Sulfhydryl Modulation of K + Channels in Rat Ventricular Myocytes

Rozanski, George J.; Zhi, Xu

doi:10.1006/jmcc.2002.2112

Cited by 22 publications

(17 citation statements)

References 31 publications

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“…Indeed, comparison of the present data with previous studies from our laboratory [16] suggests that some electrophysiological effects of diamide may be independent of cellular GSSG accumulation. In particular, dialyzing ventricular myocytes with GSSG decreases I peak density without changing I ss and without significant changes in voltagedependent parameters [16]. By comparison, diamide markedly inhibited I peak and I ss ( Fig.…”

Section: Redox Modulation Of Protein Thiolssupporting

confidence: 83%

“…and single ventricular myocytes were dissociated from excised, perfused hearts by a collagenase digestion procedure described previously [16,18,19]. Dissociated myocytes from left ventricle and septum were suspended in Dulbecco's modified Eagle's medium and stored in an incubator at 35° C until used, usually within 6 h of isolation.…”

Section: Isolation Of Ventricular Myocytes Patch-clamp Techniquementioning

confidence: 99%

“…Many cardiac ion channels have been shown to be sensitive to ROS and related thiol-reactive molecules in a reversible manner that suggests the channel protein itself or a modulator of the channel is controlled by cellular redox state [14][15][16][17]. In most cases, the reversibility or prevention of oxidative changes to ion channels has been examined using exogenous reductants such as dithiothreitol.…”

Section: Introductionmentioning

confidence: 99%

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Oxidoreductase regulation of Kv currents in rat ventricle

Liang

et al. 2008

Journal of Molecular and Cellular Cardiology

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Oxidative stress contributes to the arrhythmogenic substrate created by myocardial ischemiareperfusion partly through a shift in cell redox state, a key modulator of protein function. The activity of many oxidation-sensitive proteins is controlled by oxidoreductase systems that regulate the redox state of cysteine thiol groups, but the impact of these systems on ion channel function is not well defined. Thus, we examined the roles of the thioredoxin and glutaredoxin systems in controlling K + channels in the ventricle. An oxidative shift in redox state was elicited in isolated rat ventricular myocytes by brief exposure to diamide, a thiol-specific, membrane-permeable oxidant. Voltageclamp studies showed that diamide decreased peak outward K + current (I peak ) evoked by depolarizing test pulses by 41% (+60 mV; p<0.05) while steady-state outward current (I ss ) measured at the end of the test pulse was decreased by 45% (p<0.05). These electrophysiological effects were not prevented by protein kinase C blockers, but the tyrosine kinase inhibitors genistein or lavendustin A blocked the suppression of both K + currents by diamide. Moreover, inhibition of I peak and I ss by diamide was reversed by dichloroacetate and an insulin-mimetic. The effect of dichloroacetate to normalize I peak after diamide was blocked by the thioredoxin system inhibitors auranofin or 13-cisretinoic acid, but I ss was not affected by either compound. A pan-specific inhibitor of glutaredoxin and thioredoxin systems, 1,3-bis-(2-chloroethyl)-1-nitrosourea, also blocked the dichloroacetate effect on I peak but only partially inhibited the recovery of I ss . These data suggest that acute regulation of cardiac K + channels by oxidoreductase systems is mediated by redox-sensitive tyrosine kinase/ phosphatase pathways. The pathways controlling I peak channels are targets of the thioredoxin system whereas those regulating I ss channels are likely controlled by the glutaredoxin system. Thus, cardiac oxidoreductase systems may be important regulators of ion channels affected by pathogenic oxidative stress.

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Section: Redox Modulation Of Protein Thiolssupporting

confidence: 83%

Section: Isolation Of Ventricular Myocytes Patch-clamp Techniquementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Oxidoreductase regulation of Kv currents in rat ventricle

Liang

et al. 2008

Journal of Molecular and Cellular Cardiology

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“…Thiol/disulfide exchange reactions at the level of cysteine residues in proteins depend on the ϪSH group of GSH and have been suggested to regulate the progression of apoptosis (68,94), Thiol-exchange reactions might also be involved in the regulation of ion channels and changes in the ionic homeostasis of the cell. In fact, previous reports demonstrate that sulfhydryl groups within cytosolic cysteine domains of ion channels directly modulate channel activity (95)(96)(97).…”

Section: Discussionmentioning

confidence: 99%

Glutathione Depletion and Disruption of Intracellular Ionic Homeostasis Regulate Lymphoid Cell Apoptosis

Franco

DeHaven

Sifre

et al. 2008

Journal of Biological Chemistry

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Intracellular glutathione (GSH) depletion is an important hallmark of apoptosis. We have recently shown that GSH depletion by its extrusion regulates apoptosis independently of excessive reactive oxygen species accumulation. However, the mechanisms by which GSH depletion regulates apoptosis are still unclear. Because disruption of intracellular ionic homeostasis, associated with apoptotic volume decrease (AVD), is necessary for the progression of apoptotic cell death, we sought to evaluate the relationship between GSH transport and ionic homeostasis during Fas ligand (FasL)-induced apoptosis in Jurkat cells. GSH depletion in response to FasL was paralleled by distinct degrees of AVD identified by differences in cellular forward scatter and electronic impedance analysis. Inhibition of GSH efflux prevented AVD, K ؉ loss, and the activation of two distinct ionic conductances, mediated by Kv1.3 and outward rectifying Cl Apoptosis or programmed cell death is a ubiquitous energydependent, evolutionary conserved process. Under physiological conditions it is important not only in the constant turnover of cells in all tissues, but also during the normal development and senescence of the organism. Moreover, its deregulation has been observed to occur as either a cause or consequence of distinct pathologies (1, 2). A clear example is apoptosis mediated by Fas ligand (FasL) 2 receptor (Fas/CD95/Apo-1) activation, which is necessary for immune system homeostasis because of its role in the rapid clearance of immunoreactive T cells maintaining the immune balance and reducing the risk of autoimmune diseases (3). Apoptosis is a highly ordered process characterized by the progressive activation of precise pathways leading to specific biochemical and morphological alterations. Initial stages of apoptosis are characterized by activation of initiator caspases, changes in the cellular redox potential, intracellular ionic homeostasis, cell shrinkage or apoptotic volume decrease (AVD), loss of membrane lipid asymmetry, and chromatin condensation. Later stages associated with the execution phase of apoptosis are characterized by execution caspase and endonuclease activation, apoptotic body formation, and cell fragmentation (4, 5). Reduced glutathione (GSH) is the most abundant low molecular weight thiol in animal cells and is the major determinant in the redox potential of the cell. It is involved in many cellular processes, including antioxidant defense, drug detoxification, signaling, and proliferation (6 -10). Glutathione loss is an early hallmark in the progression of cell death in response to different apoptotic stimuli (11)(12)(13)(14)(15)(16)(17)(18)(19). Death receptor (including Fas)-induced GSH depletion has been clearly associated with the activation of a plasma membrane transport mechanism and not to its oxidation by reactive oxygen species (ROS) (20 -23). Several studies have shown a correlation between GSH efflux and the progression of apoptosis, and inhibition of GSH loss is able to rescue cells from cell death progress...

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“…Indeed, recently this mechanistic link was confirmed showing that redox-activated CaMKII and enhanced late I Na are required for AP prolongation and EADs (68, 136). Depending on the sources and levels of ROS, a ROS-induced enhancement of I Ca and transient outward K current (I to ) inhibition by oxidation of SH groups may additionally contribute (111).…”

Section: Ros-associated Arrhythmiasmentioning

confidence: 99%

Redox Regulation of Sodium and Calcium Handling

Wagner

Rokita

Anderson

et al. 2013

Antioxidants & Redox Signaling

142

119

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Significance: In heart failure (HF), contractile dysfunction and arrhythmias result from disturbed intracellular Ca handling. Activated stress kinases like cAMP-dependent protein kinase A (PKA), protein kinase C (PKC), and Ca/calmodulin-dependent protein kinase II (CaMKII), which are known to influence many Ca-regulatory proteins, are mechanistically involved. Recent Advances: Beside classical activation pathways, it is becoming increasingly evident that reactive oxygen species (ROS) can directly oxidize these kinases, leading to alternative activation. Since HF is associated with increased ROS generation, ROS-activated serine/threonine kinases may play a crucial role in the disturbance of cellular Ca homeostasis. Many of the previously described ROS effects on ion channels and transporters are possibly mediated by these stress kinases. For instance, ROS have been shown to oxidize and activate CaMKII, thereby increasing Na influx through voltage-gated Na channels, which can lead to intracellular Na accumulation and action potential prolongation. Consequently, Ca entry via activated NCX is favored, which together with ROS-induced dysfunction of the sarcoplasmic reticulum can lead to dramatic intracellular Ca accumulation, diminished contractility, and arrhythmias. Critical Issues: While low amounts of ROS may regulate kinase activity, excessive uncontrolled ROS production may lead to direct redox modification of Ca handling proteins. Therefore, depending on the source and amount of ROS generated, ROS could have very different effects on Ca-handling proteins. Future Directions: The discrimination between fine-tuned ROS signaling and unspecific ROS damage may be crucial for the understanding of heart failure development and important for the investigation of targeted treatment strategies.

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Sulfhydryl Modulation of K + Channels in Rat Ventricular Myocytes

Cited by 22 publications

References 31 publications

Oxidoreductase regulation of Kv currents in rat ventricle

Oxidoreductase regulation of Kv currents in rat ventricle

Glutathione Depletion and Disruption of Intracellular Ionic Homeostasis Regulate Lymphoid Cell Apoptosis

Redox Regulation of Sodium and Calcium Handling

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