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• W2296928053 endingPage "2489" @default.
• W2296928053 startingPage "2476" @default.
• W2296928053 abstract "Hyperaldosteronism is associated with an increased prevalence of atrial fibrillation (AF). Mutations in KCNE3 have been associated with AF, and Kcne3-/- mice exhibit hyperaldosteronism. In this study, we used recently developed Kcne3-/- mice to study atrial electrophysiology with respect to development of aldosterone-dependent AF. In invasive electrophysiology studies, Kcne3-/- mice displayed a reduced atrial effective refractory period (AERP) and inducible episodes of paroxysmal AF. The cellular arrhythmogenic correlate for AF predisposition was a significant increase in atrial Kv currents generated by the micromolar 4-aminopyridine-sensitive Kv current encoded by Kv1.5. Electrophysiological alterations in Kcne3-/- mice were aldosterone dependent and were associated with increased Rab4, -5, and -9-dependent recycling of Kv1.5 channels to the Z-disc/T-tubulus region and lateral membrane via activation of the Akt/AS160 pathway. Treatment with spironolactone inhibited Akt/AS160 phosphorylation, reduced Rab-dependent Kv1.5 recycling, normalized AERP and atrial Kv currents to the wild-type level, and reduced arrhythmia induction in Kcne3-/- mice. Kcne3 deletion in mice predisposes to AF by a heretofore unrecognized mechanism—namely, increased aldosterone-dependent Kv1.5 recycling via Rab GTPases. The findings uncover detailed molecular mechanisms underpinning a channelopathy-linked form of AF and emphasize the inevitability of considering extracardiac mechanisms in genetic arrhythmia syndromes.— Lisewski, U., Koehncke, C., Wilck, N., Buschmeyer, B., Pieske, B., Roepke, T. K. Increased aldosterone-dependent Kv1.5 recycling predisposes to pacing-induced atrial fibrillation in Kcne3-/- mice. FASEB J. 30, 2476-2489 (2016). www.fasebj.org" @default.
• W2296928053 created "2016-06-24" @default.
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• W2296928053 date "2016-03-16" @default.
• W2296928053 modified "2023-09-30" @default.
• W2296928053 title "Increased aldosterone‐dependent Kv1.5 recycling predisposes to pacing‐induced atrial fibrillation in <i>Kcne3</i> ^‐/‐ mice" @default.
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• W2296928053 doi "https://doi.org/10.1096/fj.201600317r" @default.
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