TY - JOUR
T1 - A conserved ring of charge in mammalian Na+ channels
T2 - A molecular regulator of the outer pore conformation during slow inactivation
AU - Xiong, Wei
AU - Farukhi, Yousaf Z.
AU - Tian, Yanli
AU - Disilvestre, Deborah
AU - Li, Ronald A.
AU - Tomaselli, Gordon F.
PY - 2006/11
Y1 - 2006/11
N2 - 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.
AB - 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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U2 - 10.1113/jphysiol.2006.115105
DO - 10.1113/jphysiol.2006.115105
M3 - Article
C2 - 16873407
AN - SCOPUS:33750402366
SN - 0022-3751
VL - 576
SP - 739
EP - 754
JO - Journal of Physiology
JF - Journal of Physiology
IS - 3
ER -