alexa The endothelial nitric-oxide synthase-caveolin regulatory cycle.
Medicine

Medicine

Translational Medicine

Author(s): Feron O, Saldana F, Michel JB, Michel T

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Abstract Nitric oxide production in the vascular endothelium is promoted by diverse agonists that transiently increase intracellular Ca2+ concentration and activate the endothelial nitric-oxide synthase (eNOS), a Ca2+/calmodulin-dependent enzyme. eNOS is acylated by the fatty acids myristate and palmitate and is targeted thereby to plasmalemmal signal-transducing domains termed caveolae. eNOS enzyme activity is markedly attenuated by its interactions with caveolin, the structural scaffolding protein of caveolae. We have discovered that in living cells, the eNOS-caveolin heteromeric complex undergoes cycles of dissociation and re-association modulated by Ca2+-mobilizing agonists. Calcium ionophore A23187 and the muscarinic cholinergic agonist carbachol both promote the dissociation of eNOS from caveolin in cultured cells, associated with translocation of eNOS from caveolae. As [Ca2+]i returns to basal levels, eNOS re-associates with caveolin, and the inhibited enzyme complex is then restored to caveolae, a process accelerated by palmitoylation of the enzyme. These data establish an eNOS-caveolin regulatory cycle, wherein enzyme activation is modulated by reversible protein-protein interactions controlled by Ca2+/calmodulin and by enzyme palmitoylation. Alterations in this cycle are likely to have an important influence on nitric oxide-dependent signaling in the vascular wall.
This article was published in J Biol Chem and referenced in Translational Medicine

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