Enhanced Ca2+-Dependent SK-Channel Gating and Membrane Trafficking in Human Atrial Fibrillation
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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Enhanced Ca2+-Dependent SK-Channel Gating and Membrane Trafficking in Human Atrial Fibrillation. / 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.
I: Circulation Research, Bind 132, Nr. 9, 2023, s. E116-E133.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Enhanced Ca2+-Dependent SK-Channel Gating and Membrane Trafficking in Human Atrial Fibrillation
AU - Heijman, Jordi
AU - Zhou, Xiaobo
AU - Morotti, Stefano
AU - Molina, Cristina E.
AU - Abu-Taha, Issam H.
AU - Tekook, Marcel
AU - Jespersen, Thomas
AU - Zhang, Yiqiao
AU - Dobrev, Shokoufeh
AU - Milting, Hendrik
AU - Gummert, Jan
AU - Karck, Matthias
AU - Kamler, Markus
AU - El-Armouche, Ali
AU - Saljic, Arnela
AU - Grandi, Eleonora
AU - Nattel, Stanley
AU - Dobrev, Dobromir
N1 - Publisher Copyright: © 2023 Lippincott Williams and Wilkins. All rights reserved.
PY - 2023
Y1 - 2023
N2 - 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 (ISK) 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: ISKwas 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 IK1and ISKas major regulators of repolarization. Increased ISKin 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 ISKbetween Ctl- and cAF-cardiomyocytes. In addition, the phosphatase-inhibitor okadaic acid reduced ISKamplitude 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 ISKin cAF-cardiomyocytes. Finally, rapid electrical activation (5 Hz, 10 minutes) of Ctl-cardiomyocytes promoted SK2 membrane-localization, increased ISKand reduced action potential duration, effects greatly attenuated by apamin. Latrunculin-A or primaquine prevented the 5-Hz-induced ISK-upregulation. Conclusions: ISKis 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 ISK, 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.
AB - 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 (ISK) 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: ISKwas 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 IK1and ISKas major regulators of repolarization. Increased ISKin 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 ISKbetween Ctl- and cAF-cardiomyocytes. In addition, the phosphatase-inhibitor okadaic acid reduced ISKamplitude 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 ISKin cAF-cardiomyocytes. Finally, rapid electrical activation (5 Hz, 10 minutes) of Ctl-cardiomyocytes promoted SK2 membrane-localization, increased ISKand reduced action potential duration, effects greatly attenuated by apamin. Latrunculin-A or primaquine prevented the 5-Hz-induced ISK-upregulation. Conclusions: ISKis 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 ISK, 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.
KW - actinin
KW - apamin
KW - atrial fibrillation
KW - atrial remodeling
KW - calmodulin
KW - protein phosphatase-2A
KW - protein transport
UR - http://www.scopus.com/inward/record.url?scp=85158020207&partnerID=8YFLogxK
U2 - 10.1161/CIRCRESAHA.122.321858
DO - 10.1161/CIRCRESAHA.122.321858
M3 - Journal article
C2 - 36927079
AN - SCOPUS:85158020207
VL - 132
SP - E116-E133
JO - Circulation Research
JF - Circulation Research
SN - 0009-7330
IS - 9
ER -
ID: 347002219