G Alpha-q/11 Protein Plays a Key Role in Insulin-Induced Glucose Transport in 3T3-L1 Adipocytes

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Molecular and Cellular Biology, October 1999, p. 6765-6774, Vol. 19, No. 10
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

G Alpha-q/11 Protein Plays a Key Role in Insulin-Induced Glucose Transport in 3T3-L1 Adipocytes

Takeshi Imamura,¹ Peter Vollenweider,¹ Katsuya Egawa,¹ Martin Clodi,¹ Kenichi Ishibashi,¹ Naoki Nakashima,¹ Satoshi Ugi,¹ John W. Adams,² Joan Heller Brown,² and Jerrold M. Olefsky¹^,^*

Department of Medicine, Division of Endocrinology and Metabolism,¹ and Department of Pharmacology,² University of California, San Diego, La Jolla, California 92093

Received 19 May 1999/Returned for modification 24 June 1999/Accepted 2 July 1999

We evaluated the role of the G alpha-q (G $alpha$ q) subunit of heterotrimeric G proteins in the insulin signaling pathway leadingto GLUT4 translocation. We inhibited endogenous G $alpha$ q function bysingle cell microinjection of anti-G $alpha$ q/11 antibody or RGS2 protein(a GAP protein for G $alpha$ q), followed by immunostaining to assessGLUT4 translocation in 3T3-L1 adipocytes. G $alpha$ q/11 antibody andRGS2 inhibited insulin-induced GLUT4 translocation by 60 or 75%,respectively, indicating that activated G $alpha$ q is important for insulin-inducedglucose transport. We then assessed the effect of overexpressingwild-type G $alpha$ q (WT-G $alpha$ q) or a constitutively active G $alpha$ q mutant (Q209L-G $alpha$ q)by using an adenovirus expression vector. In the basal state,Q209L-G $alpha$ q expression stimulated 2-deoxy-D-glucose uptake and GLUT4translocation to 70% of the maximal insulin effect. This effectof Q209L-G $alpha$ q was inhibited by wortmannin, suggesting that it isphosphatidylinositol 3-kinase (PI3-kinase) dependent. We furthershow that Q209L-G $alpha$ q stimulates PI3-kinase activity in p110 $alpha$ andp110 $gamma$ immunoprecipitates by 3- and 8-fold, respectively, whereasinsulin stimulates this activity mostly in p110 $alpha$ by 10-fold. Nevertheless,only microinjection of anti-p110 $alpha$ (and not p110 $gamma$ ) antibody inhibitedboth insulin- and Q209L-G $alpha$ q-induced GLUT4 translocation, suggestingthat the metabolic effects induced by Q209L-G $alpha$ q are dependenton the p110 $alpha$ subunit of PI3-kinase. In summary, (i) G $alpha$ q appearsto play a necessary role in insulin-stimulated glucose transport,(ii) G $alpha$ q action in the insulin signaling pathway is upstream ofand dependent upon PI3-kinase, and (iii) G $alpha$ q can transmit signalsfrom the insulin receptor to the p110 $alpha$ subunit of PI3-kinase,which leads to GLUT4translocation.

^* Corresponding author. Mailing address: Dept. of Medicine (0673), University of California, San Diego, 9500 Gilman Dr., LaJolla, CA 92093. Phone: (858) 534-6651. Fax: (858) 534-6653. E-mail:jolefsky{at}ucsd.edu.

Molecular and Cellular Biology, October 1999, p. 6765-6774, Vol. 19, No. 10
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

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