Small and Intermediate Calcium Activated Potassium Channels in the Heart: Role and Strategies in the Treatment of Cardiovascular Diseases

Weisbrod, David

doi:10.3389/fphys.2020.590534

Cited by 24 publications

(19 citation statements)

References 161 publications

(260 reference statements)

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“…SK channels have been mostly studied in the nervous system where their function has been attributed to control of neuronal excitability and AP firing rate through membrane hyperpolarization, with ramifications for synaptic plasticity, learning and memory and possible involvement in the pathogenesis of Parkinson's disease (Lam et al., 2013; Sun et al., 2020). In the heart, SK channels are expressed in both atria (Skibsbye et al., 2014; Tuteja et al., 2005; Xu et al., 2003) and ventricles (Haugaard et al., 2015; Weisbrod, 2020), including in humans (Skibsbye et al., 2014; Xu et al., 2003). In the atria, SK channels were shown to contribute to AP repolarization (Diness et al., 2020; Skibsbye et al., 2014) and have been linked to atrial fibrillation (Diness et al., 2020; Haugaard et al., 2015; Skibsbye et al., 2014).…”

Section: Discussionmentioning

confidence: 99%

“…Several studies have failed to demonstrate changes in AP morphology during SK inhibition and, consequently, it was proposed that SK channels do not play a role in the repolarization of healthy ventricles. However, expression of SK channels increases in pathologies associated with elevated [Ca 2+ ] i , such as heart failure (Chang et al., 2013; Weisbrod, 2020), and SK channels may play a protective role by increasing repolarization reserve of the myocardium (Hsueh et al., 2013). Our data in rabbit ventricular myocytes fall in line with the aforementioned observations as blocking SK channels by apamin or UCL1684 induced only a minor prolongation of the AP (Fig.…”

Section: Discussionmentioning

confidence: 99%

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Activation of small conductance Ca²⁺‐activated K⁺ channels suppresses Ca²⁺ transient and action potential alternans in ventricular myocytes

Kanaporis

Blatter

2022

The Journal of Physiology

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At the cellular level, cardiac alternans is observed as beat‐to‐beat alternations in contraction strength, action potential (AP) morphology and Ca2+ transient (CaT) amplitude, and is a risk factor for cardiac arrhythmia. The (patho)physiological roles of small conductance Ca2+‐activated K+ (SK) channels in ventricles are poorly understood. We tested the hypothesis that in single rabbit ventricular myocytes pharmacological modulation of SK channels plays a causative role for the development of pacing‐induced CaT and AP duration (APD) alternans. SK channel blockers (apamin, UCL1684) had only a minor effect on AP repolarization. However, SK channel activation by NS309 resulted in significant APD shortening, demonstrating that functional SK channels are well expressed in ventricular myocytes. The effects of NS309 were prevented or reversed by apamin and UCL1684, indicating that NS309 acted on SK channels. SK channel activation abolished or reduced the degree of pacing‐induced CaT and APD alternans. Inhibition of KV7.1 (with HMR1556) and KV11.1 (with E4031) channels was used to mimic conditions of long QT syndromes type‐1 and type‐2, respectively. Both HMR1556 and E4031 enhanced CaT alternans that was prevented by SK channel activation. In AP voltage‐clamped cells the SK channel activator had no effect on CaT alternans, confirming that suppression of CaT alternans was caused by APD shortening. APD shortening contributed to protection from alternans by lowering sarcoplasmic reticulum Ca2+ content and curtailing Ca2+ release. The data suggest that SK activation could be a potential intervention to avert development of alternans with important ramifications for arrhythmia prevention and therapy for patients with long QT syndrome. Key points At the cellular level, cardiac alternans is observed as beat‐to‐beat alternations in contraction strength, action potential (AP) morphology and intracellular Ca2+ release amplitude, and is a risk factor for cardiac arrhythmia. The (patho)physiological roles of small conductance Ca2+‐activated K+ (SK) channels in ventricles are poorly understood. We investigated whether pharmacological modulation of SK channels affects the development of cardiac alternans in normal ventricular cells and in cells with drug‐induced long QT syndrome (LQTS). While SK channel blockers have only a minor effect on AP morphology, their activation leads to AP shortening and abolishes or reduces the degree of pacing‐induced Ca2+ and AP alternans. AP shortening contributed to protection against alternans by lowering sarcoplasmic reticulum Ca2+ content and curtailing Ca2+ release. The data suggest SK activation as a potential intervention to avert the development of alternans with important ramifications for arrhythmia prevention for patients with LQTS.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Activation of small conductance Ca²⁺‐activated K⁺ channels suppresses Ca²⁺ transient and action potential alternans in ventricular myocytes

Kanaporis

Blatter

2022

The Journal of Physiology

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“…In a similar way, other ion currents in the model are not fully defined. For example, some K + channels and isoforms of the Na + /K + -ATPase are modulated by localized Ca 2+ concentrations ( Tian and Xie, 2008 ; Weisbrod, 2020 ). However, the model does not include any Ca 2+ -dependent terms in the definitions of these currents.…”

Section: Discussionmentioning

confidence: 99%

Effects of Sarcolemmal Background Ca2+ Entry and Sarcoplasmic Ca2+ Leak Currents on Electrophysiology and Ca2+ Transients in Human Ventricular Cardiomyocytes: A Computational Comparison

Streiff

Sachse

2022

Front. Physiol.

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The intricate regulation of the compartmental Ca2+ concentrations in cardiomyocytes is critical for electrophysiology, excitation-contraction coupling, and other signaling pathways. Research into the complex signaling pathways is motivated by cardiac pathologies including arrhythmia and maladaptive myocyte remodeling, which result from Ca2+ dysregulation. Of interest to this investigation are two types of Ca2+ currents in cardiomyocytes: 1) background Ca2+ entry, i.e., Ca2+ transport across the sarcolemma from the extracellular space into the cytosol, and 2) Ca2+ leak from the sarcoplasmic reticulum (SR) across the SR membrane into the cytosol. Candidates for the ion channels underlying background Ca2+ entry and SR Ca2+ leak channels include members of the mechano-modulated transient receptor potential (TRP) family. We used a mathematical model of a human ventricular myocyte to analyze the individual contributions of background Ca2+ entry and SR Ca2+ leak to the modulation of Ca2+ transients and SR Ca2+ load at rest and during action potentials. Background Ca2+ entry exhibited a positive relationship with both [Ca2+]i and [Ca2+]SR. Modulating SR Ca2+ leak had opposite effects of background Ca2+ entry. Effects of SR Ca2+ leak on Ca2+ were particularly pronounced at lower pacing frequency. In contrast to the pronounced effects of background and leak Ca2+ currents on Ca2+ concentrations, the effects on cellular electrophysiology were marginal. Our studies provide quantitative insights into the differential modulation of compartmental Ca2+ concentrations by the background and leak Ca2+ currents. Furthermore, our studies support the hypothesis that TRP channels play a role in strain-modulation of cardiac contractility. In summary, our investigations shed light on the physiological effects of the background and leak Ca2+ currents and their contribution to the development of disease caused by Ca2+ dysregulation.

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“…We and others have shown the critical role of K + , Na + , and Ca 2+ channel dysfunction in cardiac arrhythmias (Remme and Bezzina, 2010;Lu et al, 2015;Chen et al, 2016;Chiamvimonvat et al, 2017;Weisbrod, 2020). Genetic variations in genes of the pore forming subunits or accessory β-subunits of the rapid and slow delayed rectifier K + channels (I Kr and I Ks ) have been linked to human arrhythmia syndromes (Chen et al, 2016;Chiamvimonvat et al, 2017).…”

Section: Structural and Electrical Remodeling In Afmentioning

confidence: 99%

The Critical Roles of Proteostasis and Endoplasmic Reticulum Stress in Atrial Fibrillation

et al. 2022

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Atrial fibrillation (AF) remains the most common arrhythmia seen clinically. The incidence of AF is increasing due to the aging population. AF is associated with a significant increase in morbidity and mortality, yet current treatment paradigms have proven largely inadequate. Therefore, there is an urgent need to develop new effective therapeutic strategies for AF. The endoplasmic reticulum (ER) in the heart plays critical roles in the regulation of excitation-contraction coupling and cardiac function. Perturbation in the ER homeostasis due to intrinsic and extrinsic factors, such as inflammation, oxidative stress, and ischemia, leads to ER stress that has been linked to multiple conditions including diabetes mellitus, neurodegeneration, cancer, heart disease, and cardiac arrhythmias. Recent studies have documented the critical roles of ER stress in the pathophysiological basis of AF. Using an animal model of chronic pressure overload, we demonstrate a significant increase in ER stress in atrial tissues. Moreover, we demonstrate that treatment with a small molecule inhibitor to inhibit the soluble epoxide hydrolase enzyme in the arachidonic acid metabolism significantly reduces ER stress as well as atrial electrical and structural remodeling. The current review article will attempt to provide a perspective on our recent understandings and current knowledge gaps on the critical roles of proteostasis and ER stress in AF progression.

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Small and Intermediate Calcium Activated Potassium Channels in the Heart: Role and Strategies in the Treatment of Cardiovascular Diseases

Cited by 24 publications

References 161 publications

Activation of small conductance Ca²⁺‐activated K⁺ channels suppresses Ca²⁺ transient and action potential alternans in ventricular myocytes

Activation of small conductance Ca²⁺‐activated K⁺ channels suppresses Ca²⁺ transient and action potential alternans in ventricular myocytes

Effects of Sarcolemmal Background Ca2+ Entry and Sarcoplasmic Ca2+ Leak Currents on Electrophysiology and Ca2+ Transients in Human Ventricular Cardiomyocytes: A Computational Comparison

The Critical Roles of Proteostasis and Endoplasmic Reticulum Stress in Atrial Fibrillation

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Small and Intermediate Calcium Activated Potassium Channels in the Heart: Role and Strategies in the Treatment of Cardiovascular Diseases

Cited by 24 publications

References 161 publications

Activation of small conductance Ca2+‐activated K+ channels suppresses Ca2+ transient and action potential alternans in ventricular myocytes

Activation of small conductance Ca2+‐activated K+ channels suppresses Ca2+ transient and action potential alternans in ventricular myocytes

Effects of Sarcolemmal Background Ca2+ Entry and Sarcoplasmic Ca2+ Leak Currents on Electrophysiology and Ca2+ Transients in Human Ventricular Cardiomyocytes: A Computational Comparison

The Critical Roles of Proteostasis and Endoplasmic Reticulum Stress in Atrial Fibrillation

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Resources

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Activation of small conductance Ca²⁺‐activated K⁺ channels suppresses Ca²⁺ transient and action potential alternans in ventricular myocytes

Activation of small conductance Ca²⁺‐activated K⁺ channels suppresses Ca²⁺ transient and action potential alternans in ventricular myocytes