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Antiarrhythmic drug‐induced modulation of Kv channel surface density in cardiomyocytes
Author(s) -
Schumacher Sarah Marie,
Zhang Lian,
Martens Jeffrey R
Publication year - 2010
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.24.1_supplement.961.16
Subject(s) - chemistry , internalization , homomeric , ion channel , quinidine , pharmacology , alanine scanning , biophysics , microbiology and biotechnology , protein subunit , biochemistry , receptor , biology , mutagenesis , mutation , gene
Conventional antiarrhythmic drugs target the ion permeability of channels. This therapeutic strategy, however, is limited by proarrhythmia in the ventricles due to a lack of ion channel selectivity and overlap in channel expression. Given the atrial specific expression of Kv1.5, and its known alterations in atrial fibrillation (AF), this channel has emerged as a primary target in academic and industrial research. In this study, treatment of HL‐1 cells expressing Kv1.5‐GFP with the class I antiarrhythmic agent quinidine resulted in a dose‐ and time‐dependent internalization of Kv1.5, concomitant to channel block, that was subunit‐dependent and stereospecific. Alanine‐scanning mutagenesis of Kv1.5 channel protein revealed partial, but not complete, overlap in the binding sites required for block and internalization. Additionally, structure‐activity relationship studies demonstrated key components of the drug molecule that are required for alterations in channel trafficking. Furthermore, we have expanded these studies to include analysis of homomeric versus heteromeric assembled channels. Together these data indicate that the pharmacophores for pore block and channel internalization may be separable. This highlights the potential for new compounds that selectively alter the membrane stability of Kv1.5 as a means to gain atrial selectivity in the treatment of AF. Supported by NIH HL0270973, JRM.