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Antiarrhythmic drug‐induced internalization of the atrial specific K+ channel, Kv1.5
Author(s) -
Schumacher Sarah Marie,
McEwen Dyke P,
Zhang Lian,
Arendt Kristin L,
Van Genderen Kristin M,
Martens Jeffrey R
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.579.4
Subject(s) - internalization , quinidine , pharmacology , chemistry , ion channel , potassium channel , drug , anti arrhythmia agents , channel blocker , atrial fibrillation , medicine , receptor , calcium , biochemistry
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‐, time‐, and temperature‐dependent internalization of Kv1.5, concomitant to channel block. Channel internalization was subunit‐dependent, stereospecific, activity‐independent, and blocked by pharmacologic 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. 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 a novel approach for treating cardiac arrhythmias. Supported by NIH HL0270973, JRM.