Acidosis Differentially Modulates Inactivation in Na(V)1.2, Na(V)1.4, and Na(V)1.5 Channels

Na(V) channels play a crucial role in neuronal and muscle excitability. Using whole-cell recordings we studied effects of low extracellular pH on the biophysical properties of Na(V)1.2, Na(V)1.4, and Na(V)1.5, expressed in cultured mammalian cells. Low pH produced different effects on different channel subtypes. Whereas Na(V)1.4 exhibited very low sensitivity to acidosis, primarily limited to partial block of macroscopic currents, the effects of low pH on gating in Na(V)1.2 and Na(V)1.5 were profound. In Na(V)1.2 low pH reduced apparent valence of steady-state fast inactivation, shifted the τ(V) to depolarizing potentials and decreased channels availability during onset to slow and use-dependent inactivation (UDI). In contrast, low pH delayed open-state inactivation in Na(V)1.5, right-shifted the voltage-dependence of window current, and increased channel availability during onset to slow and UDI. These results suggest that protons affect channel availability in an isoform-specific manner. A computer model incorporating these results demonstrates their effects on membrane excitability.