Extracellular Protons Inhibit Charge Immobilization in the Cardiac Voltage-Gated Sodium Channel

Low pH depolarizes the voltage-dependence of cardiac voltage-gated sodium (Na_V1.5) channel activation and fast inactivation and destabilizes the fast-inactivated state. The molecular basis for these changes in protein behavior has not been reported. We hypothesized that changes in the kinetics of voltage sensor movement may destabilize the fast-inactivated state in Na_V1.5. To test this idea, we recorded Na_V1.5 gating currents in Xenopus oocytes using a cut-open voltage-clamp with extracellular solution titrated to either pH 7.4 or pH 6.0. Reducing extracellular pH significantly depolarized the voltage-dependence of both the Q_ON/V and Q_OFF/V curves, and reduced the total charge immobilized during depolarization. We conclude that destabilized fast-inactivation and reduced charge immobilization in Na_V1.5 at low pH are functionally related effects.