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Abstract
Protons impart isoform-specific modulation of inactivation in neuronal, skeletal muscle, and cardiac voltage-gated sodium (Na(V)) channels. Although the structural basis of proton block in Na(V) channels has been well described, the amino acid residues responsible for the changes in Na(V) kinetics during extracellular acidosis are as yet unknown. We expressed wild-type (WT) and two pore mutant constructs (H880Q and C373F) of the human cardiac Na(V) channel, Na(V)1.5, in Xenopus oocytes. C373F and H880Q both attenuated proton block, abolished proton modulation of use-dependent inactivation, and altered pH modulation of the steady-state and kinetic parameters of slow inactivation. Additionally, C373F significantly reduced the maximum probability of use-dependent inactivation and slow inactivation, relative to WT. H880Q also significantly reduced the maximum probability of slow inactivation and shifted the voltage dependence of activation and fast inactivation to more positive potentials, relative to WT. These data suggest that Cys-373 and His-880 in Na(V)1.5 are proton sensors for use-dependent and slow inactivation and have implications in isoform-specific modulation of Na(V) channels.
Highlights
Protons modify cardiac sodium channel function, potentially contributing to cardiac arrhythmia during and following ischemia
The H880Q and C373F mutants displayed a significant reduction in proton block at pH 6.0 relative to WT channels (Fig. 1)
At pH 6.0, the maximum channel conductance was reduced by 38.7 Ϯ 2.0, 27.0 Ϯ 2.6, and 19.4 Ϯ 2.2% relative to pH 7.4 for WT, H880Q, and C373F channels, respectively (Fig. 1, B, C, and D)
Summary
Protons modify cardiac sodium channel function, potentially contributing to cardiac arrhythmia during and following ischemia. Results: Protons binding amino acids at the pore alter cardiac sodium channel function. Protons impart isoform-specific modulation of inactivation in neuronal, skeletal muscle, and cardiac voltage-gated sodium (NaV) channels. C373F significantly reduced the maximum probability of use-dependent inactivation and slow inactivation, relative to WT. H880Q significantly reduced the maximum probability of slow inactivation and shifted the voltage dependence of activation and fast inactivation to more positive potentials, relative to WT. These data suggest that Cys-373 and His880 in NaV1.5 are proton sensors for use-dependent and slow inactivation and have implications in isoform-specific modulation of NaV channels
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