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First published on December 2, 2005; DOI: 10.1124/mol.105.018846

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Received for publication September 26, 2005.
Revised December 1, 2005.
Accepted for publication December 2, 2005.

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

Alexandra V Andreeva 1, Rita Vaiskunaite 1, Mikhail A Kutuzov 1, Jasmina Profirovic 1, Randal A Skidgel 1, Tatyana A Voyno-Yasenetskaya 1*

1 University of Illinois

* Address correspondence to: E-mail: tvy{at}uic.edu

Abstract

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 heat shock protein 90 (Hsp90), regulate eNOS activity. Here we report a novel mechanism of G-protein-dependent regulation of eNOS. We demonstrate that in mammalian cells, 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 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 of eNOS mRNA. SiRNA-mediated depletion of endogenous G{alpha}12 decreases eNOS levels. A quantitative correlation can be detected between the extent of downregulation of G{alpha}12 and eNOS in endothelial cells following 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.


Key words: Thrombin/PAR, Nitric oxide synthases, G12,13;other G's


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