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  • Title: Novel mechanisms of G protein-dependent regulation of endothelial nitric-oxide synthase.
    Author: Andreeva AV, Vaiskunaite R, Kutuzov MA, Profirovic J, Skidgel RA, Voyno-Yasenetskaya T.
    Journal: Mol Pharmacol; 2006 Mar; 69(3):975-82. PubMed ID: 16326932.
    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 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 alpha12) can form a complex with eNOS in an activation- and Hsp90-independent manner. Our data show that G alpha12 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 alpha12 increases the expression of eNOS by increasing half-life of both eNOS protein and eNOS mRNA. Small interfering RNA-mediated depletion of endogenous G alpha12 decreases eNOS levels. A quantitative correlation can be detected between the extent of down-regulation of G alpha12 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.
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