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J Physiol Volume 543, Number 1, 71-84, August 15, 2002 DOI: 10.1113/jphysiol.2002.021014
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Journal of Physiology (2002), 543.1, pp. 71-84
© Copyright 2002 The Physiological Society
DOI: 10.1113/jphysiol.2002.021014

Role of outer ring carboxylates of the rat skeletal muscle sodium channel pore in proton block

A. Khan, L. Romantseva, A. Lam, G. Lipkind and H. A. Fozzard

The Cardiac Electrophysiology Laboratories, Departments of Medicine and of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL 60637, USA

Voltage-gated Na+ current is reduced by acid solution. Protons reduce peak Na+ conductance by lowering single channel conductance and shift the voltage range of gating by neutralizing surface charges. Structure-function studies identify six carboxyls and a lysine in the channel's outer vestibule. We examined the roles of the superficial ring of carboxyls in acid block of Nav1.4 (the rat skeletal muscle Na+ channel isoform) by measuring the effects of their neutralization or their substitution by lysine on sensitivity to acid solutions, using the two-micropipette voltage clamp in Xenopus oocytes. Alteration of the outer ring of carboxylates had little effect on the voltage for half-activation of Na+ current, as if they are distant from the channels' voltage sensors. The mutations did not abolish proton block; rather, they all shifted the pKa (-log of the dissociation constant) in the acid direction. Effects of neutralization on pKa were not identical for different mutations, with E758Q > D1241A > D1532N > E403Q. E758K showed double the effect of E758Q, and the other lysine mutations all produced larger effects than the neutralizing mutations. Calculation of the electrostatic potential produced by these carboxylates using a pore model showed that the pKa values of carboxylates of Glu-403, Glu-758, and Asp-1532 are shifted to values similar to the experimentally measured pKa. Calculations also predict the experimentally observed changes in pKa that result from mutational neutralization or introduction of a positive charge. We propose that proton block results from partial protonation of these outer ring carboxylates and that all of the carboxylates contribute to a composite Na+ site.



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