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  • Title: A conserved ring of charge in mammalian Na+ channels: a molecular regulator of the outer pore conformation during slow inactivation.
    Author: Xiong W, Farukhi YZ, Tian Y, Disilvestre D, Li RA, Tomaselli GF.
    Journal: J Physiol; 2006 Nov 01; 576(Pt 3):739-54. PubMed ID: 16873407.
    Abstract:
    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.
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