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

Overview

Journal Circ Res

Specialty Cardiology & Vascular Diseases

Date 2023 Mar 17

PMID 36927079

Authors

Jordi Heijman

Xiaobo Zhou

Stefano Morotti

Cristina E Molina

Issam H Abu-Taha

Marcel Tekook

Thomas Jespersen

Yiqiao Zhang

Shokoufeh Dobrev

Hendrik Milting

Jan Gummert

Matthias Karck

Markus Kamler

Ali El-Armouche

Arnela Saljic

Eleonora Grandi

Stanley Nattel

Dobromir Dobrev

Affiliations

Soon will be listed here.

Abstract

Background: 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.

Methods: 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).

Results: 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.

Conclusions: 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.

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References

Skibsbye L, Poulet C, Diness J, Bentzen B, Yuan L, Kappert U . Small-conductance calcium-activated potassium (SK) channels contribute to action potential repolarization in human atria. Cardiovasc Res. 2014; 103(1):156-67. DOI: 10.1093/cvr/cvu121. View

Bosch R, Zeng X, Grammer J, Popovic K, Mewis C, Kuhlkamp V . Ionic mechanisms of electrical remodeling in human atrial fibrillation. Cardiovasc Res. 2000; 44(1):121-31. DOI: 10.1016/s0008-6363(99)00178-9. View

Peyronnet R, Ravens U . Atria-selective antiarrhythmic drugs in need of alliance partners. Pharmacol Res. 2019; 145:104262. DOI: 10.1016/j.phrs.2019.104262. View

Hindricks G, Potpara T, Dagres N, Arbelo E, Bax J, Blomstrom-Lundqvist C . 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the.... Eur Heart J. 2020; 42(5):373-498. DOI: 10.1093/eurheartj/ehaa612. View

Caballero R, Gonzalez de la Fuente M, Gomez R, Barana A, Amoros I, Dolz-Gaiton P . In humans, chronic atrial fibrillation decreases the transient outward current and ultrarapid component of the delayed rectifier current differentially on each atria and increases the slow component of the delayed rectifier current in both. J Am Coll Cardiol. 2010; 55(21):2346-54. DOI: 10.1016/j.jacc.2010.02.028. View

Dobrev D, Ravens U . Remodeling of cardiomyocyte ion channels in human atrial fibrillation. Basic Res Cardiol. 2003; 98(3):137-48. DOI: 10.1007/s00395-003-0409-8. View

Diness J, Skibsbye L, Jespersen T, Bartels E, Sorensen U, Hansen R . Effects on atrial fibrillation in aged hypertensive rats by Ca(2+)-activated K(+) channel inhibition. Hypertension. 2011; 57(6):1129-35. DOI: 10.1161/HYPERTENSIONAHA.111.170613. View

Neef S, Dybkova N, Sossalla S, Ort K, Fluschnik N, Neumann K . CaMKII-dependent diastolic SR Ca2+ leak and elevated diastolic Ca2+ levels in right atrial myocardium of patients with atrial fibrillation. Circ Res. 2010; 106(6):1134-44. DOI: 10.1161/CIRCRESAHA.109.203836. View

Li M, Li T, Lei M, Tan X, Yang Y, Liu T . [Increased small conductance calcium-activated potassium channel (SK2 channel) current in atrial myocytes of patients with persistent atrial fibrillation]. Zhonghua Xin Xue Guan Bing Za Zhi. 2011; 39(2):147-51. View

10.

Zhou X, Feng Y, Sun Q, Lukowski R, Qiu Y, Spiger K . Nucleoside diphosphate kinase B-activated intermediate conductance potassium channels are critical for neointima formation in mouse carotid arteries. Arterioscler Thromb Vasc Biol. 2015; 35(8):1852-61. DOI: 10.1161/ATVBAHA.115.305881. View

11.

Zhang Z, Ledford H, Park S, Wang W, Rafizadeh S, Kim H . Distinct subcellular mechanisms for the enhancement of the surface membrane expression of SK2 channel by its interacting proteins, α-actinin2 and filamin A. J Physiol. 2016; 595(7):2271-2284. PMC: 5374114. DOI: 10.1113/JP272942. View

12.

Wang H, Li T, Zhang L, Yang Y, Zeng X . [Effects of intracellular calcium alteration on SK currents in atrial cardiomyocytes from patients with atrial fibrillation]. Zhongguo Ying Yong Sheng Li Xue Za Zhi. 2014; 30(4):296-300, 305. View

13.

Schmidt C, Wiedmann F, Voigt N, Zhou X, Heijman J, Lang S . Upregulation of K(2P)3.1 K+ Current Causes Action Potential Shortening in Patients With Chronic Atrial Fibrillation. Circulation. 2015; 132(2):82-92. DOI: 10.1161/CIRCULATIONAHA.114.012657. View

14.

Diness J, Kirchhoff J, Speerschneider T, Abildgaard L, Edvardsson N, Sorensen U . The K2 Channel Inhibitor AP30663 Selectively Increases Atrial Refractoriness, Converts Vernakalant-Resistant Atrial Fibrillation and Prevents Its Reinduction in Conscious Pigs. Front Pharmacol. 2020; 11:159. PMC: 7059611. DOI: 10.3389/fphar.2020.00159. View

15.

Lu L, Timofeyev V, Li N, Rafizadeh S, Singapuri A, Harris T . Alpha-actinin2 cytoskeletal protein is required for the functional membrane localization of a Ca2+-activated K+ channel (SK2 channel). Proc Natl Acad Sci U S A. 2009; 106(43):18402-7. PMC: 2775294. DOI: 10.1073/pnas.0908207106. View

16.

Voigt N, Heijman J, Trausch A, Mintert-Jancke E, Pott L, Ravens U . Impaired Na⁺-dependent regulation of acetylcholine-activated inward-rectifier K⁺ current modulates action potential rate dependence in patients with chronic atrial fibrillation. J Mol Cell Cardiol. 2013; 61:142-52. DOI: 10.1016/j.yjmcc.2013.03.011. View

17.

Kernik D, Morotti S, Wu H, Garg P, Duff H, Kurokawa J . A computational model of induced pluripotent stem-cell derived cardiomyocytes incorporating experimental variability from multiple data sources. J Physiol. 2019; 597(17):4533-4564. PMC: 6767694. DOI: 10.1113/JP277724. View

18.

Heijman J, Voigt N, Nattel S, Dobrev D . Cellular and molecular electrophysiology of atrial fibrillation initiation, maintenance, and progression. Circ Res. 2014; 114(9):1483-99. DOI: 10.1161/CIRCRESAHA.114.302226. View

19.

Qi X, Yeh Y, Xiao L, Burstein B, Maguy A, Chartier D . Cellular signaling underlying atrial tachycardia remodeling of L-type calcium current. Circ Res. 2008; 103(8):845-54. DOI: 10.1161/CIRCRESAHA.108.175463. View

20.

Ni Y, Wang T, Zhuo X, Song B, Zhang J, Wei F . Bisoprolol reversed small conductance calcium-activated potassium channel (SK) remodeling in a volume-overload rat model. Mol Cell Biochem. 2013; 384(1-2):95-103. DOI: 10.1007/s11010-013-1785-5. View