[Ca2+]  Elevation and Oxidative Stress Induce KCNQ1 Protein Translocation from the Cytosol to the Cell Surface and Increase Slow Delayed Rectifier (IKs) in Cardiac Myocytes

Wang, Yuhong; Zankov, Dimitar P.; Jiang, Min; Zhang, Mei; Henderson, Scott C.; Tseng, Gea‐Ny

doi:10.1074/jbc.m113.504746

Cited by 26 publications

(30 citation statements)

References 35 publications

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“…In PVC myocytes, I Ks became negatively related to APD, supporting a scenario that under stressful conditions, I Ks as a ‘repolarization reserve’ may become more important in APD repolarization 17 . The PVC #3 myocyte in Fig.8C and 8D supports this scenario.…”

Section: Discussionsupporting

confidence: 52%

Cellular mechanism of premature ventricular contraction–induced cardiomyopathy

et al. 2014

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Background Frequent premature ventricular contractions (PVCs) are associated with increased risk for sudden cardiac death (SCD) and can cause secondary cardiomyopathy (CM). Objective We sought to determine the mechanism(s) responsible for prolonged refractory period and LV dysfunction demonstrated in our canine model of PVC-induced CM. Methods Single myocytes were isolated from LV free wall of PVC and control canines, and used for patch clamp recording, [Ca]i measurements and immunocytochemistry/confocal microscopy. LV tissues adjacent to area of myocyte isolation were used for immunoblot quantification of protein expression. Results In PVC group, LVEF declined from 57.6±1.5% to 30.4±3.1% after ≥ 4 months of ventricular bigeminy. Compared to control myocytes, PVC myocytes had reduced densities of both outward (Ito and IK1) and inward (ICaL) currents, but no consistent changes in IKr or IKs. The reduction in Ito, IK1 and ICaL was accompanied by decreased protein levels of their channel subunits. The degrees of reduction in Ito, IK1 and ICaL varied among PVC myocytes, creating marked heterogeneity in action potential (AP) configurations and durations. PVC myocytes showed impaired Ca-induced Ca release from SR, without increase in SR Ca leak or decrease in SR Ca store. This was accompanied by a decrease in dyad scaffolding protein, junctophilin-2, and loss of Cav1.2 registry with Ca-releasing channels (RyR2). Conclusion PVCs increase dispersion of AP configuration/duration, a risk factor for SCD, due to heterogeneous reduction in Ito, IK1 and ICaL. The E-C coupling is impaired due to decrease in ICaL and Cav1.2 misalignment with respect to RyR2.

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Section: Discussionsupporting

confidence: 52%

Cellular mechanism of premature ventricular contraction–induced cardiomyopathy

et al. 2014

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“…A logic expectation is that KCNQ1 and KCNE1 should be well colocalized on myocyte surface to conduct I Ks . However, our observations from guinea pig ventricular myocytes indicate that this is not the case: KCNQ1 exhibits a striation pattern along the z-lines, while KCNE1 is on the peripheral surface 11 . The mechanism for KCNQ1 and KCNE1 segregation, and its implication for the control of I Ks amplitude in normal and diseased hearts are not clear.…”

Section: Introductionmentioning

confidence: 63%

“…Fluorescent protein-tagged KCNQ1 and KCNE1 (Q1-GFP and E1-dsR, in plasmids or adenoviruses) have been described 11 . Angiotensin type-1 receptor (AT1R), Ca-binding deficient calmodulin (CaM 1234 ), and GFP-nanobody (Nb) were gifts from Drs.…”

Section: Methodsmentioning

confidence: 99%

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Adult Ventricular Myocytes Segregate KCNQ1 and KCNE1 to Keep the I _Ks Amplitude in Check Until When Larger I _Ks Is Needed

Jiang

Wang

Tseng

2017

Circ: Arrhythmia and Electrophysiology

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Background KCNQ1 and KCNE1 assemble to form the slow delayed rectifier (IKs) channel critical for shortening ventricular action potentials during high β-adrenergic tone. However, too much IKs under basal conditions poses an arrhythmogenic risk. Our objective is to understand how adult ventricular myocytes regulate the IKs amplitudes under basal conditions and in response to stress. Methods and Results We express fluorescently-tagged KCNQ1 and KCNE1 in adult ventricular myocytes, and follow their biogenesis and trafficking paths. We also study the distribution patterns of native KCNQ1 and KCNE1, and their relationship to IKs amplitudes, in chronically stressed ventricular myocytes, and use COS-7 cell expression to probe the underlying mechanism. We show that KCNQ1 and KCNE1 are both translated in the perinuclear region but traffic by different routes, independent of each other, to their separate subcellular locations. KCNQ1 mainly resides in the junctional sarcoplasmic reticulum (jSR) while KCNE1 resides on the cell surface. Under basal conditions, only a small portion of KCNQ1 reaches the cell surface to support the IKs function. However, in response to chronic stress, KCNQ1 traffics from jSR to the cell surface to boost the IKs amplitude in a process depending on Ca binding to calmodulin. Conclusions In adult ventricular myocytes KCNE1 maintains a stable presence on the cell surface, while KCNQ1 is dynamic in its localization. KCNQ1 is largely in an intracellular reservoir under basal conditions, but can traffic to the cell surface and boost the IKs amplitude in response to stress.

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“…Although the experiments by Plant et al are performed in Chinese hamster ovary (CHO) cells, the cell surface densities of the KCNQ1 and KCNE1 subunits were significantly greater when coexpressed in the same cell, indicating that coassembly mediates trafficking to the plasma membrane (14). Photobleaching fluorescently tagged KCNQ1 and KCNE1 subunits expressed in cardiomyocytes is needed to determine whether unpartnered KCNQ1 and KCNE1 subunits can traffic independently, as a recent study suggests (16). In addition, these single molecule approaches may also shed some light on the K + channel-KCNE partnerships and trafficking patterns in the heart, where all five KCNE regulatory subunits are endogenously expressed (17) with several different cardiac K + channels (including KCNQ1) that can coassemble with more than one KCNE partner (18).…”

Section: Arrhythmic Implicationsmentioning

confidence: 99%

Stoichiometry of the cardiac I _Ks complex

Kobertz

2014

Proc. Natl. Acad. Sci. U.S.A.

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[Ca2+] Elevation and Oxidative Stress Induce KCNQ1 Protein Translocation from the Cytosol to the Cell Surface and Increase Slow Delayed Rectifier (IKs) in Cardiac Myocytes

Cited by 26 publications

References 35 publications

Cellular mechanism of premature ventricular contraction–induced cardiomyopathy

Cellular mechanism of premature ventricular contraction–induced cardiomyopathy

Adult Ventricular Myocytes Segregate KCNQ1 and KCNE1 to Keep the I _Ks Amplitude in Check Until When Larger I _Ks Is Needed

Stoichiometry of the cardiac I _Ks complex

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[Ca2+] Elevation and Oxidative Stress Induce KCNQ1 Protein Translocation from the Cytosol to the Cell Surface and Increase Slow Delayed Rectifier (IKs) in Cardiac Myocytes

Cited by 26 publications

References 35 publications

Cellular mechanism of premature ventricular contraction–induced cardiomyopathy

Cellular mechanism of premature ventricular contraction–induced cardiomyopathy

Adult Ventricular Myocytes Segregate KCNQ1 and KCNE1 to Keep the I Ks Amplitude in Check Until When Larger I Ks Is Needed

Stoichiometry of the cardiac I Ks complex

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Adult Ventricular Myocytes Segregate KCNQ1 and KCNE1 to Keep the I _Ks Amplitude in Check Until When Larger I _Ks Is Needed

Stoichiometry of the cardiac I _Ks complex