Extracellular protons inhibit charge immobilization in the cardiac voltage-gated sodium channel.

Low pH depolarizes the voltage-dependence of cardiac voltage-gated sodium (NaV1.5) 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 NaV1.5. To test this idea, we recorded NaV1.5 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 QON/V and QOFF/V curves, and reduced the total charge immobilized during depolarization. We conclude that destabilized fast-inactivation and reduced charge immobilization in NaV1.5 at low pH are functionally related effects.