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

Yury Y Vilin,Peter C Ruben,Colin H Peters

doi:10.3389/fphar.2012.00109

Abstract

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 NaV1.2, NaV1.4, and NaV1.5, expressed in cultured mammalian cells. Low pH produced different effects on different channel subtypes. Whereas NaV1.4 exhibited very low sensitivity to acidosis, primarily limited to partial block of macroscopic currents, the effects of low pH on gating in NaV1.2 and NaV1.5 were profound. In NaV1.2 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 NaV1.5, 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.

Highlights

Extracellular pH is a major factor that controls activity of many physiological processes
EFFECTS OF LOW pH ON ACTIVATION AND STEADY-STATE FI IN NaV1.2, NaV1.4, NaV1.5 Previous studies demonstrated that acidic pH decreases the amplitude of macroscopic sodium currents
In contrast to NaV1.2 and NaV1.4, the decay of macroscopic currents in NaV1.5 at pH 6.0 was slower compared to the control family of currents at pH 7.4 (Figure 1G). These results suggest that low pH alters properties of open-state inactivation

Summary

Introduction

Extracellular pH is a major factor that controls activity of many physiological processes. Previous studies in vivo and in situ demonstrated that pathological conditions, such as hypoxia and/or ischemia considerably decrease extracellular pH. During focal ischemia in rabbit brain, extracellular pH drops to as low as 6.0 (Meyer, 1990). Physical exercise of medium-tomaximum intensity may decrease pH in human skeletal muscle to 6.4 (Hermansen and Osnes, 1972). Unlike neuronal (NaV1.2) and skeletal muscle (NaV1.4) subtypes, the cardiac sodium channel subtype (NaV1.5) may exhibit persistent Na currents (I NaP) in response to low extracellular pH, which is considered to be a predisposing factor for cardiac arrhythmias (Amin et al, 2010). The I NaP induced by low pH in only NaV1.5 raises a question regarding the possible specificity of pH effects on different NaV subtypes

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