This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 104/12/1390    most recent CIRCRESAHA.108.192773v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Schumacher, S. M. Articles by Martens, J. R. Search for Related Content PubMed PubMed Citation Articles by Schumacher, S. M. Articles by Martens, J. R. Related Collections Cardiovascular Pharmacology Cell biology/structural biology Ion channels/membrane transport

(Circulation Research. 2009;104:1390.)
© 2009 American Heart Association, Inc.

Cellular Biology

Antiarrhythmic Drug-Induced Internalization of the Atrial-Specific K⁺ Channel Kv1.5

Sarah M. Schumacher, Dyke P. McEwen, Lian Zhang, Kristin L. Arendt, Kristin M. Van Genderen, Jeffrey R. Martens

From the Department of Pharmacology, University of Michigan, Ann Arbor.

Correspondence to Jeffrey R. Martens, Department of Pharmacology, 1301 MSRBIII, 1150 W Medical Center Dr, Ann Arbor, MI 48109-0632. E-mail martensj{at}umich.edu

Conventional antiarrhythmic drugs target the ion permeability of channels, but increasing evidence suggests that functional ion channel density can also be modified pharmacologically. Kv1.5 mediates the ultrarapid potassium current (I_Kur) that controls atrial action potential duration. Given the atrial-specific expression of Kv1.5 and its alterations in human atrial fibrillation, significant effort has been made to identify novel channel blockers. In this study, treatment of HL-1 atrial myocytes expressing Kv1.5-GFP with the class I antiarrhythmic agent quinidine resulted in a dose- and temperature-dependent internalization of Kv1.5, concomitant with channel block. This quinidine-induced channel internalization was confirmed in acutely dissociated neonatal myocytes. Channel internalization was subunit-dependent, activity-independent, stereospecific, and blocked by pharmacological disruption of the endocytic machinery. Pore block and channel internalization partially overlap in the structural requirements for drug binding. Surprisingly, quinidine-induced endocytosis was calcium-dependent and therefore unrecognized by previous biophysical studies focused on isolating channel–drug interactions. Importantly, whereas acute quinidine-induced internalization was reversible, chronic treatment led to channel degradation. Together, these data reveal a novel mechanism of antiarrhythmic drug action and highlight the possibility for new agents that selectively modulate the stability of channel protein in the membrane as an approach for treating cardiac arrhythmias.

Key Words: potassium channel • trafficking • cardiac • antiarrhythmic