AUTHOR=Vilin Yury Y., Peters Colin H., Ruben Peter 

TITLE=Acidosis Differentially Modulates Inactivation in NaV1.2, NaV1.4, and NaV1.5 Channels

JOURNAL=Frontiers in Pharmacology

VOLUME=3

YEAR=2012

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2012.00109

DOI=10.3389/fphar.2012.00109

ISSN=1663-9812

ABSTRACT=<p>Na<sub>V</sub> 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<sub>V</sub>1.2, Na<sub>V</sub>1.4, and Na<sub>V</sub>1.5, expressed in cultured mammalian cells. Low pH produced different effects on different channel subtypes. Whereas Na<sub>V</sub>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<sub>V</sub>1.2 and Na<sub>V</sub>1.5 were profound. In Na<sub>V</sub>1.2 low pH reduced apparent valence of steady-state fast inactivation, shifted the τ(<italic>V</italic>) 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<sub>V</sub>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.</p>