Extracellular Proton Modulation of the Cardiac Voltage-Gated Sodium Channel, NaV1.5

Abstract

Low pH depolarizes the voltage dependence of voltage-gated sodium (NaV) channel activation and fast inactivation. A complete description of NaV channel proton modulation, however, has not been reported. The majority of NaV channel proton modulation studies have been completed in intact tissue. Additionally, several NaV channel isoforms are expressed in cardiac tissue. Characterizing the proton modulation of the cardiac NaV channel, NaV1.5, will thus help define its contribution to ischemic arrhythmogenesis, where extracellular pH drops from pH 7.4 to as low as pH 6.0 within ∼10 min of its onset. We expressed the human variant of NaV1.5 with and without the modulating β1 subunit in Xenopus oocytes. Lowering extracellular pH from 7.4 to 6.0 affected a range of biophysical gating properties heretofore unreported. Specifically, acidic pH destabilized the fast-inactivated and slow-inactivated states, and elevated persistent INa. These data were incorporated into a ventricular action potential model that displayed a reduced maximum rate of depolarization as well as disparate increases in epicardial, mid-myocardial, and endocardial action potential durations, indicative of an increased heterogeneity of repolarization. Portions of these data were previously reported in abstract form.