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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 (Galpha q) subunit of heterotrimeric G proteins in the insulin signaling pathway leading to GLUT4 translocation. We inhibited endogenous Galpha q function by single cell microinjection of anti-Galpha q/11 antibody or RGS2 protein (a GAP protein for Galpha q), followed by immunostaining to assess GLUT4 translocation in 3T3-L1 adipocytes. Galpha q/11 antibody and RGS2 inhibited insulin-induced GLUT4 translocation by 60 or 75%, respectively, indicating that activated Galpha q is important for insulin-induced glucose transport. We then assessed the effect of overexpressing wild-type Galpha q (WT-Galpha q) or a constitutively active Galpha q mutant (Q209L-Galpha q) by using an adenovirus expression vector. In the basal state, Q209L-Galpha q expression stimulated 2-deoxy-D-glucose uptake and GLUT4 translocation to 70% of the maximal insulin effect. This effect of Q209L-Galpha q was inhibited by wortmannin, suggesting that it is phosphatidylinositol 3-kinase (PI3-kinase) dependent. We further show that Q209L-Galpha q stimulates PI3-kinase activity in p110alpha and p110gamma immunoprecipitates by 3- and 8-fold, respectively, whereas insulin stimulates this activity mostly in p110alpha by 10-fold. Nevertheless, only microinjection of anti-p110alpha (and not p110gamma ) antibody inhibited both insulin- and Q209L-Galpha q-induced GLUT4 translocation, suggesting that the metabolic effects induced by Q209L-Galpha q are dependent on the p110alpha subunit of PI3-kinase. In summary, (i) Galpha q appears to play a necessary role in insulin-stimulated glucose transport, (ii) Galpha q action in the insulin signaling pathway is upstream of and dependent upon PI3-kinase, and (iii) Galpha q can transmit signals from the insulin receptor to the p110alpha subunit of PI3-kinase, which leads to GLUT4 translocation.

* Corresponding author. Mailing address: Dept. of Medicine (0673), University of California, San Diego, 9500 Gilman Dr., La Jolla, 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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