title: Increased aldosterone-dependent Kv1.5 recycling predisposes to pacing-induced atrial fibrillation in Kcne3-/- mice.
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.
authors.affiliation: Experimental and Clinical Research Center, Berlin, Germany;
authors.forename: Ulrike
authors.initials: U
authors.lastname: Lisewski
authors.affiliation: Experimental and Clinical Research Center, Berlin, Germany; Department of Cardiology, Campus Virchow, Universitätsmedizin Berlin, Berlin, Germany; and.
authors.forename: Clemens
authors.initials: C
authors.lastname: Koehncke
authors.affiliation: Experimental and Clinical Research Center, Berlin, Germany;
authors.forename: Nicola
authors.initials: N
authors.lastname: Wilck
authors.affiliation: Experimental and Clinical Research Center, Berlin, Germany;
authors.forename: Bastian
authors.initials: B
authors.lastname: Buschmeyer
authors.affiliation: Department of Cardiology, Campus Virchow, Universitätsmedizin Berlin, Berlin, Germany; and.
authors.forename: Burkert
authors.initials: B
authors.lastname: Pieske
authors.affiliation: Experimental and Clinical Research Center, Berlin, Germany; Department of Cardiology and Angiology, Campus Mitte, Charité, Universitätsmedizin Berlin, Berlin, Germany torsten-kai.roepke@charite.de.
authors.forename: Torsten K
authors.initials: TK
authors.lastname: Roepke
mesh_terms: D000311:Adrenal Glands / Q000473:pathology; D000450:Aldosterone / Q000378:metabolism*; D000818:Animals; D001281:Atrial Fibrillation / Q000209:etiology*; D055724:Electrophysiological Phenomena; D020690:GTPase-Activating Proteins / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology; D006929:Hyperaldosteronism / Q000235:genetics / Q000378:metabolism; D051666:Kv1.5 Potassium Channel / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000378:metabolism; D018408:Patch-Clamp Techniques; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D013148:Spironolactone / Q000494:pharmacology; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C452880:Atp5md protein, rat; D020690:GTPase-Activating Proteins; C498827:Kcne3 protein, mouse; D051666:Kv1.5 Potassium Channel; D008565:Membrane Proteins; D024642:Potassium Channels, Voltage-Gated; C505647:Tbc1d4 protein, mouse; D013148:Spironolactone; D000450:Aldosterone; D051057:Proto-Oncogene Proteins c-akt; D020691:rab GTP-Binding Proteins
keywords: KCNE; Kv channel; aldosteronism; arrhythmia; trafficking