Interaction of Neuronal Nitric-oxide Synthase with Caveolin-3 in Skeletal Muscle

Venema, Virginia J.; Ju, Hong; Zou, Rong; Venema, Richard C.

doi:10.1074/jbc.272.45.28187

Cited by 233 publications

(137 citation statements)

References 28 publications

(38 reference statements)

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“…We found, however, no evidence of increased expression or altered interaction of caveolins with NOS enzymes in muscle of STZ-diabetic rats. Unlike a previous study where nNOS was shown to coimmunoprecipitate with caveolin-3 in skeletal muscle [30], we could not detect any association of these two proteins in our study. Caveolin-3 immunoprecipitation was done in the presence of several different detergents [octylglucoside, Triton X-100, or 3-[(3-cholamidopropyl)-dimethylammonio]-1-propanesulphonate (CHAPS)] with similar results (data not shown).…”

Section: Discussioncontrasting

confidence: 55%

“…The lack of detectable nNOS-caveolin-3 interaction cannot be explained by the limit of detection of nNOS or eNOS by immunoblotting because caveolin-3 was quantifiably immunoprecipitated from up to 400 mg of the CSM fraction and NOS enzymes can be readily detected from 10 mg of CSM membranes. One possible explanation is that in the previous study [30] caveolin-3 was immunoprecipitated from total muscle homogenates whereas we have used semi-purified CSM fractions as starting material. It is possible that the interaction between nNOS and caveolin-3 is specifically localised to some cellular compartments (e. g. cytoskeletal elements) not isolated by our fractionation procedure.…”

Section: Discussionmentioning

confidence: 95%

“…Because direct binding of eNOS and nNOS on the scaffolding domains of caveolins inhibits enzymatic activity [30,41], it was of interest to test for possible alterations of eNOS and nNOS binding to skeletal muscle caveolins in diabetes. Caveolin-1 has been shown to be expressed in skeletal muscle capillaries whereas caveolin-3 is found in the myofibres [25].…”

Section: Discussionmentioning

confidence: 99%

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Mechanism of impaired nitric oxide synthase activity in skeletal muscle of streptozotocin-induced diabetic rats

2000

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Type I (insulin-dependent) diabetes mellitus is characterised by pronounced insulin resistance for glucose disposal in skeletal muscle [1,2]. This metabolic impairment is at least in part related to a post-insulin signalling defect in the expression and translocation of GLUT4 glucose transporters to the muscle cell surface [3±5]. The lack of insulin action on glucose metabolism in muscle of people with Type I diabetes could also be explained by an impaired vasodilatory effect of insulin on the muscle vasculature [2], although this impairment has not been confirmed in a more recent study [1]. Several studies have shown that endothelium-dependent relaxation is altered in Abstract Aims/hypothesis. The aims of our study were to investigate whether nitric oxide synthase (NOS) activity is impaired in skeletal muscle of insulin-deficient [Type I (insulin-dependent)] diabetic rats and if the case, to determine the mechanism of NOS dysregulation in this disorder. Methods. Rats were rendered diabetic by streptozotocin injection (65 mg/kg, i. v.) and NOS activity and expression in gastrocnemius muscles were studied 1, 2, 3 or 4 weeks after diabetes induction. Results. The diabetic state was associated with a progressive reduction (down to 42 % of control values after 4 weeks) in muscle NOS activity compared with control rats. Using reverse transcriptase-polymerase chain reaction, we could not detect statistically significant changes in the expression of either neuronal NOS (nNOS) or endothelial NOS (eNOS) mRNAs in diabetic muscle. The contents of nNOS and eNOS protein were, however, progressively reduced in muscle homogenates of diabetic rats and these alterations were prevented by insulin treatment. Subcellular fractionation of skeletal muscle showed that both nNOS and eNOS proteins are mainly localised to the plasma membrane with lower abundance in T-tubules and not detectable in sarcoplasmic reticulum-enriched fractions. After 1 week of diabetes, eNOS protein content was decreased only in the plasma membrane whereas nNOS protein abundance was not affected at this time. Neither the expression nor the interaction of caveolin-1 and caveolin-3 with NOS enzymes was found to be altered in muscle of diabetic rats. Conclusion/interpretation. These results show that skeletal muscle NOS activity is impaired during the progression of insulin-deficient diabetes and reduced NOS activity is associated with a decreased abundance of both nNOS and eNOS proteins, which appears to involve post-transcriptional mechanisms.

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Section: Discussioncontrasting

confidence: 55%

Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

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Mechanism of impaired nitric oxide synthase activity in skeletal muscle of streptozotocin-induced diabetic rats

2000

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“…40 Activity of all 3 NOS isoforms is modulated by proteinprotein interactions. 41 Protein inhibitor of neuronal NOS (PIN), 42,43 caveolin-1, 44 caveolin-3, 45 and several proteins bearing PDZ domains 46 that influence targeting to discrete membrane domains of excitable tissues regulate NOS 1 activity. Although some of these proteins have been localized to the kidney, 47 we know of no studies investigating the role of these proteins in renal NOS 1 activity.…”

Section: Regulation Of Nos Activitymentioning

confidence: 99%

Recent Advances in the Regulation of Nitric Oxide in the Kidney

Herrera

Garvin

2005

Hypertension

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Abstract-Nitric oxide (NO) plays important roles in the regulation of renal function and the long-term control of blood pressure. New roles of NO have been proposed recently in diabetes, nephrotoxicity, and pregnancy. NO derived from all 3 NOS isoforms contributes to the overall regulation of kidney function, and recent advances in our understanding of their regulation have been made lately. In this regard, substrate and cofactor availability play important roles in regulating nitric oxide synthase (NOS) activity not only by limiting enzyme activity but also by influencing the coupling of NOS with its cofactors, tetrahydrobiopterin and NADPH. Protein-protein interactions are now recognized to be important negative and positive regulators of NOS. Phosphorylation is another component of the mechanism whereby NOS is activated or deactivated. Increased NOS expression can also influence enzyme activity; however, the degree of expression does not always correlate with enzyme activity because increased NO levels can result in inhibition of NOS. Finally, other potential regulators of NOS such as endogenous L-arginine analogs may also be important. In this article, we summarize recent advances in the regulation of activity and expression of the NOS isoforms within the kidney. renal function and long-term regulation of blood pressure. [1][2][3][4] This is best evidenced by the fact that inhibiting intrarenal NO production increased blood pressure. 5 In addition, reduced NO has been identified as a common denominator of many hypertensive models. 6 -9 The effects of NO on blood pressure via actions in the kidney occur through multiple mechanisms. These include increasing renal blood flow caused by vasodilatation, 10 increasing glomerular filtration, 11 inhibiting sodium transport along the nephron, 12-14 and regulating release of renin. 15 NO produced by each of the 3 nitric oxide synthases (NOS), NOS 1, NOS 2, and NOS 3, reportedly contributes to the regulation of renal function. Inhibition of NOS activity within the kidney is known to lead to sodium retention and hypertension. This review addresses recent advances in our understanding of the role played by renal NO in various physiological and pathophysiological conditions, as well as how NO production is regulated. Roles for Renal NOHistorically, NO produced by the kidney has been thought of primarily as a factor that regulates urinary volume and sodium excretion. The physiological effects of NO can be mediated via changes in renal hemodynamics and/or salt and water absorption by the nephron. NO reduces renal vascular tone in part by dilating the afferent arteriole. 16 It also increases glomerular filtration rate. 11 NO modulates renin secretion by the juxtaglomerular apparatus 15 and tubuloglomerular feedback. 3 Finally, NO regulates transport in various nephron segments as reviewed recently by Ortiz and Garvin. 12 More recently it has been recognized that in a number of pathophysiological conditions, the actions of NO on renal hemodynamics and/or nephron transport are ...

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“…CAV-1 has been reported to negatively regulate the downstream activation of many signaling molecules, including the EGFR, Src family tyrosine kinases, and components of the Ras/MAP kinase pathway (26,27). There was a higher IHC expression of baseline CAV-1 staining in the tumors (P281 and P247) sensitive to bosutinib compared with resistant tumors (P215 and P420), and bosutinib treatment augmented the CAV-1 expression in sensitive cases compared with untreated tumors (Fig.…”

Section: Cav-1 Expression In Tumor Xenografts By Reverse Transcriptiomentioning

confidence: 80%

Efficacy and pharmacodynamic effects of bosutinib (SKI-606), a Src/Abl inhibitor, in freshly generated human pancreas cancer xenografts

Messersmith

Rajeshkumar

Tan

et al. 2009

Molecular Cancer Therapeutics

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Recently, Src tyrosine kinase has emerged as an attractive target for anticancer therapy, and Src is overexpressed in pancreatic cancer. The purpose of the study was to investigate the in vivo efficacy and pharmacodynamic effects of bosutinib (SKI-606), a Src/Abl inhibitor, using a panel of human pancreatic tumor xenografts. Surgically resected human pancreatic tumors were implanted into female nude mice and randomized to bosutinib versus control. Src and other pathways were analyzed by Western Blot, IHC, and Affymetrix U133 Plus 2.0 gene arrays. Of 15 patient tumors, 3 patient tumors were found to be sensitive to bosutinib, defined as tumor growth of <45% than that of control tumors. There were no definite differences between sensitive and resistant tumors in the baseline Src kinase pathway protein expression assessed by Western Blot. Caveolin-1 expression, as assessed by reverse transcription-PCR and immunohistochemistry, was frequently higher in sensitive cases. In sensitive tumors, bosutinib resulted in increased apoptosis. Phosphorylation of key signaling molecules downstream of Src, signal transducers and activators of transcription 3, and signal transducers and activators of transcription 3, were significantly inhibited by bosutinib. K-Top Scoring Pairs analysis of gene arrays gave a six-gene classifier that predicted resistance versus sensitivity in six validation cases. These results may aid the clinical development of bosutinib and other Src inhibitors in pancreas cancer.

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Interaction of Neuronal Nitric-oxide Synthase with Caveolin-3 in Skeletal Muscle

Cited by 233 publications

References 28 publications

Mechanism of impaired nitric oxide synthase activity in skeletal muscle of streptozotocin-induced diabetic rats

Mechanism of impaired nitric oxide synthase activity in skeletal muscle of streptozotocin-induced diabetic rats

Recent Advances in the Regulation of Nitric Oxide in the Kidney

Efficacy and pharmacodynamic effects of bosutinib (SKI-606), a Src/Abl inhibitor, in freshly generated human pancreas cancer xenografts

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