Proliferation of regulatory mechanisms for eNOS: an emerging role for the cytoskeleton
2002; American Physical Society; Volume: 282; Issue: 6 Linguagem: Inglês
10.1152/ajplung.00045.2002
ISSN1522-1504
Autores Tópico(s)Ion Transport and Channel Regulation
ResumoEDITORIAL FOCUSProliferation of regulatory mechanisms for eNOS: an emerging role for the cytoskeletonRandal A. SkidgelRandal A. Skidgel Department of Pharmacology, University of Illinois College of Medicine, Chicago, Illinois 60612Published Online:01 Jun 2002https://doi.org/10.1152/ajplung.00045.2002MoreSectionsPDF (52 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations nitric oxide (NO) is a biologically active gas generated from the precursor arginine by one of three known NO synthases. NO produced by the endothelial nitric oxide synthase (eNOS) plays a crucial role in the regulation of a variety of cardiovascular and pulmonary functions in both normal and pathological conditions (14). It was noted early on that NO generation from endothelial cells requires calcium, and the dependence of eNOS activity on calcium/calmodulin binding was proven after purification and characterization of the enzyme (23). Increased intracellular calcium is thus an important regulator of eNOS activity and explains the ability of agonists such as bradykinin, acetylcholine, and thrombin to stimulate NO production via interaction with their respective G protein-coupled receptors. However, it is now becoming clear that the control of eNOS activity is much more complex, as reflected in the titles of two recent reviews on the subject (8,19).One important regulator of eNOS function is caveolin-1. Caveolin is an essential component of caveolae, 50–100 nm of flask-shaped microinvaginations in the cell membrane that are the location of an important pool of eNOS in endothelial cells (9). Binding of eNOS to the scaffolding domain of caveolin-1 inhibits its activity both in vitro and in vivo, and this effect can be mimicked by a synthetic peptide containing the scaffolding domain sequence (8). It is thought that activation of eNOS by the binding of calcium/calmodulin releases the caveolin inhibition due either to a conformational change or to dissociation of eNOS from caveolin (8). The tonic inhibition of eNOS by caveolin-1 in vivo was recently confirmed in studies on caveolin-1 knockout mice that exhibited blunted responses to vasoconstrictors and enhanced responses to acetylcholine due to increased vascular NO production (5, 25,26).Caveolin-1 is not the only protein that can regulate eNOS activity. The bradykinin receptor inhibits eNOS by binding to it through intracellular domain 4, and the interaction is disrupted by the binding of bradykinin to the receptor (17). NOSIP (eNOS interacting protein) is a 34-kDa protein that binds with high affinity to eNOS, and the binding can be dissociated with a synthetic caveolin-1 scaffolding domain peptide (4). Although NOSIP does not directly inhibit eNOS activity in vitro, coexpression with eNOS reduces ionomycin-induced NO production by causing redistribution of eNOS from the plasma membrane to intracellular compartments (4). Dynamin-2, a large GTPase thought to be involved in vesicle formation and trafficking, can associate directly with eNOS and augment its activity (2). The physiological relevance of these protein-eNOS interactions remains to be defined.A recently discovered mechanism for activating eNOS is by phosphorylation of the protein, stimulated by agonists such as vascular endothelial growth factor (VEGF) and sphingosine 1-phosphate, or by shear stress (8, 19). In general, this activation is slower in onset and more prolonged than that which is stimulated by agonist-induced increases in intracellular calcium. A critical phosphorylation site in eNOS has been identified as Ser1179(bovine) or Ser1177 (human) (8). Although several protein kinases have been reported to phosphorylate eNOS, a pathway of primary importance involves activation of Akt or protein kinase B (8). Akt can directly phosphorylate eNOS, resulting in enzyme that is up to 20 times more active at optimal calcium/calmodulin concentrations (10) and is activated at lower levels of calcium/calmodulin (7). It has also been reported that phosphorylation at Thr497 negatively regulates eNOS activity (8). For example, eNOS activation by bradykinin does not result in phosphorylation of Ser1179but does require dephosphorylation of Thr497(13). Protein kinase A signaling also activates eNOS due to dephosphorylation of Thr497 and phosphorylation of Ser1179, whereas protein kinase C activation has the opposite effect on phosphorylation at these sites, causing inactivation of eNOS (22).Another important factor that regulates eNOS activity is its localization within the cell (21). It has been known for some time that eNOS is both myristoylated and palmitoylated and that appropriate acylation is required for the correct targeting of eNOS to the caveolar microdomains of the plasma membrane and intracellular membranes (8, 20). Elimination of the appropriate acylation signals inhibits NO release, eNOS activity, and eNOS phosphorylation in response to agonists, indicating that proper subcellular localization is necessary for optimal functioning and receptor-mediated stimulation of eNOS activity (6, 8, 20). It has been proposed that downregulation of eNOS activity after agonist stimulation is a result of redistribution of the enzyme from the caveolae/plasma membrane to either the cytosol or internal membranes (20), although some studies have failed to show such a redistribution. For example, it was recently reported (6) that activation of eNOS by VEGF or by overexpression of Akt increased phosphorylated eNOS in both the plasma membrane/caveolar fraction as well as intracellular membranes (likely Golgi) without a change in cellular distribution of the enzyme. Furthermore, NO was generated not only in the vicinity of the plasma membrane but also at high levels intracellularly, in the perinuclear region. Thus eNOS on both the plasma membrane/caveolae and intracellular membranes can be activated by agonists without a net change in subcellular distribution (6).Heat shock protein 90 (HSP90) is an essential, highly expressed cytosolic protein that can be upregulated during stress (24). Similar to other heat shock proteins, HSP90 plays an important role as a chaperone in regulating protein folding and maturation, but it also interacts with signal transduction proteins such as Src kinases, Raf, or Gβγ-subunits (24). Although the functions of many of these interactions are unclear, HSP90 was recently shown to be an essential component of Gα12-induced serum response element activation, cytoskeletal changes, and mitogenic response (28). HSP90 also plays an important role in the regulation of eNOS activity; agonists such as VEGF, histamine, and shear stress increase the association of HSP90 with eNOS, which enhances eNOS activation (11). Further details regarding the regulation of eNOS by HSP90 have since been revealed in a variety of studies (8). For example, eNOS, caveolin-1, and HSP90 coimmunoprecipitate in a macromolecular complex, and HSP90 enhances the displacement of eNOS from caveolin-1 (12). In addition, eNOS-HSP90 complexes are less sensitive to inhibition by a caveolin scaffolding domain peptide (12). HSP90 also mediates the VEGF-stimulated transition of eNOS from a calcium-dependent activation state to phosphorylation-dependent potentiation through recruitment of Akt to the eNOS/HSP90 complex to phosphorylate Ser1177(1). Because HSP90 is not known to directly interact with caveolin, there have been two models proposed (8) to explain the dynamic interactions between eNOS, caveolin, and HSP90:1) Recruitment or activation of HSP90 and calmodulin to eNOS results in weak displacement of eNOS from caveolin, but the complex remains in caveolae; and 2) HSP90 and calcium-activated calmodulin interact with eNOS and, while still bound to caveolin, cause a conformational change in eNOS that allows for efficient stimulation-response coupling.As can be seen from this brief overview, eNOS activity is regulated by a complex, coordinated interplay between many different proteins. However, the details by which these control mechanisms work are not well understood. In addition, the physical localization of eNOS is likely an important factor that regulates its ability to interact with these modulators and mediators. In this context, the paper by Su et al., one of the current articles in focus (Ref. 27, see p. L1183 in this issue), reveals another level of regulation for eNOS that connects the activation process to the integrity of the cytoskeleton. Besides adding another piece to the eNOS regulation puzzle, it opens up a potentially fruitful area for investigation. The essence of the study is the demonstration that the state of microtubule polymerization affects endothelial cell NO production and eNOS activity and, furthermore, that this response is mediated through HSP90.The investigators (27) treated porcine pulmonary artery endothelial cells for 2–4 h with either taxol (to stabilize microtubules) or nocodazole (to inhibit microtubule polymerization) and then measured NO production using the intracellular fluorescent probe 4,5-diaminofluorescein diacetate and assayed eNOS activity by measuring [3H]arginine to [3H]citrulline conversion. Pretreatment of cells with taxol resulted in an increase in NO production, whereas treatment with nocodazole reduced NO production (27). The effect of nocodazole was blocked when coadministered with taxol, indicating a specific effect on microtubule formation was responsible for the results. Interestingly, this effect is mediated by HSP90, as shown by two pieces of evidence. First, coimmunoprecipitation of eNOS and HSP90 was increased by taxol and decreased by nocodazole. Second, geldanamycin, an antibiotic that binds to the nucleotide-binding site of HSP90 and blocks its activity (24), inhibited the ability of taxol to increase eNOS activity (27). These treatments had no effect on protein levels of HSP90, eNOS, or tubulin, indicating the results were due to changes in the association of existing molecules (27). Surprisingly, there was also no effect of taxol or nocodazole on the coimmunoprecipitation of eNOS with tubulin or HSP90 with tubulin. These data indicate that tubulin polymerization strengthens the interaction between eNOS and HSP90 or increases the amount of HSP90 associated with eNOS without changing the bulk association of these molecules with tubulin. However, there remains the possibility that microtubule depolymerization might alter tubulin binding to HSP90/eNOS at a restricted local level (e.g., in the vicinity of caveolae) that could affect NO production but would not be detectable by immunoprecipitation of the proteins from the whole cell. Immunoprecipitation studies of caveolar preparations from cells treated with microtubule-active agents would be informative in this regard.In a recently published paper (30), investigators from the same group provided evidence for another connection between eNOS-mediated NO production and the cytoskeleton. They reported that stabilization of actin polymerization with jasplankinolide increased arginine transport and NO production in porcine pulmonary artery endothelial cells, whereas treatment with swinholide A to disrupt actin microfilaments decreased arginine transport and NO production (30). These treatments had no effect on expression of eNOS or the arginine transporter and did not affect eNOS activity in isolated membrane fractions. Thus the state of actin polymerization likely affected the efficiency of arginine transport and substrate supply for eNOS, possibly by changing the proximity of the arginine transporter to eNOS.Together, the above studies highlight the importance of the cytoskeleton in regulating the signal transduction process leading to the generation of NO by endothelial cells. These results are consistent with an earlier study that showed the cytoskeleton to be important for mechanotransduction of shear stress-induced NO production in rabbit aortic rings (15). Cytoskeletal interactions and integrity are important regulators of a variety of signaling processes and are now thought to play an important role in vascular changes in hypertension (16). Determining how these effects are mediated will require further study, but the physical organization of the various components into a complex that is efficiently coupled is a likely possibility.One way in which the cytoskeleton might interact with and regulate the eNOS system is through caveolin or caveolar integrity. The possible interactions of caveolin or caveolae with microtubules have not been clearly defined, but there are a few studies that hint at a connection. For example, caveolin-1 expression is highly upregulated in taxol-resistant A549 human lung carcinoma cells, and taxol induces upregulation of caveolin-1 expression in the same cell line (29). In addition, one step in the process of caveolin cycling between the plasma membrane and Golgi, transfer from the endoplasmic reticulum/Golgi intermediate compartment (or ERGIC) to the Golgi, requires microtubules (3). Although caveolin is obviously an important regulator of eNOS activity (5, 8, 26), these data do not provide a ready explanation for the results reported by Su et al. (27) in which taxol increased and nocodazole decreased eNOS activity. This is because increased caveolin-1 expression by taxol should inhibit eNOS activity, and inhibition of caveolin trafficking by nocodazole would be expected to cause accumulation of caveolin in the ERGIC (3) and relative depletion in the plasma membrane, which should increase eNOS activity, opposite of the actual effects of these reagents on endothelial NO production (27).The results of Su et al. (27) show that microtubule integrity affects the ability of HSP90 to bind and activate eNOS. The role of the cytoskeleton in regulating the function of HSP90 is not well understood. In general, chaperones such as HSP90 can affect the formation and function of the cytoskeleton under normal conditions and protect it under stress via their chaperone actions (18). Although HSP90 is primarily a cytosolic protein, there is evidence that it can associate with microtubules and possibly cytokeratin intermediate filaments as well (18). The function of HSP90-cytoskeletal interactions has not been rigorously investigated, but there is indirect evidence that it may be important. For example, HSP90 plays a critical role in binding and regulating the activity of steroid hormone receptors, and it may also facilitate trafficking of the receptors to the nucleus by interacting with the microtubular system (24).The results of Su et al. (27) raise many interesting questions that will likely be addressed in future investigations. For example, is the activation of eNOS by agonist-induced increases in intracellular calcium also affected by microtubule polymerization? This question was not directly addressed by Su et al. (27). An earlier study indicates that this may not be the case because administration of nocodazole to isolated arterial ring preparations did not affect acetylcholine-induced NO production (15). Thus the main role of the cytoskeleton might be to enhance the phosphorylation-induced activation of eNOS by Akt or other protein kinases in response to stimuli such as VEGF, sphingosine 1-phosphate, or shear stress. This is consistent with the known ability of HSP90 to recruit and enhance Akt-mediated phosphorylation of eNOS (1). It would thus be interesting to investigate the phosphorylation state of eNOS in response to treatment with microtubule-disrupting or -stabilizing agents. Another question raised by the study of Su et al. (27) is whether microtubule depolymerization leads to displacement of eNOS from its appropriate subcellular location by disrupting caveolae or other subcellular structures. Microtubule disruption might, therefore, have an effect analogous to that which is seen with acylation-deficient eNOS mutants that results in mislocalized eNOS with reduced activity. A detailed investigation of the subcellular distribution of eNOS after microtubule disruption would be informative in this regard. Another interesting question arises from the finding that the state of microtubule polymerization does not affect the ability of tubulin to associate with HSP90 or eNOS. How, then, do taxol and nocodazole affect the HSP90-eNOS interaction? An explanation favored by the authors (27) is that increased tubulin polymerization brings HSP90 physically closer to eNOS, promoting their association. This is a plausible explanation, although another possibility consistent with the data is that tubulin polymerization alters the conformation of bound HSP90, increasing its affinity for eNOS, which results in enhanced eNOS activity.The findings of Su et al. (27) provide a mechanistic explanation for earlier reports of the ability of microtubule-depolymerizing agents to potentiate pressor responses to vasoconstrictor agents (16) and reduce shear stress-induced NO production in rabbit aortic rings (15). These results could also have clinical relevance because cytoskeletal integrity and disruption play an important role in signal transduction cascades intimately related to cardiovascular diseases (16). Further investigations into the relationship between the cytoskeleton and eNOS will undoubtedly bring new insight into the ways this important enzyme is regulated in the pulmonary and cardiovascular systems in both normal and disease states.FOOTNOTESAddress for reprint requests and other correspondence: R. A. Skidgel, Dept. of Pharmacology (m/c 868), Univ. of Illinois College of Medicine, 835 S. 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Skidgel1 June 2003 | American Journal of Physiology-Heart and Circulatory Physiology, Vol. 284, No. 6Microtubule Damaging Agents and Apoptosis More from this issue > Volume 282Issue 6June 2002Pages L1179-L1182 Copyright & PermissionsCopyright © 2002 the American Physiological Societyhttps://doi.org/10.1152/ajplung.00045.2002PubMed12003771History Published online 1 June 2002 Published in print 1 June 2002 Metrics
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