ID | 118213 |
著者 |
Ji, Yuan
UMCU
Qile, Muge
UMCU
Nalos, Lukas
Charles University
Houtman, Marien J.C.
UMCU
Romunde, Fee L.
UMCU
Heukers, Raimond
Utrecht University
van Bergen en Henegouwen, Paul M.P.
Utrecht University
Vos, Marc A.
UMCU
van der Heyden, Marcel A.G.
UMCU
|
キーワード | inward rectifier
KIR2.1
degradation
lysosome
amiodarone
dronedarone
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資料タイプ |
学術雑誌論文
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抄録 | Drug-induced ion channel trafficking disturbance can cause cardiac arrhythmias. The subcellular level at which drugs interfere in trafficking pathways is largely unknown. KIR2.1 inward rectifier channels, largely responsible for the cardiac inward rectifier current (IK1), are degraded in lysosomes. Amiodarone and dronedarone are class III antiarrhythmics. Chronic use of amiodarone, and to a lesser extent dronedarone, causes serious adverse effects to several organs and tissue types, including the heart. Both drugs have been described to interfere in the late-endosome/lysosome system. Here we defined the potential interference in KIR2.1 backward trafficking by amiodarone and dronedarone. Both drugs inhibited IK1 in isolated rabbit ventricular cardiomyocytes at supraclinical doses only. In HK-KWGF cells, both drugs dose- and time-dependently increased KIR2.1 expression (2.0 ± 0.2-fold with amiodarone: 10 μM, 24 hrs; 2.3 ± 0.3-fold with dronedarone: 5 μM, 24 hrs) and late-endosomal/lysosomal KIR2.1 accumulation. Increased KIR2.1 expression level was also observed in the presence of Nav1.5 co-expression. Augmented KIR2.1 protein levels and intracellular accumulation were also observed in COS-7, END-2, MES-1 and EPI-7 cells. Both drugs had no effect on Kv11.1 ion channel protein expression levels. Finally, amiodarone (73.3 ± 10.3% P < 0.05 at −120 mV, 5 μM) enhanced IKIR2.1 upon 24-hrs treatment, whereas dronedarone tended to increase IKIR2.1 and it did not reach significance (43.8 ± 5.5%, P = 0.26 at −120 mV; 2 μM). We conclude that chronic amiodarone, and potentially also dronedarone, treatment can result in enhanced IK1 by inhibiting KIR2.1 degradation.
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掲載誌名 |
Journal of Cellular and Molecular Medicine
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ISSN | 15824934
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出版者 | Wiley|Foundation for Cellular and Molecular Medicine
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巻 | 21
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号 | 10
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開始ページ | 2514
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終了ページ | 2523
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発行日 | 2017-04-19
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権利情報 | This is an open access article under the terms of the Creative Commons Attribution License(https://creativecommons.org/licenses/by/4.0/), which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
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出版社版DOI | |
出版社版URL | |
フルテキストファイル | |
言語 |
eng
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著者版フラグ |
出版社版
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部局 |
病院
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