Class III antiarrhythmic drugs amiodarone and dronedarone impair KIR2.1 backward trafficking
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....
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| Veröffentlicht in: | Journal of cellular and molecular medicine 2017-10, Vol.21 (10), p.2514-2523 |
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| creator | Ji, Yuan Takanari, Hiroki Qile, Muge Nalos, Lukas Houtman, Marien J.C. Romunde, Fee L. Heukers, Raimond Bergen en Henegouwen, Paul M.P. Vos, Marc A. Heyden, Marcel A.G. |
| description | 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 |
| doi_str_mv | 10.1111/jcmm.13172 |
| format | Article |
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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.</description><identifier>ISSN: 1582-1838</identifier><identifier>EISSN: 1582-4934</identifier><identifier>DOI: 10.1111/jcmm.13172</identifier><identifier>PMID: 28425222</identifier><language>eng</language><publisher>Hoboken: John Wiley and Sons Inc</publisher><subject>amiodarone ; degradation ; dronedarone ; inward rectifier ; KIR 2.1 ; lysosome ; Original</subject><ispartof>Journal of cellular and molecular medicine, 2017-10, Vol.21 (10), p.2514-2523</ispartof><rights>2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><orcidid>0000-0002-4225-7942</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5618701/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5618701/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,1416,11561,27923,27924,45573,45574,46051,46475,53790,53792</link.rule.ids></links><search><creatorcontrib>Ji, Yuan</creatorcontrib><creatorcontrib>Takanari, Hiroki</creatorcontrib><creatorcontrib>Qile, Muge</creatorcontrib><creatorcontrib>Nalos, Lukas</creatorcontrib><creatorcontrib>Houtman, Marien J.C.</creatorcontrib><creatorcontrib>Romunde, Fee L.</creatorcontrib><creatorcontrib>Heukers, Raimond</creatorcontrib><creatorcontrib>Bergen en Henegouwen, Paul M.P.</creatorcontrib><creatorcontrib>Vos, Marc A.</creatorcontrib><creatorcontrib>Heyden, Marcel A.G.</creatorcontrib><title>Class III antiarrhythmic drugs amiodarone and dronedarone impair KIR2.1 backward trafficking</title><title>Journal of cellular and molecular medicine</title><description>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.</description><subject>amiodarone</subject><subject>degradation</subject><subject>dronedarone</subject><subject>inward rectifier</subject><subject>KIR 2.1</subject><subject>lysosome</subject><subject>Original</subject><issn>1582-1838</issn><issn>1582-4934</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>WIN</sourceid><recordid>eNpVUMtOwzAQtBCIlsKFL8gPpHjtxHEuSCjiEWiFhOCGZDl-tG7jpHJaqv496UNI7GVnd7Sj2UHoFvAY-rpbKO_HQCEjZ2gIKSdxktPk_ISBUz5AV123wJgyoPklGhCekJQQMkTfRS27LirLMpLN2skQ5rv13DsV6bCZdZH0rtUytI3ped0ve3SanV9JF6K38oOMIaqkWm5l0NE6SGudWrpmdo0urKw7c3PqI_T19PhZvMST9-eyeJjEDQEgMec5YZVkObG6sqkkJKuM5ZjhLMXMpJBYbhTJlaFMYqApw1btX9SVzsEyOkL3R93VpvJGK9P0JmqxCs7LsBOtdOI_07i5mLU_ImXAs15xhOAosHW12f0dAhb7gMU-YHEIWLwW0-kB0V9bWHCy</recordid><startdate>201710</startdate><enddate>201710</enddate><creator>Ji, Yuan</creator><creator>Takanari, Hiroki</creator><creator>Qile, Muge</creator><creator>Nalos, Lukas</creator><creator>Houtman, Marien J.C.</creator><creator>Romunde, Fee L.</creator><creator>Heukers, Raimond</creator><creator>Bergen en Henegouwen, Paul M.P.</creator><creator>Vos, Marc A.</creator><creator>Heyden, Marcel A.G.</creator><general>John Wiley and Sons Inc</general><scope>24P</scope><scope>WIN</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-4225-7942</orcidid></search><sort><creationdate>201710</creationdate><title>Class III antiarrhythmic drugs amiodarone and dronedarone impair KIR2.1 backward trafficking</title><author>Ji, Yuan ; Takanari, Hiroki ; Qile, Muge ; Nalos, Lukas ; Houtman, Marien J.C. ; Romunde, Fee L. ; Heukers, Raimond ; Bergen en Henegouwen, Paul M.P. ; Vos, Marc A. ; Heyden, Marcel A.G.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-n2112-88926ba692fdbf5a227bef80607506e514f8ec29ce36a013560fc4934dbd91f63</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>amiodarone</topic><topic>degradation</topic><topic>dronedarone</topic><topic>inward rectifier</topic><topic>KIR 2.1</topic><topic>lysosome</topic><topic>Original</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ji, Yuan</creatorcontrib><creatorcontrib>Takanari, Hiroki</creatorcontrib><creatorcontrib>Qile, Muge</creatorcontrib><creatorcontrib>Nalos, Lukas</creatorcontrib><creatorcontrib>Houtman, Marien J.C.</creatorcontrib><creatorcontrib>Romunde, Fee L.</creatorcontrib><creatorcontrib>Heukers, Raimond</creatorcontrib><creatorcontrib>Bergen en Henegouwen, Paul M.P.</creatorcontrib><creatorcontrib>Vos, Marc A.</creatorcontrib><creatorcontrib>Heyden, Marcel A.G.</creatorcontrib><collection>Wiley-Blackwell Open Access Titles</collection><collection>Wiley Free Content</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of cellular and molecular medicine</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ji, Yuan</au><au>Takanari, Hiroki</au><au>Qile, Muge</au><au>Nalos, Lukas</au><au>Houtman, Marien J.C.</au><au>Romunde, Fee L.</au><au>Heukers, Raimond</au><au>Bergen en Henegouwen, Paul M.P.</au><au>Vos, Marc A.</au><au>Heyden, Marcel A.G.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Class III antiarrhythmic drugs amiodarone and dronedarone impair KIR2.1 backward trafficking</atitle><jtitle>Journal of cellular and molecular medicine</jtitle><date>2017-10</date><risdate>2017</risdate><volume>21</volume><issue>10</issue><spage>2514</spage><epage>2523</epage><pages>2514-2523</pages><issn>1582-1838</issn><eissn>1582-4934</eissn><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 (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.</abstract><cop>Hoboken</cop><pub>John Wiley and Sons Inc</pub><pmid>28425222</pmid><doi>10.1111/jcmm.13172</doi><tpages>10</tpages><orcidid>https://orcid.org/0000-0002-4225-7942</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | amiodarone degradation dronedarone inward rectifier KIR 2.1 lysosome Original |
| title | Class III antiarrhythmic drugs amiodarone and dronedarone impair KIR2.1 backward trafficking |
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