUT4 translocation. Furthermore, inhibitors of GRK2 can lead to enhanced insulin sensitivity.
AB - 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 α-subunit, Gαq/11, can mediate insulin-stimulated glucose transport. GRK2 contains a regulator of G protein signaling (RGS) domain with specificity for Gαq/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 Gαq/11 signaling to GLUT4 translocation. Furthermore, inhibitors of GRK2 can lead to enhanced insulin sensitivity.
KW - Gαq/11
KW - GLUT4 translocation
KW - GRK2
KW - Insulin signal transduction
UR - http://www.scopus.com/inward/record.url?scp=3543038233&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=3543038233&partnerID=8YFLogxK
U2 - 10.1038/sj.emboj.7600297
DO - 10.1038/sj.emboj.7600297
M3 - Article
C2 - 15241473
AN - SCOPUS:3543038233
VL - 23
SP - 2821
EP - 2829
JO - EMBO Journal
JF - EMBO Journal
SN - 0261-4189
IS - 14
ER -