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eNOS activation and regulation

Stable Identifier
Homo sapiens
Locations in the PathwayBrowser

Originally identified as endothelium-derived relaxing factor, eNOS derived NO is a critical signaling molecule in vascular homeostasis. It regulates blood pressure and vascular tone, and is involved in vascular smooth muscle cell proliferation, platelet aggregation, and leukocyte adhesion. Loss of the bioavailability of endothelium derived NO is a key feature of endothelial dysfunction and is implicated in the pathogenesis of cardiovascular disease such as hypertension and atherosclerosis. The endothelial isoform eNOS is unique among the nitric oxide synthase (NOS) family in that it is co-translationally modified at its amino terminus by myristoylation and is further acylated by palmitoylation (two residues next to the myristoylation site). These modifications target eNOS to the plasma membrane caveolae and lipid rafts.

eNOS activation and subsequent nitric oxide (NO) production is stimulated by a variety of stimuli, such as fluid shear stress generated by blood flow, vascular endothelial growth factor (VEGF), bradykinin, estrogen, insulin, and angiopoietin. The activity of eNOS is further regulated by numerous post-translational modifications, including protein-protein interactions, phosphorylation, and subcellular localization.

Following activation, eNOS shuttles between caveolae and other subcellular compartments such as the noncaveolar plasma membrane portions, Golgi apparatus, and perinuclear structures. This subcellular distribution is variable depending upon cell type and mode of activation. Subcellular localization of eNOS has a profound effect on its ability to produce NO as the availability of its substrates and cofactors will vary with location. eNOS is primarily particulate, and depending on the cell type, eNOS can be found in several membrane compartments: plasma membrane caveolae, lipid rafts, and intracellular membranes such as the Golgi complex. In addition, it has been reported that eNOS can also be detected in the nucleus, however, the conditions associated with nuclear localization of eNOS and its precise role in this cell compartment remains to be determined.

Several stimuli can trigger a transient displacement of eNOS from the plasma membrane to other subcellular locations. This process can be mediated through various protein-protein interactions and/or changes in post-translational modifications. Knowledge of the precise molecular mechanisms governing the intracellular redistribution process is still rather limited.

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