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Molecular Pharmacology Fast Forward
First published on December 2, 2005; DOI: 10.1124/mol.105.018846

0026-895X/06/6903-975-982$20.00
Mol Pharmacol 69:975-982, 2006

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Novel Mechanisms of G Protein-Dependent Regulation of Endothelial Nitric-Oxide Synthase

Alexandra V. Andreeva, Rita Vaiskunaite, Mikhail A. Kutuzov, Jasmina Profirovic, Randal A. Skidgel, and Tatyana Voyno-Yasenetskaya

Department of Pharmacology, College of Medicine, University of Illinois at Chicago, Chicago, Illinois

Endothelial nitric-oxide synthase (eNOS) plays a crucial role in the regulation of a variety of cardiovascular and pulmonary functions in both normal and pathological conditions. Multiple signaling inputs, including calcium, caveolin-1, phosphorylation by several kinases, and binding to the 90-kDa heat shock protein (Hsp90), regulate eNOS activity. Here, we report a novel mechanism of G protein-dependent regulation of eNOS. We demonstrate that in mammalian cells, the {alpha} subunit of heterotrimeric G12 protein (G{alpha}12) can form a complex with eNOS in an activation- and Hsp90-independent manner. Our data show that G{alpha}12 does not affect eNOS-specific activity, but it strongly enhances total eNOS activity by increasing cellular levels of eNOS. Experiments using inhibition of protein or mRNA synthesis show that G{alpha}12 increases the expression of eNOS by increasing half-life of both eNOS protein and eNOS mRNA. Small interfering RNA-mediated depletion of endogenous G{alpha}12 decreases eNOS levels. A quantitative correlation can be detected between the extent of down-regulation of G{alpha}12 and eNOS in endothelial cells after prolonged treatment with thrombin. G protein-dependent increase of eNOS expression represents a novel mechanism by which heterotrimeric G proteins can regulate the activity of downstream signaling molecules.

Received September 13, 2005; accepted December 2, 2005

Address correspondence to: Dr. Tatyana Voyno-Yasenetskaya, Department of Pharmacology (MC 868), University of Illinois, College of Medicine, 909 S. Wolcott Ave., Rm 4137, Chicago, IL 60612. E-mail: tvy{at}uic.edu


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Endothelial Nitric-Oxide Synthase Reveals a New Face in G Protein Signaling
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