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SHR Neuro Cancer Cardio Lipid Metab Microb

Heijman, J; Zhou, X; Morotti, S; Molina, CE; Abu-Taha, IH; Tekook, M; Jespersen, T; Zhang, Y; Dobrev, S; Milting, H; Gummert, J; Karck, M; Kamler, M; El-Armouche, A; Saljic, A; Grandi, E; Nattel, S; Dobrev, D.
Enhanced Ca²⁺-Dependent SK-Channel Gating and Membrane Trafficking in Human Atrial Fibrillation.
Circ Res. 2023; 132(9): e116-e133. Doi: 10.1161/CIRCRESAHA.122.321858 [OPEN ACCESS]
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Leading authors Med Uni Graz

Heijman Jordi

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Abstract:

BACKGROUND: Small-conductance Ca²⁺-activated K⁺ (SK)-channel inhibitors have antiarrhythmic effects in animal models of atrial fibrillation (AF), presenting a potential novel antiarrhythmic option. However, the regulation of SK-channels in human atrial cardiomyocytes and its modification in patients with AF are poorly understood and were the object of this study. METHODS: Apamin-sensitive SK-channel current (I_SK) and action potentials were recorded in human right-atrial cardiomyocytes from sinus rhythm control (Ctl) patients or patients with (long-standing persistent) chronic AF (cAF). RESULTS: I_SK was significantly higher, and apamin caused larger action potential prolongation in cAF- versus Ctl-cardiomyocytes. Sensitivity analyses in an in silico human atrial cardiomyocyte model identified I_K1 and I_SK as major regulators of repolarization. Increased I_SK in cAF was not associated with increases in mRNA/protein levels of SK-channel subunits in either right- or left-atrial tissue homogenates or right-atrial cardiomyocytes, but the abundance of SK2 at the sarcolemma was larger in cAF versus Ctl in both tissue-slices and cardiomyocytes. Latrunculin-A and primaquine (anterograde and retrograde protein-trafficking inhibitors) eliminated the differences in SK2 membrane levels and I_SK between Ctl- and cAF-cardiomyocytes. In addition, the phosphatase-inhibitor okadaic acid reduced I_SK amplitude and abolished the difference between Ctl- and cAF-cardiomyocytes, indicating that reduced calmodulin-Thr80 phosphorylation due to increased protein phosphatase-2A levels in the SK-channel complex likely contribute to the greater I_SK in cAF-cardiomyocytes. Finally, rapid electrical activation (5 Hz, 10 minutes) of Ctl-cardiomyocytes promoted SK2 membrane-localization, increased I_SK and reduced action potential duration, effects greatly attenuated by apamin. Latrunculin-A or primaquine prevented the 5-Hz-induced I_SK-upregulation. CONCLUSIONS: I_SK is upregulated in patients with cAF due to enhanced channel function, mediated by phosphatase-2A-dependent calmodulin-Thr80 dephosphorylation and tachycardia-dependent enhanced trafficking and targeting of SK-channel subunits to the sarcolemma. The observed AF-associated increases in I_SK, which promote reentry-stabilizing action potential duration shortening, suggest an important role for SK-channels in AF auto-promotion and provide a rationale for pursuing the antiarrhythmic effects of SK-channel inhibition in humans.

Find related publications in this database (using NLM MeSH Indexing)

Animals - administration & dosage

Humans - administration & dosage

Atrial Fibrillation - metabolism

Apamin - metabolism, pharmacology

Primaquine - metabolism, pharmacology

Calmodulin - metabolism

Heart Atria - metabolism

Myocytes, Cardiac - metabolism

Anti-Arrhythmia Agents - therapeutic use

Action Potentials - physiology

Small-Conductance Calcium-Activated Potassium Channels - metabolism

Find related publications in this database (Keywords)

actinin

apamin

atrial fibrillation

atrial remodeling

calmodulin

protein phosphatase-2A

protein transport

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