Proton Modulation of Gating Currents in the Cardiac Voltage-Gated Sodium Channel, NaV1.5

Abstract

Low pH reduces single channel conductance and destabilizes the fast-inactivated state of the cardiac voltage-gated sodium channel (NaV1.5) by increasing both window and persistent currents (Jones et al., 2011, Biophys. J. 101(7)). Since fast inactivation is tightly coupled to NaV channel voltage sensor activation, we hypothesized that alterations in the kinetics of voltage sensor movement may underlie the destabilization of the fast-inactivated state in NaV1.5. To test this, we expressed NaV1.5 channels in Xenopus oocytes and recorded gating currents using a cut-open voltage clamp with extracellular solution titrated to either pH 7.4 (control) or pH 6.0. At pH 6.0, compared to pH 7.4, the V1/2 of the Q(V) curve was significantly depolarized (from −57.8±4.3 mV to −40.8±5.1 mV). Additionally, the slow time constant of charge recovery was significantly reduced from 16.1±5.0 ms at pH 7.4 to 9.7±4.2 ms at pH 6.0. These data suggest a molecular basis for the increased persistent and window currents previously shown in NaV1.5 channels at reduced extracellular pH. Specifically, protons may electrostatically affect the rate of voltage sensor movement, either by directly binding to extracellular residues (e.g. H880) or indirectly by binding to carboxylates in the pore domain (Kahn et al., J Physiol. 2002, 543). (Supported by an NSERC Discovery Grant to PCR, a CFI Infrastructure grant to PCR and TC, and a CIHR Vanier Scholarship to DKJ.)