Voltage-gated sodium (NaV) channels generate the action potential upstroke in most electrically excitable cells. The cardiac-isoform, NaV1.5, is the predominant NaV channel in cardiac muscle. Changes in NaV1.5 channel function often lead to cardiac dysfunction resulting in syncope, cardiac arrhythmia, and even sudden cardiac death. Extracellular protons block NaV1.5 channel conductance with a pKa ≈ 6.0 and shift the voltage-dependence of NaV1.5 channel function to more positive potentials. During cardiac ischemia extracellular pH drops to as low as pH 6.0 within 10 minutes of its onset. A detailed analysis of the effects of protons on NaV1.5 channel function has not been completed. Further, the molecular underpinnings of the proton-channel interaction remain unknown. Characterizing NaV1.5 channel proton modulation will contribute to the treatment and prevention of the life-threatening events that occur during and following cardiac ischemia and acidosis. In this study wild-type and mutant NaV1.5 channels were expressed in Xenopus laevis oocytes. Ionic and gating NaV1.5 currents were recorded with extracellular solution titrated to pH 4.0 through pH 8.0 using a cut-open voltage clamp. These data demonstrate three critical findings: (1) extracellular protons destabilize the fast and slow-inactivated states of NaV1.5 channels, (2) destabilization of the fast-inactivated state occurs through proton modulation of NaV1.5 channel gating charge, (3) protons interact within the NaV1.5 channel pore to modulate the slow-inactivated state
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