Proton Inhibition of Sodium Channels: Mechanism of Gating Shifts and Reduced Conductance

Proton Inhibition of Sodium Channels: Mechanism of Gating Shifts and Reduced Conductance Extracellular acidosis affects both permeation and gating of the expressed rat skeletal muscle Na+ channel (μ1). Reduction of the extracellular pH produced a progressive decrease in the maximal whole-cell conductance and a depolarizing shift in the whole-cell current-voltage relationship. A smaller depolarizing shift in the steady-state inactivation curve was observed. The pK of the reduction of maximal conductance was 6.1 over the pH range studied. An upper limit estimate of the pK of the shift of the half-activation voltage was 6.1. The relative reduction in the maximal whole-cell conductance did not change with higher [Na+] o . The conductance of single fenvalerate-modified Na+ channels was reduced by extracellular protons. Although the single-channel conductance increased with higher [Na+] o , the maximal conductances at pH 7.6, 7.0 and 6.0 did not converge at [Na+] o up to 280 mm, inconsistent with a simple electrostatic effect. A model incorporating both Na+ and H+ binding in the pore and cation binding to a Gouy-Chapman surface charge provided a robust fit to the single-channel conductance data with an estimated surface charge density of 1e−/439Å2. Neither surface charge nor proton block alone suffices to explain the effects of extracellular acidosis on Na+ channel permeation; both effects play major roles in mediating the response to extracellular pH. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png The Journal of Membrane Biology Springer Journals

Proton Inhibition of Sodium Channels: Mechanism of Gating Shifts and Reduced Conductance

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Publisher
Springer-Verlag
Copyright
Copyright © Inc. by 1997 Springer-Verlag New York
Subject
Life Sciences; Biochemistry, general; Human Physiology
ISSN
0022-2631
eISSN
1432-1424
D.O.I.
10.1007/s002329900164
Publisher site
See Article on Publisher Site

Abstract

Extracellular acidosis affects both permeation and gating of the expressed rat skeletal muscle Na+ channel (μ1). Reduction of the extracellular pH produced a progressive decrease in the maximal whole-cell conductance and a depolarizing shift in the whole-cell current-voltage relationship. A smaller depolarizing shift in the steady-state inactivation curve was observed. The pK of the reduction of maximal conductance was 6.1 over the pH range studied. An upper limit estimate of the pK of the shift of the half-activation voltage was 6.1. The relative reduction in the maximal whole-cell conductance did not change with higher [Na+] o . The conductance of single fenvalerate-modified Na+ channels was reduced by extracellular protons. Although the single-channel conductance increased with higher [Na+] o , the maximal conductances at pH 7.6, 7.0 and 6.0 did not converge at [Na+] o up to 280 mm, inconsistent with a simple electrostatic effect. A model incorporating both Na+ and H+ binding in the pore and cation binding to a Gouy-Chapman surface charge provided a robust fit to the single-channel conductance data with an estimated surface charge density of 1e−/439Å2. Neither surface charge nor proton block alone suffices to explain the effects of extracellular acidosis on Na+ channel permeation; both effects play major roles in mediating the response to extracellular pH.

Journal

The Journal of Membrane BiologySpringer Journals

Published: Jan 15, 1997

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