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First published online May 24, 2004
doi: 10.1242/10.1242/jcs.01165

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eNOS at a glance

Department of Pharmacology and Vascular Cell Signaling Program, Boyer Center for Molecular Medicine, Yale University School of Medicine, New Haven, CT 06536, USA

(e-mail: william.sessa{at}yale.edu)

	Introduction

Top Introduction Various extracellular signals... Intrinsic control of eNOS... Regulated protein-protein... Effectors of NO References

 
Endothelium-derived nitric oxide (NO) is a critical regulator of cardiovascular homeostasis. Endothelial nitric oxide synthase (eNOS or NOS3)-derived NO is an endogenous vasodilatory gas that continually regulates the diameter of blood vessels and maintains an anti-proliferative and anti-apoptotic environment in the vessel wall. Initially thought to be a simple, calmodulin (CaM) regulated enzyme, it is clear that eNOS has evolved to be tightly controlled by co- and post-translational lipid modifications, phosphorylation on multiple residues and regulated protein-protein interactions (Fulton et al., 2001).

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	Various extracellular signals can promote NO release from endothelial cells

Top Introduction Various extracellular signals... Intrinsic control of eNOS... Regulated protein-protein... Effectors of NO References

 
Physiologically, endothelial cells are exposed to the hemodynamic forces of blood including laminar shear stress. Shear stress, via G proteins (Gs), can activate several signal transduction pathways, including the phosphoinoside 3-kinase (PI3K) and adenylate cyclase (AC) pathways, leading to eNOS activation via phosphorylation of serine residues (S617 and S1179 for Akt, and S635 and S1179 for PKA), which promote eNOS activation. Shear stress also increases S116 phosphorylation; however, the kinase responsible for this phosphorylation and the function of S116 are not well understood (Boo and Jo, 2003). Additional stimuli, such as vascular endothelial growth factor (VEGF), estrogen, sphingosine 1-phosphate (S-1-P) and bradykinin, can bind to their cognate receptors and also stimulate PI3K/Akt. However, they also activate phospholipase C- (PLC-) to increase cytoplasmic calcium and diacylglycerol (DAG) levels. The increase in cytoplasmic calcium levels activates CaM, which binds to the canonical CaM-binding domain in eNOS to promote the alignment of the oxygenase and reductase domains of eNOS, leading to efficient NO synthesis. In addition, CaM can activate CaM kinase II, which may phosphorylate eNOS on S1179. Increases in DAG levels can activate PKC to phosphorylate T497, which may negatively regulate eNOS or influence its coupling. Finally, metabolic stress triggering the breakdown of ATP will stimulate AMP kinase (AMPK) to phosphorylate eNOS on S1179 (Chen et al., 1999; Dimmeler et al., 1998; Fleming et al., 2001; Fulton et al., 1999; Harris et al., 2001; Haynes et al., 2000; Igarashi and Michel, 2001; Lin et al., 2003; Michell et al., 2002; Morales-Ruiz et al., 2001; Simoncini et al., 2000).

	Intrinsic control of eNOS function

Top Introduction Various extracellular signals... Intrinsic control of eNOS... Regulated protein-protein... Effectors of NO References

 
Co-translational N-terminal myristoylation on G2 and post-translational cysteine palmitoylation on C15 and C26 control the subcellular targeting of eNOS to the cytoplasmic aspect of the Golgi complex and to plasmalemmal caveolae (García-Cardeña et al., 1996; Liu et al., 1995; Liu et al., 1997; Liu and Sessa, 1994). Similar to nNOS and iNOS, eNOS contains a C-terminal reductase domain, which binds NADPH, and transfers electrons from NADPH to FAD to FMN, and ultimately to the N-terminal oxygenase domain, which contains a heme, and binding sites for arginine, tetrahydrobiopterin and CaM. eNOS utilizes molecular oxygen and electrons from NADPH to oxidize the substrate L-arginine into the intermediate OH-L-arginine, which is then oxidized into NO and L-citrulline (Griffith and Stuehr, 1995). Two autoinhibitory control elements (ACE-I and ACE-II) impede eNOS activation and influence the calcium/CaM sensitivity of the enzyme (Lane and Gross, 2002; Salerno et al., 1997). Given the localization of T497, S617 and S635 in ACE-1 and S1179 in ACE-II, it is likely that phosphorylation removes the steric hindrance imparted by these non-catalytic inserts and permits better fidelity of electron flux from the reductase domain to NO generation in the oxygenase domain (McCabe et al., 2000).

	Regulated protein-protein interactions

Top Introduction Various extracellular signals... Intrinsic control of eNOS... Regulated protein-protein... Effectors of NO References

 
eNOS can interact with various proteins in its `less active' and `more active' states. N-myristoylated and palmitoylated membrane-bound eNOS associates with the caveolae coat protein caveolin-1 (Cav-1) and with heat shock protein 90 (Hsp90). The C-terminal Hsp70-interacting protein (CHIP) interacts with both Hsp70 and Hsp90, and negatively regulates eNOS trafficking into the Golgi complex. By contrast, the nitric oxide synthase-interacting protein (NOSIP) and the nitric oxide synthase traffic inducer (NOSTRIN) can negatively regulate eNOS localization in the plasma membrane (Jiang et al., 2003; Nedvetsky et al., 2002; Zabel et al., 2002). Endothelial cell stimulation by various stimuli (top) activates eNOS catalysis [i.e. the conversion of L-arginine (L-Arg) to NO] through its association with CaM. Whether CaM is always bound and small changes in calcium determine calcium-CaM dependence, more CaM is recruited to eNOS by large fluxes in cytoplasmic calcium or how phosphorylation influences the calcium/CaM requirements of the enzyme in situ are not known. However, the actions of CaM are thought to be facilitated in cells by the recruitment of Hsp90 to eNOS and from the dissociation of eNOS from Cav-1. Both calcium-dependent and -independent stimuli have been shown to induce phosphorylation of S1179 on eNOS. Phosphorylation of this residue by Akt, PKA or AMPK is associated with increased enzyme activity. Other proteins have been show to be associated with increased eNOS activity or NO release, such as dynamin (Dyn), porin and the NO effector soluble guanylyl cyclase (sGC).

	Effectors of NO

Top Introduction Various extracellular signals... Intrinsic control of eNOS... Regulated protein-protein... Effectors of NO References

 
Once NO is produced by the endothelium, it can regulate several aspects of vascular function via activation of the primary NO receptor, sGC, or initiate nitrosation reactions with iron-sulphur-centered proteins or proteins with reactive thiols (S-nitrosylation). In the vascular system, NO-dependent relaxation of vascular smooth muscle is predominatly sGC and protein kinas G (PKG) dependent, whereas the anti-proliferative actions and ion channel modulation of NO can be via PKG or via nitrosation reactions (Feil et al., 2003; Miranda et al., 2003). Nitrosylation of caspase-3 and caspase-8 inactivates the proteins, thus leading to inhibition of apoptosis (Stamler et al., 2001).

	References

Top Introduction Various extracellular signals... Intrinsic control of eNOS... Regulated protein-protein... Effectors of NO References

 

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