Depth asymmetries of the pore-lining segments of the Na+ channel revealed by cysteine mutagenesis

Nipavan Chiamvimonvat, M. Teresa Pérez-García, Ravi Ranjan, Eduardo Marban, Gordon F. Tomaselli

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Abstract

We used serial cysteine mutagenesis to study the structure of the outer vestibule and selectivity region of the voltage-gated Na+ channel. The voltage dependence of Cd2+ block enabled us to determine the locations within the electrical field of cysteine-substituted mutants in the P segments of all four domains. The fractional electrical distances of the substituted cysteines were compared with the differential sensitivity to modification by sulfhydryl-specific modifying reagents. These experiments indicate that the P segment of domain II is external, while the domain IV P segment is displaced internally, compared with the first and third domain P segments. Sulfhydryls with a steep voltage dependence for Cd2+ block produced changes in monovalent cation selectivity; these included substitutions at the presumed selectivity filter, as well as residues in the domain IV P segment not previously recognized as determinants of selectivity. A new structural model is presented in which each of the P segments contribute unique loops that penetrate the membrane to varying depths to form the channel pore.

Original languageEnglish (US)
Pages (from-to)1037-1047
Number of pages11
JournalNeuron
Volume16
Issue number5
DOIs
StatePublished - May 1996
Externally publishedYes

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ASJC Scopus subject areas

  • Neuroscience(all)

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