Heterogeneous Upregulation of Apamin‐Sensitive Potassium Currents in Failing Human Ventricles

Chang, Po Cheng; Turker, Isik; Lopshire, John C.; Masroor, Saqib; Nguyen, Bich Lien; Wen, Tao; Rubart, Michael; Chen, Peng Sheng; Chen, Zhenhui; Ai, Tomohiko

doi:10.1161/jaha.112.004713

Cited by 85 publications

(103 citation statements)

References 38 publications

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“…The channels are found to be expressed at a higher level in atria compared with ventricles (6). Our findings have subsequently been supported by several different laboratories (9,(29)(30)(31)(32)(33). We further demonstrate that SK channels play critical roles in pacemaking cells (34).…”

Section: Computational Prediction Of α-Actinin2supporting

confidence: 82%

Functional interaction with filamin A and intracellular Ca ²⁺ enhance the surface membrane expression of a small-conductance Ca ²⁺ -activated K ⁺ (SK2) channel

Rafizadeh¹,

Zhang²,

Woltz³

et al. 2014

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

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For an excitable cell to function properly, a precise number of ion channel proteins need to be trafficked to distinct locations on the cell surface membrane, through a network and anchoring activity of cytoskeletal proteins. Not surprisingly, mutations in anchoring proteins have profound effects on membrane excitability. Ca 2+ -activated K + channels (K Ca 2 or SK) have been shown to play critical roles in shaping the cardiac atrial action potential profile. Here, we demonstrate that filamin A, a cytoskeletal protein, augments the trafficking of SK2 channels in cardiac myocytes. The trafficking of SK2 channel is Ca 2+ -dependent. Further, the Ca 2+ dependence relies on another channel-interacting protein, α-actinin2, revealing a tight, yet intriguing, assembly of cytoskeletal proteins that orchestrate membrane expression of SK2 channels in cardiac myocytes. We assert that changes in SK channel trafficking would significantly alter atrial action potential and consequently atrial excitability. Identification of therapeutic targets to manipulate the subcellular localization of SK channels is likely to be clinically efficacious. The findings here may transcend the area of SK2 channel studies and may have implications not only in cardiac myocytes but in other types of excitable cells.ion channel trafficking | atrial myocytes | atrial fibrillation S mall-conductance Ca 2+ -activated K + (SK or K Ca 2) channels are highly unique in that they are gated solely by changes in intracellular Ca 2+ (Ca 2+ i ) concentration. Hence, the channels function to integrate changes in Ca 2+ concentration with changes in membrane potentials. SK channels have been shown to be expressed in a wide variety of cells (1-3) and mediate afterhyperpolarizations following action potentials in neurons (1, 4, 5). We have previously documented the expression of several isoforms of SK channels in human and mouse atrial myocytes that mediate the repolarization phase of the atrial action potentials (6, 7). We further demonstrated that SK2 (K Ca 2.2) channel knockout mice are prone to the development of atrial arrhythmias and atrial fibrillation (AF) (8). Conversely, a recent study by Diness et al. suggests that inhibition of SK channels may prevent AF (9). Together, these studies underpin the importance of the precise control for the expression of these ion channels in atria and their potential to serve as a future therapeutic target for AF.Current antiarrhythmic agents target the permeation and gating properties of ion channel proteins; however, increasing evidence suggests that membrane localization of ion channels may also be pharmacologically altered (10). Furthermore, a number of disorders have been associated with mistrafficking of ion channel proteins (11,12). We have previously demonstrated the critical role of α-actinin2, a cytoskeletal protein, in the surface membrane localization of cardiac SK2 channels (13,14). Specifically, we demonstrated that cardiac SK2 channel interacts with α-actinin2 cytoskeletal protein via the EF hand motifs in α...

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Section: Computational Prediction Of α-Actinin2supporting

confidence: 82%

Functional interaction with filamin A and intracellular Ca ²⁺ enhance the surface membrane expression of a small-conductance Ca ²⁺ -activated K ⁺ (SK2) channel

Rafizadeh¹,

Zhang²,

Woltz³

et al. 2014

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

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“…Large variations of I KAS densities have also been observed in VMs 8, 15, 35. The mechanisms by which some cells had more I KAS than others remain unclear.…”

Section: Discussionmentioning

confidence: 99%

“…Subsequent studies showed that both SK channel proteins and apamin‐sensitive SK currents ( I KAS ) are abundantly present in the atria, atrioventricular node, pulmonary vein, and ventricular myocytes (VMs) of different species and play an important role in repolarization and arrhythmogenesis especially in heart failure and myocardial ischemia 5, 6. In both normal and failing ventricles, prolongation of the pacing cycle length (PCL) further increases the importance of I KAS in repolarization 7, 8. However, the importance of I KAS in the His‐Purkinje system remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Small‐Conductance Calcium‐Activated Potassium Current in Normal Rabbit Cardiac Purkinje Cells

Reher

Wang

Hsueh

et al. 2017

JAHA

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BackgroundPurkinje cells (PCs) are important in cardiac arrhythmogenesis. Whether small‐conductance calcium‐activated potassium (SK) channels are present in PCs remains unclear. We tested the hypotheses that subtype 2 SK (SK2) channel proteins and apamin‐sensitive SK currents are abundantly present in PCs.Methods and ResultsWe studied 25 normal rabbit ventricles, including 13 patch‐clamp studies, 4 for Western blotting, and 8 for immunohistochemical staining. Transmembrane action potentials were recorded in current‐clamp mode using the perforated‐patch technique. For PCs, the apamin (100 nmol/L) significantly prolonged action potential duration measured to 80% repolarization by an average of 10.4 ms (95% CI, 0.11–20.72) (n=9, P=0.047). Voltage‐clamp study showed that apamin‐sensitive SK current density was significantly larger in PCs compared with ventricular myocytes at potentials ≥0 mV. Western blotting of SK2 expression showed that the SK2 protein expression in the midmyocardium was 58% (P=0.028) and the epicardium was 50% (P=0.018) of that in the pseudotendons. Immunostaining of SK2 protein showed that PCs stained stronger than ventricular myocytes. Confocal microscope study showed SK2 protein was distributed to the periphery of the PCs.Conclusions SK2 proteins are more abundantly present in the PCs than in the ventricular myocytes of normal rabbit ventricles. Apamin‐sensitive SK current is important in ventricular repolarization of normal PCs.

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“…The atrial IKCa was formulated as a time-independent passive K + current whose conductance depends strongly on the intracellular calcium concentration, [Ca 2+ ]i, following a Hill equation [11], [12]. Parameterization was achieved by fitting experimental data from isolated ventricular myocytes from HF patients [11], to give Equation (1):…”

Section: Formulation Of Ikca In Heart Failurementioning

confidence: 99%

“…Parameterization was achieved by fitting experimental data from isolated ventricular myocytes from HF patients [11], to give Equation (1):…”

Section: Formulation Of Ikca In Heart Failurementioning

confidence: 99%

The Efficacy of Class III Anti-arrhythmic Drug Action in 3D Canine Atrial Models: Is the Blockade of IKCa Pro- or Anti-arrhythmic?

Varela

Dar

Hancox

et al. 2017

Computing in Cardiology Conference (CinC)

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Small conductance calcium-activated potassium channel current, IKCa, has IntroductionAtrial fibrillation (AF) is the most common sustained cardiac arrhythmia, affecting 3% of the adult population of developed countries. AF is associated with increased morbidity and mortality and its incidence is expected to rise in the near future, making it an urgent and important health problem [1].Although anti-arrhythmic drugs (AADs) are the first line therapy for recent onset AF, their cardioversion efficacy can be as low as 50% [1]. AADs often carry significant side effects, namely the potential to induce lifethreatening ventricular arrhythmias. These pro-arrhythmic side effects can be minimised if AADs are designed to target atrial-selective ionic channels, which have a negligible contribution to the ventricular action potential.One of such targets is the K + ultra-rapid delayed rectifier current, IKur, which is expressed in human atrial cells, but not in human ventricles [2]. This is in contrast with the rapid delayed rectifier current, IKr, which is ubiquitous throughout the heart and the blockade of which may lead to life-threatening Torsade de Pointes [2].Recently, ionic current carried by small-conductance calcium-dependent K + channels, IKCa, has been characterised in human and canine atrial cells, but, significantly, not in ventricular myocytes, making IKCa a potentially desirable target of anti-arrhythmic drug action in AF. Genomic associations between IKCa and AF have also been established [3].Although blocking IKCa is known to increase the action potential duration (APD) in canine atrial cells [3]-[6], there is some controversy as to whether its blockade is proor anti-arrhythmic. Blocking IKCa has been found to facilitate the initiation of atrial arrhythmias [3], [6], by increasing both APD and APD heterogeneity in the canine left atrium (LA). Other studies have instead found that IKCa blockade, through prolongation of APD, led to reduced AF duration [4] and AF termination [5]. It is also at the moment not clear whether IKCa is overexpressed in the presence of AF remodelling [4] or not [7].In this paper, we aim to reconcile the disparate experimental findings about IKCa's effect on AF using insights from computational models. To this end, we introduce a new mathematical formulation for IKCa and include it in our recently developed canine atrial cell models [8]. We use these updated canine models to investigate the effect on APD of blockades of IKr, IKur and IKCa in several atrial remodelling conditions. We then determine the effectiveness of these blockades in realistic 3D canine atrial models [8] and interpret these findings in the light of the drugs' effects on APD and APD dispersion across the entire atria, using the formalism previously applied to investigate the effectiveness of multi-channelblocking AADs [8].

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Heterogeneous Upregulation of Apamin‐Sensitive Potassium Currents in Failing Human Ventricles

Cited by 85 publications

References 38 publications

Functional interaction with filamin A and intracellular Ca ²⁺ enhance the surface membrane expression of a small-conductance Ca ²⁺ -activated K ⁺ (SK2) channel

Functional interaction with filamin A and intracellular Ca ²⁺ enhance the surface membrane expression of a small-conductance Ca ²⁺ -activated K ⁺ (SK2) channel

Small‐Conductance Calcium‐Activated Potassium Current in Normal Rabbit Cardiac Purkinje Cells

The Efficacy of Class III Anti-arrhythmic Drug Action in 3D Canine Atrial Models: Is the Blockade of IKCa Pro- or Anti-arrhythmic?

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Heterogeneous Upregulation of Apamin‐Sensitive Potassium Currents in Failing Human Ventricles

Cited by 85 publications

References 38 publications

Functional interaction with filamin A and intracellular Ca 2+ enhance the surface membrane expression of a small-conductance Ca 2+ -activated K + (SK2) channel

Functional interaction with filamin A and intracellular Ca 2+ enhance the surface membrane expression of a small-conductance Ca 2+ -activated K + (SK2) channel

Small‐Conductance Calcium‐Activated Potassium Current in Normal Rabbit Cardiac Purkinje Cells

The Efficacy of Class III Anti-arrhythmic Drug Action in 3D Canine Atrial Models: Is the Blockade of IKCa Pro- or Anti-arrhythmic?

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Product

Resources

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Functional interaction with filamin A and intracellular Ca ²⁺ enhance the surface membrane expression of a small-conductance Ca ²⁺ -activated K ⁺ (SK2) channel

Functional interaction with filamin A and intracellular Ca ²⁺ enhance the surface membrane expression of a small-conductance Ca ²⁺ -activated K ⁺ (SK2) channel