Cellular regulation of endothelial nitric oxide synthase

2001 ◽  
Vol 280 (2) ◽  
pp. F193-F206 ◽  
Author(s):  
Roland Govers ◽  
Ton J. Rabelink
Keyword(s):  
Nitric Oxide ◽  
Protein Interactions ◽  
Cellular Localization ◽  
Fluid Shear Stress ◽  
Transcriptional Level ◽  
Protein Protein Interactions ◽  
Cellular Regulation ◽  
Complex Regulation ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

Renal function is highly dependent on endothelium-derived nitric oxide (NO). Several renal disorders have been linked to impaired NO bioavailability. The enzyme that is responsible for the synthesis of NO within the renal endothelium is endothelial NO synthase (eNOS). eNOS-mediated NO generation is a highly regulated cellular event, which is induced by calcium-mobilizing agonists and fluid shear stress. eNOS activity is regulated at the transcriptional level but also by a variety of modifications, such as acylation and phosphorylation, by its cellular localization, and by protein-protein interactions. The present review focuses on the complex regulation of eNOS within the endothelial cell.

Molecular mechanisms involved in the regulation of the endothelial nitric oxide synthase

2003 ◽  
Vol 284 (1) ◽  
pp. R1-R12 ◽  
Author(s):  
Ingrid Fleming ◽  
Rudi Busse
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Endothelial Nitric Oxide Synthase ◽  
Molecular Mechanisms ◽  
Fluid Shear Stress ◽  
Intracellular Localization ◽  
Heat Shock Protein 90 ◽  
Enos Activity ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

The endothelial nitric oxide synthase (eNOS), the expression of which is regulated by a range of transcriptional and posttranscriptional mechanisms, generates nitric oxide (NO) in response to a number of stimuli. The physiologically most important determinants for the continuous generation of NO and thus the regulation of local blood flow are fluid shear stress and pulsatile stretch. Although eNOS activity is coupled to changes in endothelial cell Ca2+ levels, an increase in Ca2+ alone is not sufficient to affect enzyme activity because the binding of calmodulin (CaM) and the flow of electrons from the reductase to the oxygenase domain of the enzyme is dependent on protein phosphorylation and dephosphorylation. Two amino acids seem to be particularly important in regulating eNOS activity and these are a serine residue in the reductase domain (Ser1177) and a threonine residue (Thr495) located within the CaM-binding domain. Simultaneous alterations in the phosphorylation of Ser1177 and Thr495 in response to a variety of stimuli are regulated by a number of kinases and phosphatases that continuously associate with and dissociate from the eNOS signaling complex. eNOS associated proteins, such as caveolin, heat shock protein 90, eNOS interacting protein, and possibly also motor proteins provide the scaffold for the formation of the protein complex as well as its intracellular localization.

Relationships between caveolae and eNOS: everything in proximity and the proximity of everything

2002 ◽  
Vol 283 (1) ◽  
pp. F1-F10 ◽  
Author(s):  
Michael S. Goligorsky ◽  
Hong Li ◽  
Sergey Brodsky ◽  
Jun Chen
Keyword(s):  
Nitric Oxide ◽  
Fluid Shear Stress ◽  
Central Element ◽  
Endothelial Permeability ◽  
Inflammatory Cells ◽  
Oxide System ◽  
Fluid Shear ◽  
Caveolin 1 ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

Caveolae, flask-shaped invaginations of the plasma membrane occupying up to 30% of cell surface in capillaries, represent a predominant location of endothelial nitric oxide synthase (eNOS) in endothelial cells. The caveolar coat protein caveolin forms high-molecular-weight, Triton-insoluble complexes through oligomerization mediated by interactions between NH2-terminal residues 61–101. eNOS is targeted to caveolae by cotranslational N-myristoylation and posttranslational palmitoylation. Caveolin-1 coimmunoprecipitates with eNOS; interaction with eNOS occurs via the caveolin-1 scaffolding domain and appears to result in the inhibition of NOS activity. The inhibitory conformation of eNOS is reversed by the addition of excess Ca2+/calmodulin and by Akt-induced phosphorylation of eNOS. Here, we shall dissect the system using the classic paradigm of a reflex loop: 1) the action of afferent elements, such as fluid shear stress and its putative caveolar sensor, on caveolae; 2) the ways in which afferent signals may affect the central element, the activation of the eNOS-nitric oxide system; and 3) several resultant well-established and novel physiologically important effector mechanisms, i.e., vasorelaxation, angiogenesis, membrane fluidity, endothelial permeability, deterrance of inflammatory cells, and prevention of platelet aggregation.

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