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Molecular basis of ranolazine block of LQT‐3 mutant sodium channels: evidence for site of action
Author(s) -
Fredj Sandra,
Sampson Kevin J,
Liu Huajun,
Kass Robert S
Publication year - 2006
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0706709
Subject(s) - ranolazine , hek 293 cells , sodium channel , cardiac action potential , myocyte , pharmacology , long qt syndrome , repolarization , patch clamp , mutant , herg , potassium channel , sodium channel blocker , chemistry , biophysics , medicine , electrophysiology , biology , receptor , sodium , qt interval , biochemistry , organic chemistry , gene
1 We studied the effects of ranolazine, an antianginal agent with promise as an antiarrhythmic drug, on wild‐type (WT) and long QT syndrome variant 3 (LQT‐3) mutant Na + channels expressed in human embryonic kidney (HEK) 293 cells and knock‐in mouse cardiomyocytes and used site‐directed mutagenesis to probe the site of action of the drug. 2 We find preferential ranolazine block of sustained vs peak Na + channel current for LQT‐3 mutant (ΔKPQ and Y1795C) channels (IC 50 =15 vs 135 μ M ) with similar results obtained in HEK 293 cells and knock‐in myocytes. 3 Ranolazine block of both peak and sustained Na + channel current is significantly reduced by mutation (F1760A) of a single residue previously shown to contribute critically to the binding site for local anesthetic (LA) molecules in the Na + channel. 4 Ranolazine significantly decreases action potential duration (APD) at 50 and 90% repolarization by 23±5 and 27±3%, respectively, in ΔKPQ mouse ventricular myocytes but has little effect on APD of WT myocytes. 5 Computational modeling of human cardiac myocyte electrical activity that incorporates our voltage‐clamp data predicts marked ranolazine‐induced APD shortening in cells expressing LQT‐3 mutant channels. 6 Our results demonstrate for the first time the utility of ranolazine as a blocker of sustained Na + channel activity induced by inherited mutations that cause human disease and further, that these effects are very likely due to interactions of ranolazine with the receptor site for LA molecules in the sodium channel.British Journal of Pharmacology (2006) 148 , 16–24. doi: 10.1038/sj.bjp.0706709