PH Modulation of the Cardiac Voltage Gated Sodium Channel, Nav1.5

Abstract

Alterations in the function of the cardiac voltage-gated sodium channel (NaV1.5) are a known cause of cardiac disease and arrhythmia. Elevated concentrations of protons decrease conductance and depolarize the voltage dependence of activation and steady-state fast inactivation (SSFI) of NaV1.5 channels (Zhang & Siegelbaum, 1991, Khan et al., 2006). A complete analysis of the effects of low pH on NaV1.5 channel kinetics has not previously been reported. We sought to characterize the effects of low pH on NaV1.5 kinetics. NaV1.5 was co-expressed in Xenopus laevis oocytes with the β1 subunit, and currents were recorded at 20 °C using the cut-open voltage clamp technique with the extracellular solution titrated to either pH 7.4 (control) or pH 6.0. Application of solution at pH 6.0 significantly depolarized the voltage dependence of activation and SSFI; −34.4 ± 0.3mV to −25.2 ± 0.2mV and −76.4 ± 0.1mV to −72.7 ± 0.2mV, respectively. The apparent valences of activation and SSFI were significantly decreased; from 3.4 ± 0.12e to 2.5 ± 0.04e, and from −4.6 ± 0.07e to −4.1 ± 0.09e, respectively. At pH 6.0, the fast time constant of use-dependent inactivation was significantly increased and the use dependent current reduction was decreased from 40.6 ± 0.12% to 34.8 ± 0.05%. The rates of open-state fast inactivation onset were significantly decreased at potentials between −30mV and +30mV, and the rates of recovery at −90mV and −80mV were significantly increased. There was also a visible increase in window current. All effects were reversible upon reperfusion of solution at pH 7.4. Taken together, these data suggest that lowering extracellular pH from 7.4 to 6.0 destabilizes the fast-inactivated state of NaV1.5 channels, an effect that could act as an arrhythmogenic trigger during ischemic events.