Enhanced Ca <sup>2+</sup> -Dependent SK-Channel Gating and Membrane Trafficking in Human Atrial Fibrillation-Reference-Cited by-同舟云学术

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

Published:2023-04-28 Issue:9 Volume:132 Page:
ISSN:0009-7330
Container-title:Circulation Research
language:en
Short-container-title:Circulation Research

Author:

Heijman Jordi¹²^ORCID,Zhou Xiaobo³⁴⁵^ORCID,Morotti Stefano⁶^ORCID,Molina Cristina E.¹⁷^ORCID,Abu-Taha Issam H.¹^ORCID,Tekook Marcel¹,Jespersen Thomas⁸,Zhang Yiqiao¹^ORCID,Dobrev Shokoufeh¹,Milting Hendrik⁹^ORCID,Gummert Jan⁹,Karck Matthias¹⁰,Kamler Markus¹¹,El-Armouche Ali¹²^ORCID,Saljic Arnela¹⁸,Grandi Eleonora⁶,Nattel Stanley¹¹³¹⁴¹⁵^ORCID,Dobrev Dobromir¹¹³¹⁶^ORCID

Affiliation:

1. Institute of Pharmacology, West German Heart and Vascular Center, Faculty of Medicine, University Duisburg-Essen, Germany (J.H., C.E.M., I.H.A.-T., M.T., Y.Z., S.D., A.S., S.N., D.D.).

2. Department of Cardiology, Cardiovascular Research Institute Maastricht, Faculty of Health, Medicine, and Life Sciences, Maastricht University, the Netherlands (J.H.).

3. First Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany (X.Z.).

4. DZHK (German Center for Cardiovascular Research), partner site Heidelberg/Mannheim, Germany (X.Z.).

5. Key Laboratory of Medical Electrophysiology, Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Collaborative Innovation Center for Prevention of Cardiovascular Diseases, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China (X.Z.).

6. Department of Pharmacology, University of California, Davis (S.M., E.G.).

7. Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf and DZHK (German Center for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Germany (C.E.M.).

8. Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark (T.J., A.S.).

9. Erich and Hanna Klessmann Institute, Heart and Diabetes Center NRW, University Hospital of the Ruhr-University Bochum, Bad Oeynhausen, Germany (H.M., J.G.).

10. Department of Cardiac Surgery, Heidelberg University Hospital, Germany (M. Karck).

11. Department of Thoracic and Cardiovascular Surgery, West German Heart and Vascular Center Essen, University Hospital Essen, Germany (M. Kamler).

12. Institute of Pharmacology, Dresden University of Technology, Germany (A.E.-A.).

13. Department of Medicine, Montreal Heart Institute and Université de Montréal (S.N., D.D.).

14. Department of Pharmacology and Therapeutics, McGill University Montreal, Canada (S.N.).

15. IHU LIRYC and Fondation Bordeaux Université, France (S.N.).

16. Department of Molecular Physiology & Biophysics, Baylor College of Medicine, Houston, TX (D.D.).

Abstract

Background: Small-conductance Ca 2+ -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.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Cardiology and Cardiovascular Medicine,Physiology

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