Differential pH-Dependent Regulation of NaV Channels

Abstract

Brain and skeletal muscle NaV 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 rNaV1.2 and hNaV1.4, stably expressed in CHO cells. Activation in both channel isoforms was unaffected at low pH. In hNaV1.4, low pH slightly increased the apparent valence of steady-state fast inactivation and accelerated recovery from the fast-inactivated state, although voltage dependence of fast inactivation was not shifted. Time course of cumulative inactivation in hNaV1.4 was unchanged at pH 6.0. In contrast, both fast and slow inactivation in rNaV1.2 were susceptible to acidification. Consistent with our previous studies, the fast-inactivated state in rNaV1.2 was destabilized at pH 6.0, as suggested first-order two-state Eyring model. Slow inactivation at pH 6.0 was more complete than at pH 7.0 and cumulative inactivation was enhanced at low pH. Thus, our data suggest that pH differentially regulates brain and skeletal muscle NaV channels. This differential regulation might reflect unique physiological roles of these isoforms and tissue-specific distributions of NaV1.2 and NaV1.4 channels.