pH Modulation of Voltage-Gated Sodium Channels

Abstract

Changes in blood and tissue pH accompany physiological and pathophysiological conditions including exercise, cardiac ischemia, ischemic stroke, and cocaine ingestion. These conditions are known to trigger the symptoms of electrical diseases in patients carrying sodium channel mutations. Protons cause a diverse set of changes to sodium channel gating, which generally lead to decreases in the amplitude of the transient sodium current and increases in the fraction of non-inactivating channels that pass persistent currents. These effects are shared with disease-causing mutants in neuronal, skeletal muscle, and cardiac tissue and may be compounded in mutants that impart greater proton sensitivity to sodium channels, suggesting a role of protons in triggering acute symptoms of electrical disease.In this chapter, we review the mechanisms of proton block of the sodium channel pore and a suggested mode of action by which protons alter channel gating. We discuss the available data on isoform specificity of proton effects and tissue level effects. Finally, we review the role that protons play in disease and our own recent studies on proton-sensitizing mutants in cardiac and skeletal muscle sodium channels.

Effects of acidosis on neuronal voltage-gated sodium channels: Nav1.1 and Nav1.3

“…1 & Nav1.3 Previous studies show that an increased concentration of positively charged H + during acidosis results in the protonation of the carboxylates of the outer channel vestibule [19,25]. Although this protonation is not the only determinant of proton block, it is a key component [19,25,33,34]. To determine the extent of proton block in Nav1.1 and Nav1.3, we measured current density from the ratio of peak current amplitude to the cell membrane capacitance (pA/pF) at pH 6.4 and pH 7.4.…”

“…This suggests that the interactions between the positively charged H + and pore carboxylates blocks the ion conductance pathway, which subsequently reduces sodium current [34]. As DEKA and EEDD are conserved across the sodium channel family, it is not surprising that, in all of the sodium channels studied thus far, proton block exists albeit with varying degrees [25,26]. This is particularly evident in Nav1.4 where previous studies have shown a reduction in current density that is neither statistically significant nor negligible [26,38].…”

“…In addition to proton block, low pH alters channel gating. The effects of protons on gating have been thoroughly studied in Nav1.5 [25]. Although the identity of the residues involved in pH-dependent changes in gating have not been fully determined, structural studies in bacterial sodium channels and potassium channels suggest that acidic residues play a role [21,39].…”

“…This electrostatic hindrance at domains I-III primarily affects activation, and at domain IV affects fast inactivation. However, the effects of protons on sodium channel gating is strongly subtype-dependent [24][25][26], (Table 5).…”

“…Recently, our group has shown that a mutation (P1158S) that alters the structure of the S4-S5 linker could increase pH-sensitivity in the otherwise pH-insensitive Nav1.4. The pathological consequences of pH modulation of sodium channel mutants with an increased sensitivity to extracellular protons, E1784K (Nav1.5) and P1158S (Nav1.4), include Brugada syndrome, long QT syndrome, periodic paralysis, and myotonia [23][24][25].…”