Sequential formation of ion pairs during activation of a sodium channel voltage sensor

Paul G. DeCaen, Vladimir Yarov-Yarovoy, Elizabeth M. Sharp, Todd Scheuer, William A. Catterall

Research output: Contribution to journalArticlepeer-review

116 Scopus citations


Electrical signaling in biology depends upon a unique electromechanical transduction process mediated by the S4 segments of voltage-gated ion channels. These transmembrane segments are driven outward by the force of the electric field on positively charged amino acid residues termed "gating charges," which are positioned at three-residue intervals in the S4 transmembrane segment, and this movement is coupled to opening of the pore. Here, we use the disulfide-locking method to demonstrate sequential ion pair formation between the fourth gating charge in the S4 segment (R4) and two acidic residues in the S2 segment during activation. R4 interacts first with E70 at the intracellular end of the S2 segment and then with D60 near the extracellular end. Analysis with the Rosetta Membrane method reveals the 3-D structures of the gating pore as these ion pairs are formed sequentially to catalyze the S4 transmembrane movement required for voltagedependent activation. Our results directly demonstrate sequential ion pair formation that is an essential feature of the sliding helix model of voltage sensor function but is not compatible with the other widely discussed gating models.

Original languageEnglish (US)
Pages (from-to)22498-22503
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number52
StatePublished - Dec 19 2009


  • Electrical excitability
  • Gating

ASJC Scopus subject areas

  • General


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