Enhanced Ca 2+ -Dependent SK-Channel Gating and Membrane Trafficking in Human Atrial Fibrillation

• Published in: Circulation research 2023-04, Vol.132 (9), p.e116-e133
• Main Authors: Heijman, Jordi, Zhou, Xiaobo, Morotti, Stefano, Molina, Cristina E., Abu-Taha, Issam H., Tekook, Marcel, Jespersen, Thomas, Zhang, Yiqiao, Dobrev, Shokoufeh, Milting, Hendrik, Gummert, Jan, Karck, Matthias, Kamler, Markus, El-Armouche, Ali, Saljic, Arnela, Grandi, Eleonora, Nattel, Stanley, Dobrev, Dobromir
• Format: Article
• Language: English
• Subjects: Action Potentials - physiology; Animals; Anti-Arrhythmia Agents - therapeutic use; Apamin - metabolism; Apamin - pharmacology; Atrial Fibrillation - metabolism; Calmodulin - metabolism; Heart Atria - metabolism; Humans; Myocytes, Cardiac - metabolism; Primaquine - metabolism; Primaquine - pharmacology; Small-Conductance Calcium-Activated Potassium Channels - metabolism
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/CIRCRESAHA.122.321858

Small-conductance Ca -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. Apamin-sensitive SK-channel current (I ) 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). I 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 and I as major regulators of repolarization. Increased I 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 between Ctl- and cAF-cardiomyocytes. In addition, the phosphatase-inhibitor okadaic acid reduced I 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 in cAF-cardiomyocytes. Finally, rapid electrical activation (5 Hz, 10 minutes) of Ctl-cardiomyocytes promoted SK2 membrane-localization, increased I and reduced action potential duration, effects greatly attenuated by apamin. Latrunculin-A or primaquine prevented the 5-Hz-induced I -upregulation. I 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 , 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.