eNOS activation

Stable Identifier
Homo sapiens
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eNOS activity is regulated by numerous post-translational modifications including phosphorylation and acylation, which also modulate its interactions with other proteins and its subcellular localization.

In general, following myristoylation and palmitoylation, eNOS localizes to caveolae in the plasma membrane, where in resting cells, it is bound to caveolin and remains inactive. Several agonists that raise intracellular calcium concentrations promote calmodulin binding to eNOS and the dissociation of caveolin from the enzyme, leading to an activated eNOS-calmodulin complex.

Phosphorylation plays a significant role in regulating eNOS activity, especially the phosphorylation of Ser1177, located within the reductase domain, which increases enzyme activity by enhancing reductase activity and calcium sensitivity. In unstimulated, cultured endothelial cells, Ser1177 is rapidly phosphorylated following a variety of stimuli: fluid shear stress, insulin, estrogen, VEGF, or bradykinin. The kinases involved in this process depend upon the stimuli applied. For instance, shear stress phosphorylates Ser1177 by activating Akt and PKA; insulin activates both Akt and the AMP-activated protein kinase (AMPK); estrogen and VEGF mainly phosphorylate eNOS via Akt; whereas the bradykinin-induced phosphorylation of Ser1177 is mediated by CaMKII. When Ser1177 is phosphorylated, NO production is increased several-fold above basal levels.

The phosphorylation of a threonine residue (Thr 495), located in the CaM binding domain, is associated with a decrease in eNOS activity. When this residue is dephosphorylated, substantially more CaM binds to eNOS and elevates enzyme activity. Stimuli associated with dephosphorylation of Thr495 (e.g., bradykinin, histamine, and Ca2+ ionophores) also increase Ca2+ levels resulting in the phosphorylation of Ser1177.

Additional phosphorylation sites, such as Ser114 and Ser633, and tyrosine phosphorylation have all been detected, but their functional relevance remains unclear. It is speculated that the tyrosine phosphorylation of eNOS is unlikely to affect enzyme activity directly, but more likely to impact the protein-protein interactions with associated scaffolding and regulatory proteins.

Literature References
PubMed ID Title Journal Year
10551886 Depalmitoylation of endothelial nitric-oxide synthase by acyl-protein thioesterase 1 is potentiated by Ca(2+)-calmodulin

Duncan, JA, Michel, T, Yeh, DC, Yamashita, S

J Biol Chem 1999
16722822 Subcellular targeting and trafficking of nitric oxide synthases

Muller-Esterl, W, Fulton, D, Oess, S, Govers, R, Icking, A

Biochem J 2006
11208594 Cellular regulation of endothelial nitric oxide synthase

Rabelink, TJ, Govers, R

Am J Physiol Renal Physiol 2001
12482742 Molecular mechanisms involved in the regulation of the endothelial nitric oxide synthase

Fleming, I, Busse, R

Am J Physiol Regul Integr Comp Physiol 2003
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