A conserved ring of charge in mammalian Na+ channels: A molecular regulator of the outer pore conformation during slow inactivation

Wei Xiong, Yousaf Z. Farukhi, Yanli Tian, Deborah Disilvestre, Ronald A. Li, Gordon F. Tomaselli

Research output: Contribution to journalArticlepeer-review

27 Scopus citations


The molecular mechanisms underlying slow inactivation in sodium channels are elusive. Our results suggest that EEDD, a highly conserved ring of charge in the external vestibule of mammalian voltage-gated sodium channels, undermines slow inactivation. By employing site-directed mutagenesis, we found that charge alterations in this asymmetric yet strong local electrostatic field of the EEDD ring significantly altered the kinetics of slow inactivation gating. Using a non-linear Poisson-Boltzmann equation, quantitative computations of the electrostatic field in a sodium channel structural model suggested a significant electrostatic repulsion between residues E403 and E758 at close proximity. Interestingly, when this electrostatic interaction was eliminated by the double mutation E403C + E758C, the kinetics of recovery from slow inactivation of the double-mutant channel was retarded by 2500% compared to control. These data suggest that the EEDD ring, located within the asymmetric electric field, is a molecular motif that critically modulates slow inactivation in sodium channels.

Original languageEnglish (US)
Pages (from-to)739-754
Number of pages16
JournalJournal of Physiology
Issue number3
StatePublished - Nov 2006
Externally publishedYes

ASJC Scopus subject areas

  • Physiology


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