Tachycardia increases NADPH oxidase activity and RyR2 S-glutathionylation in ventricular muscle

Sánchez, Gittith; Pedrozo, Zully; Domenech, Raúl; Hidalgo, Cecilia; Donoso, P

doi:10.1016/j.yjmcc.2005.08.010

Cited by 119 publications

(88 citation statements)

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“…This enzyme generates ROS, which in isolated triads decrease the total sulfhydryl content and activate RyR1 through S-glutathionylation, a specific cysteine redox modification that enhances calcium release mediated by RyR1 (38) or RyR2 (29). We propose that in intact muscle fibers, RyR1 channels, which are essential components of the E-C coupling molecular machinery, are downstream targets of this T-tubule NOX activity.…”

Section: Discussionmentioning

confidence: 96%

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A Transverse Tubule NADPH Oxidase Activity Stimulates Calcium Release from Isolated Triads via Ryanodine Receptor Type 1 S -Glutathionylation

Hidalgo

Pecchi

Barrientos

et al. 2006

Journal of Biological Chemistry

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171

147

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We report here the presence of an NADPH oxidase (NOX) activity both in intact and in isolated transverse tubules and in triads isolated from mammalian skeletal muscle, as established by immunochemical, enzymatic, and pharmacological criteria. Immunohistochemical determinations with NOX antibodies showed that the gp91 phox membrane subunit and the cytoplasmic regulatory p47 phox subunit co-localized in transverse tubules of adult mice fibers with the ␣ 1s subunit of dihydropyridine receptors. Western blot analysis revealed that isolated triads contained the integral membrane subunits gp91 phox and p22 phox , which were markedly enriched in isolated transverse tubules but absent from junctional sarcoplasmic reticulum vesicles. Isolated triads and transverse tubules, but not junctional sarcoplasmic reticulum, also contained varying amounts of the cytoplasmic NOX regulatory subunits p47 phox and p67 phox . NADPH or NADH elicited superoxide anion and hydrogen peroxide generation by isolated triads; both activities were inhibited by NOX inhibitors but not by rotenone. NADH diminished the total thiol content of triads by one-third; catalase or apocynin, a NOX inhibitor, prevented this effect. NADPH enhanced the activity of ryanodine receptor type 1 (RyR1) in triads, measured through [ 3 H]ryanodine binding and calcium release kinetics, and increased significantly RyR1 S-glutathionylation over basal levels. Preincubation with reducing agents or NOX inhibitors abolished the enhancement of RyR1 activity produced by NADPH and prevented NADPH-induced RyR1 S-glutathionylation. We propose that reactive oxygen species generated by the transverse tubule NOX activate via redox modification the neighboring RyR1 Ca 2؉ release channels. Possible implications of this putative mechanism for skeletal muscle function are discussed.The NADPH oxidases (NOX) 3 are flavoprotein enzymes that use NADPH as electron donor to mediate the univalent reduction of molecular oxygen to superoxide anion (1), a free radical that by spontaneous or enzymatically catalyzed dismutation is readily converted into H 2 O 2 . The phagocytic NOX isoform (NOX2) was first discovered as a pivotal component of the neutrophil respiratory burst (2, 3). The functional NOX2 enzyme is composed of two integral plasma membrane subunits, gp91 phox and p22phox , which make up cytochrome b 558 , plus three cytosolic regulatory subunits: p40 phox , p47 phox , and p67 phox (2, 4). A variety of tissues, including endothelial cells (5), smooth muscle cells (6), neurons (7-9), and astrocytes (7, 10), possess nonphagocytic NOX homologues (11,12). Several reports indicate that NOX2 and its homologues have a central role in the generation of reactive oxygen species (ROS) in response to diverse physiological extracellular stimuli (13-17). Moreover, membrane depolarization stimulates NOX activity in phagocytes (18) and endothelial cells (19,20). NOX stimulation is also apparent following agonist-induced stimulation of N-methyl-D-aspartate receptors in hippocampal neurons (21). Some N...

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Section: Discussionmentioning

confidence: 96%

“…NADPH addition to microsomes isolated from heart muscle significantly enhances, via NOX activation, both RyR2 S-glutathionylation and Ca 2ϩ -induced Ca 2ϩ release (CICR) (29). Skeletal muscle homogenates also contain all of the NOX2 protein components and display an activity that generates superoxide anion at the expense of NADH oxidation (30).…”

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confidence: 99%

A Transverse Tubule NADPH Oxidase Activity Stimulates Calcium Release from Isolated Triads via Ryanodine Receptor Type 1 S -Glutathionylation

Hidalgo

Pecchi

Barrientos

et al. 2006

Journal of Biological Chemistry

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171

147

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“…Whether oxidative PKA and PKG activation has any functional consequences in cardiomyocytes remains to be investigated. Prominent examples are the RyRs, which can be modified upon oxidation, S-nitrosation and Sglutathionylation (Wehrens et al 2005;Meissner 2010;Niggli et al 2013).The RyRs are known to be sensitive to redox modifications: tetrameric RyR2 contains 364 cysteines, 84 of which have free thiol groups that can be S-nitrosylated (González et al 2008) glutathionylated (Sánchez et al 2005).…”

Section: Titin As a Potential Biomarker In Chagas' Diseasementioning

confidence: 99%

A change of heart: oxidative stress in governing muscle function?

Breitkreuz

Hamdani

2015

Biophys Rev

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Redox/cysteine modification of proteins that regulate calcium cycling can affect contraction in striated muscles. Understanding the nature of these modifications would present the possibility of enhancing cardiac function through reversible cysteine modification of proteins, with potential therapeutic value in heart failure with diastolic dysfunction. Both heart failure and muscular dystrophy are characterized by abnormal redox balance and nitrosative stress. Recent evidence supports the synergistic role of oxidative stress and inflammation in the progression of heart failure with preserved ejection fraction, in concert with endothelial dysfunction and impaired nitric oxide-cyclic guanosine monophosphate-protein kinase G signalling via modification of the giant protein titin. Although antioxidant therapeutics in heart failure with diastolic dysfunction have no marked beneficial effects on the outcome of patients, it, however, remains critical to the understanding of the complex interactions of oxidative/nitrosative stress with pro-inflammatory mechanisms, metabolic dysfunction, and the redox modification of proteins characteristic of heart failure. These may highlight novel approaches to therapeutic strategies for heart failure with diastolic dysfunction. In this review, we provide an overview of oxidative stress and its effects on pathophysiological pathways. We describe the molecular mechanisms driving oxidative modification of proteins and subsequent effects on contractile function, and, finally, we discuss potential therapeutic opportunities for heart failure with diastolic dysfunction.

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“…Reactive oxygen species, such as hydrogen peroxide (H 2 O 2 ) and superoxide anion radical, activate the channel (30 -33). A sarcoplasmic reticulum (SR)-associated NAD(P)H oxidase coupled to superoxide anion radical production has been shown to modulate RyR-mediated Ca 2ϩ release in skeletal and cardiac muscle (33)(34)(35)(36) RyR1 (27,37), formation of high molecular weight complexes with triadin (38, 39), and calmodulin binding (32, 40 -45). In this study, we present evidence that the critical interaction of the native skeletal and cardiac muscle RyR with FKBP12/12.6 is redox-sensitive.…”

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Redox Sensitivity of the Ryanodine Receptor Interaction with FK506-binding Protein

Zissimopoulos

Docrat

Lai

2007

Journal of Biological Chemistry

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The ryanodine receptor (RyR) calcium release channel functions as a redox sensor that is sensitive to channel modulators. The FK506-binding protein (FKBP) is an important regulator of channel activity, and disruption of the RyR2-FKBP12.6 association has been implicated in cardiac disease. In the present study, we investigated whether the RyR-FKBP association is redoxregulated. Using co-immunoprecipitation assays of solubilized native RyR2 from cardiac muscle sarcoplasmic reticulum ( and diamide differentially affected the RyR2-FKBP12.6 interaction, decreasing binding to ϳ75 and ϳ50% of control, respectively. In addition, the effect of H 2 O 2 was negligible when the channel was in its closed state or when applied after FKBP binding had occurred, whereas diamide was always effective. A cysteine-null mutant FKBP12.6 retained redox-sensitive interaction with RyR2, suggesting that the effect of the redox reagents is exclusively via sites on the ryanodine receptor. K201 (or JTV519), a drug that has been proposed to prevent FKBP12.6 dissociation from the RyR2 channel complex, did not restore normal FKBP binding under oxidizing conditions. Our results indicate that the redox state of the RyR is intimately connected with FKBP binding affinity. Ryanodine receptors (RyRs)2 are tetrameric intracellular Ca 2ϩ channels that mediate the release of Ca 2ϩ from the sarco/ endoplasmic reticulum in muscle and nonmuscle cells (1). Three genes coding for mammalian RyRs have been identified: RyR1 in skeletal muscle, RyR2 in heart and brain, and RyR3 in a number of tissues. The deduced primary structure of all RyRs suggests a hydrophobic C terminus forming the channel pore, with the remaining ϳ80% being cytoplasmic. RyR channel activity is regulated by Ca 2ϩ , Mg 2ϩ , ATP, phosphorylation and redox status, and a number of accessory proteins.The immunophilin, FK506-binding protein (FKBP), a receptor protein for the immunosuppressants, FK506 and rapamycin, is an essential component of the RyR-Ca 2ϩ release channel complex in both skeletal and cardiac muscle (2, 3). RyR1 binds to both FKBP12 and FKBP12.6 with similar affinities (4), whereas RyR2 associates specifically with the FKBP12.6 isoform (3, 5). The stoichiometry of the association is four molecules of FKBP per RyR tetrameric channel (i.e. one FKBP molecule for each RyR protomer) (3, 6). Mapping studies have failed to identify a unique FKBP-binding site, with evidence presented for three distinct RyR regions (N-terminal, central, and C-terminal domains) (7-12), suggesting that FKBP interaction may be stabilized by multiple physical contacts and/or may be conformation-sensitive. The functional effects of FKBP association with RyR have been suggested to include stabilization of the full conductance state (7,13,14), channel closure (5, 6, 15), and coupled gating between neighboring channels (16,17). These effects are highlighted in abnormal or disease states, where defective regulation of the RyR-FKBP association has been implicated in cardiomyopathy (18), cardiac hypertrophy (19), h...

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Tachycardia increases NADPH oxidase activity and RyR2 S-glutathionylation in ventricular muscle

Cited by 119 publications

References 38 publications

A Transverse Tubule NADPH Oxidase Activity Stimulates Calcium Release from Isolated Triads via Ryanodine Receptor Type 1 S -Glutathionylation

A Transverse Tubule NADPH Oxidase Activity Stimulates Calcium Release from Isolated Triads via Ryanodine Receptor Type 1 S -Glutathionylation

A change of heart: oxidative stress in governing muscle function?

Redox Sensitivity of the Ryanodine Receptor Interaction with FK506-binding Protein

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