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This Article Full Text Full Text (PDF) Supplemental data All Versions of this Article: 576/3/739    most recent jphysiol.2006.115105v1 Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Xiong, W. Articles by Tomaselli, G. F. Search for Related Content PubMed PubMed Citation Articles by Xiong, W. Articles by Tomaselli, G. F. Related Collections Molecular and Genomic

¹ Molecular and Cellular Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA

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.

(Received 9 June 2006; accepted after revision 24 July 2006; first published online 27 July 2006)
Corresponding author G. F. Tomaselli: Department of Medicine, Johns Hopkins University School of Medicine, 720 Rutland Ave/Ross 844, Baltimore, MD 21205, USA. Email: gtomase1{at}jhmi.edu

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