Functional consequences of methionine oxidation of hERG potassium channels

Su, Zhi; Limberis, James T.; Martin, Ruth L.; Xu, Rong; Kolbe, Katrin; Heinemann, Stefan H.; Hoshi, Toshinori; Cox, Bryan F.; Gintant, Gary A.

doi:10.1016/j.bcp.2007.06.002

Cited by 36 publications

(26 citation statements)

References 50 publications

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“…This observation may be consistent with posttranslational modulation of hERG channel function. In fact, oxidative modulation of hERG channels has been recently reported to alter I Kr (45).…”

Section: Discussionmentioning

confidence: 99%

Repolarization abnormalities and afterdepolarizations in a canine model of sudden cardiac death

Sridhar

Nishijima²,

Terentyev³

et al. 2008

American Journal of Physiology-Regulatory, Integrative and Comp

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-Ventricular tachyarrhythmias are the most common cause of sudden cardiac death (SCD); a healed myocardial infarction increases the risk of SCD. We determined the contribution of specific repolarization abnormalities to ventricular tachyarrhythmias in a postinfarction model of SCD. For our methods, we used a postinfarction canine model of SCD, where an exercise and ischemia test was used to stratify animals as either susceptible (VF ϩ ) or resistant (VF Ϫ ) to sustained ventricular tachyarrhythmias. Our results show no changes in global left ventricular contractility or volumes occurred after infarction. At 8 -10 wk postmyocardial infarction, myocytes were isolated from the left ventricular midmyocardial wall and studied. In the VF ϩ animals, myocyte action potential (AP) prolongation occurred at 50 and 90% repolarization (P Ͻ 0.05) and was associated with increased variability of AP duration and afterdepolarizations. Multiple repolarizing K ϩ currents (IKr, Ito) and inward IK1 were also reduced (P Ͻ 0.05) in myocytes from VF ϩ animals compared with control, noninfarcted dogs. In contrast, only Ito was reduced in VF Ϫ myocytes compared with controls (P Ͻ 0.05). While afterdepolarizations were not elicited at baseline in myocytes from VF Ϫ animals, afterdepolarizations were consistently elicited after the addition of an I Kr blocker. In conclusion, the loss of repolarization reserve via reductions in multiple repolarizing currents in the VF ϩ myocytes leads to AP prolongation, repolarization instability, and afterdepolarizations in myocytes from animals susceptible to SCD. These abnormalities may provide a substrate for initiation of postmyocardial infarction ventricular tachyarrhythmias. potassium currents; repolarization reserve; myocardial infarction SUDDEN CARDIAC DEATH (SCD) is a major cause of cardiovascular mortality in the United States, accounting for ϳ500,000 deaths annually. Ambulatory ECG recordings have established that the vast majority (Ͼ80%) of these deaths result from tachyarrhythmias that culminate in ventricular fibrillation (VF; Refs. 1,5,19,21). Post mortem examinations indicate that scar tissue due to a previous myocardial infarction (MI) is present in approximately one-third of SCD subjects (51). It has been estimated that up to 80% of SCD results from myocardial ischemia or its sequelae (40).Ventricular arrhythmias often occur when there is an underlying electrophysiolgical substrate; alterations in repolarizing potassium currents are known to contribute to arrhythmogenesis (32). Specifically, alterations in inward rectifier K ϩ current (I K1 ), and the repolarizing K ϩ currents: transient outward current (I to ) and/or the delayed rectifier K ϩ currents (I Kr and I Ks ), are arrhythmogenic. The specific abnormalities in repolarization that predispose to arrhythmias in the setting of a healed MI have not been well defined. Numerous studies (13,34,35) have identified electrophysiological abnormalities in the hours to days after MI in canine models. At 5 and 14 days postinfarction, there is ...

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Section: Discussionmentioning

confidence: 99%

Repolarization abnormalities and afterdepolarizations in a canine model of sudden cardiac death

Sridhar

Nishijima²,

Terentyev³

et al. 2008

American Journal of Physiology-Regulatory, Integrative and Comp

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“…(55). Yet another study found that the hERG K + channel could be inactivated by Met oxidation by chloramine-T in HEK293 cells and that this process could be attenuated by MsrA, suggesting the importance of reversible Met oxidation and reduction in the control of hERG K + channel function (63). It has also been suggested that regulation of Met oxidation in a protein involved in calcium flux may play an important role in regulating energy metabolism and adaptation to oxidative stress (3).…”

Section: Fig 3 Selenocysteine-containing Msrb1mentioning

confidence: 99%

Regulation of Protein Function by Reversible Methionine Oxidation and the Role of Selenoprotein MsrB1

Kaya

Lee

Gladyshev

2015

Antioxidants & Redox Signaling

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Significance: Protein structure and function can be regulated via post-translational modifications by numerous enzymatic and nonenzymatic mechanisms. Regulation involving oxidation of sulfur-containing residues emerged as a key mechanism of redox control. Unraveling the participants and principles of such regulation is necessary for understanding the biological significance of redox control of cellular processes. Recent Advances: Reversible oxidation of methionine residues by monooxygenases of the Mical family and subsequent reduction of methionine sulfoxides by a selenocysteine-containing methionine sulfoxide reductase B1 (MsrB1) was found to control the assembly and disassembly of actin in mammals, and the Mical/MsrB pair similarly regulates actin in fruit flies. This finding has opened up new avenues for understanding the use of stereospecific methionine oxidation in regulating cellular processes and the roles of MsrB1 and Micals in regulation of actin dynamics. Critical Issues: So far, Micals have been the only known partners of MsrB1, and actin is the only target. It is important to identify additional substrates of Micals and characterize other Mical-like enzymes. Future Directions: Oxidation of methionine, reviewed here, is an emerging but not well-established mechanism. Studies suggest that methionine oxidation is a form of oxidative damage of proteins, a modification that alters protein structure or function, a tool in redox signaling, and a mechanism that controls protein function. Understanding the functional impact of reversible oxidation of methionine will require identification of targets, substrates, and regulators of Micals and Msrs. Linking the biological processes, in which these proteins participate, might also lead to insights into disease conditions, which involve regulation of actin by Micals and Msrs. Antioxid. Redox Signal. 23,[814][815][816][817][818][819][820][821][822]

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“…The activation was slowed during depolarization to 30 mV but accelerated during depolarization to 0 or -10 mV and the deactivation was also accelerated upon repolarization. In the presence of recombinant bovine MsrA a diminished effect of ChT was observed (123). The result indicated that methionine oxidation is at least partially responsible for the Kv11.1 current inhibition.…”

Section: Sahoo Et Almentioning

confidence: 84%

“…Su et al (123) have shown that ChT, which preferentially oxidizes methionine, significantly decreased Kv11.1 current. The activation was slowed during depolarization to 30 mV but accelerated during depolarization to 0 or -10 mV and the deactivation was also accelerated upon repolarization.…”

Section: Sahoo Et Almentioning

confidence: 98%

Oxidative Modulation of Voltage-Gated Potassium Channels

Sahoo

Hoshi

Heinemann

2014

Antioxidants & Redox Signaling

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Significance: Voltage-gated K + channels are a large family of K + -selective ion channel protein complexes that open on membrane depolarization. These K + channels are expressed in diverse tissues and their function is vital for numerous physiological processes, in particular of neurons and muscle cells. Potentially reversible oxidative regulation of voltage-gated K + channels by reactive species such as reactive oxygen species (ROS) represents a contributing mechanism of normal cellular plasticity and may play important roles in diverse pathologies including neurodegenerative diseases. Recent Advances: Studies using various protocols of oxidative modification, site-directed mutagenesis, and structural and kinetic modeling provide a broader phenomenology and emerging mechanistic insights. Critical Issues: Physicochemical mechanisms of the functional consequences of oxidative modifications of voltage-gated K + channels are only beginning to be revealed. In vivo documentation of oxidative modifications of specific amino-acid residues of various voltage-gated K + channel proteins, including the target specificity issue, is largely absent. Future Directions: High-resolution chemical and proteomic analysis of ion channel proteins with respect to oxidative modification combined with ongoing studies on channel structure and function will provide a better understanding of how the function of voltage-gated K + channels is tuned by ROS and the corresponding reducing enzymes to meet cellular needs. Antioxid. Redox Signal. 21, 933-952.

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Functional consequences of methionine oxidation of hERG potassium channels

Cited by 36 publications

References 50 publications

Repolarization abnormalities and afterdepolarizations in a canine model of sudden cardiac death

Repolarization abnormalities and afterdepolarizations in a canine model of sudden cardiac death

Regulation of Protein Function by Reversible Methionine Oxidation and the Role of Selenoprotein MsrB1

Oxidative Modulation of Voltage-Gated Potassium Channels

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