Class III antiarrhythmic drugs amiodarone and dronedarone impair KIR2.1 backward trafficking

Yuan Ji; Hiroki Takanari; Muge Qile; Lukas Nalos; Marien J.C. Houtman; Fee L. Romunde; Raimond Heukers; Paul M.P. van Bergen en Henegouwen; Marc A. Vos; Marcel A.G. van der Heyden

doi:10.1111/jcmm.13172

Class III antiarrhythmic drugs amiodarone and dronedarone impair K_IR2.1 backward trafficking

Yuan Ji
, Hiroki Takanari
, Muge Qile
, Lukas Nalos
, Marien J.C. Houtman
, Fee L. Romunde
, Raimond Heukers
, Paul M.P. van Bergen en Henegouwen
, Marc A. Vos
, Marcel A.G. van der Heyden^*

^*Corresponding author for this work

Cell Biology, Neurobiology and Biophysics

Utrecht University
Charles University
extern

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Drug-induced ion channel trafficking disturbance can cause cardiac arrhythmias. The subcellular level at which drugs interfere in trafficking pathways is largely unknown. K_IR2.1 inward rectifier channels, largely responsible for the cardiac inward rectifier current (I_K ₁), 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 K_IR2.1 backward trafficking by amiodarone and dronedarone. Both drugs inhibited I_K ₁ in isolated rabbit ventricular cardiomyocytes at supraclinical doses only. In HK-KWGF cells, both drugs dose- and time-dependently increased K_IR2.1 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 K_IR2.1 accumulation. Increased K_IR2.1 expression level was also observed in the presence of Na_v1.5 co-expression. Augmented K_IR2.1 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 K_v11.1 ion channel protein expression levels. Finally, amiodarone (73.3 ± 10.3% P < 0.05 at −120 mV, 5 μM) enhanced I_KIR _2.1 upon 24-hrs treatment, whereas dronedarone tended to increase I_KIR _2.1 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 I_K ₁ by inhibiting K_IR2.1 degradation.

Original language	English
Pages (from-to)	2514-2523
Number of pages	10
Journal	Journal of Cellular and Molecular Medicine
Volume	21
Issue number	10
DOIs	https://doi.org/10.1111/jcmm.13172
Publication status	Published - Oct 2017

Bibliographical note

Funding Information:
We thank Laura G. Freriks and Ralph G. Tieland for their helpful contributions at the early stages of the current studies. We thank Craig T. January (University of Wisconsin, USA) for providing HEK-hERG cells, Nenad Bursac (Duke University, Durham, USA) for providing Ex293 cells and Christine Mummery (Hubrecht Laboratory, Utrecht, Netherlands) for providing END-2, MES-1 and EPI-7 cells. The research leading to the results has received funding from EU project ?increasing of the R&D capacity at Charles University through new positions for graduates of doctoral studies? CX.1.07/2.3.00/30.0061: Utrecht University Focus and Massa Program Nanobullets; Y.J. and M.Q. are recipients of a scholarship from the Chinese Scholarship Council.

Publisher Copyright:
© 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Funding

We thank Laura G. Freriks and Ralph G. Tieland for their helpful contributions at the early stages of the current studies. We thank Craig T. January (University of Wisconsin, USA) for providing HEK-hERG cells, Nenad Bursac (Duke University, Durham, USA) for providing Ex293 cells and Christine Mummery (Hubrecht Laboratory, Utrecht, Netherlands) for providing END-2, MES-1 and EPI-7 cells. The research leading to the results has received funding from EU project ?increasing of the R&D capacity at Charles University through new positions for graduates of doctoral studies? CX.1.07/2.3.00/30.0061: Utrecht University Focus and Massa Program Nanobullets; Y.J. and M.Q. are recipients of a scholarship from the Chinese Scholarship Council.

Keywords

amiodarone
degradation
dronedarone
inward rectifier
K
lysosome

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J Cellular Molecular Medi - 2017 - Ji - Class III antiarrhythmic drugs amiodarone and dronedarone impair KIR2 1 backwardFinal published version, 860 KBLicence: CC BY

Cite this

@article{d926700180f949959b9d06a195751e0e,

title = "Class III antiarrhythmic drugs amiodarone and dronedarone impair KIR2.1 backward trafficking",

abstract = "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 (IK 1), 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 IK 1 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 IKIR 2.1 upon 24-hrs treatment, whereas dronedarone tended to increase IKIR 2.1 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 IK 1 by inhibiting KIR2.1 degradation.",

keywords = "amiodarone, degradation, dronedarone, inward rectifier, K, lysosome",

author = "Yuan Ji and Hiroki Takanari and Muge Qile and Lukas Nalos and Houtman, \{Marien J.C.\} and Romunde, \{Fee L.\} and Raimond Heukers and \{van Bergen en Henegouwen\}, \{Paul M.P.\} and Vos, \{Marc A.\} and \{van der Heyden\}, \{Marcel A.G.\}",

note = "Funding Information: We thank Laura G. Freriks and Ralph G. Tieland for their helpful contributions at the early stages of the current studies. We thank Craig T. January (University of Wisconsin, USA) for providing HEK-hERG cells, Nenad Bursac (Duke University, Durham, USA) for providing Ex293 cells and Christine Mummery (Hubrecht Laboratory, Utrecht, Netherlands) for providing END-2, MES-1 and EPI-7 cells. The research leading to the results has received funding from EU project ?increasing of the R\&D capacity at Charles University through new positions for graduates of doctoral studies? CX.1.07/2.3.00/30.0061: Utrecht University Focus and Massa Program Nanobullets; Y.J. and M.Q. are recipients of a scholarship from the Chinese Scholarship Council. Publisher Copyright: {\textcopyright} 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley \& Sons Ltd and Foundation for Cellular and Molecular Medicine.",

year = "2017",

month = oct,

doi = "10.1111/jcmm.13172",

language = "English",

volume = "21",

pages = "2514--2523",

journal = "Journal of Cellular and Molecular Medicine",

issn = "1582-1838",

publisher = "John Wiley and Sons Inc.",

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TY - JOUR

T1 - Class III antiarrhythmic drugs amiodarone and dronedarone impair KIR2.1 backward trafficking

AU - Ji, Yuan

AU - Takanari, Hiroki

AU - Qile, Muge

AU - Nalos, Lukas

AU - Houtman, Marien J.C.

AU - Romunde, Fee L.

AU - Heukers, Raimond

AU - van Bergen en Henegouwen, Paul M.P.

AU - Vos, Marc A.

AU - van der Heyden, Marcel A.G.

N1 - Funding Information: We thank Laura G. Freriks and Ralph G. Tieland for their helpful contributions at the early stages of the current studies. We thank Craig T. January (University of Wisconsin, USA) for providing HEK-hERG cells, Nenad Bursac (Duke University, Durham, USA) for providing Ex293 cells and Christine Mummery (Hubrecht Laboratory, Utrecht, Netherlands) for providing END-2, MES-1 and EPI-7 cells. The research leading to the results has received funding from EU project ?increasing of the R&D capacity at Charles University through new positions for graduates of doctoral studies? CX.1.07/2.3.00/30.0061: Utrecht University Focus and Massa Program Nanobullets; Y.J. and M.Q. are recipients of a scholarship from the Chinese Scholarship Council. Publisher Copyright: © 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

PY - 2017/10

Y1 - 2017/10

N2 - 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 (IK 1), 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 IK 1 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 IKIR 2.1 upon 24-hrs treatment, whereas dronedarone tended to increase IKIR 2.1 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 IK 1 by inhibiting KIR2.1 degradation.

AB - 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 (IK 1), 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 IK 1 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 IKIR 2.1 upon 24-hrs treatment, whereas dronedarone tended to increase IKIR 2.1 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 IK 1 by inhibiting KIR2.1 degradation.

KW - amiodarone

KW - degradation

KW - dronedarone

KW - inward rectifier

KW - K

KW - lysosome

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VL - 21

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JO - Journal of Cellular and Molecular Medicine

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