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 journalArticle

25 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)739-754
Number of pages16
JournalJournal of Physiology
Volume576
Issue number3
DOIs
StatePublished - Nov 1 2006
Externally publishedYes

Fingerprint

Static Electricity
Sodium Channels
Voltage-Gated Sodium Channels
Structural Models
Site-Directed Mutagenesis
Mutation

ASJC Scopus subject areas

  • Physiology

Cite this

A conserved ring of charge in mammalian Na+ channels : A molecular regulator of the outer pore conformation during slow inactivation. / Xiong, Wei; Farukhi, Yousaf Z.; Tian, Yanli; Disilvestre, Deborah; Li, Ronald A.; Tomaselli, Gordon F.

In: Journal of Physiology, Vol. 576, No. 3, 01.11.2006, p. 739-754.

Research output: Contribution to journalArticle

Xiong, Wei ; Farukhi, Yousaf Z. ; Tian, Yanli ; Disilvestre, Deborah ; Li, Ronald A. ; Tomaselli, Gordon F. / A conserved ring of charge in mammalian Na+ channels : A molecular regulator of the outer pore conformation during slow inactivation. In: Journal of Physiology. 2006 ; Vol. 576, No. 3. pp. 739-754.
@article{583bb2f0ec66415bb011e67be022e483,
title = "A conserved ring of charge in mammalian Na+ channels: A molecular regulator of the outer pore conformation during slow inactivation",
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.",
author = "Wei Xiong and Farukhi, {Yousaf Z.} and Yanli Tian and Deborah Disilvestre and Li, {Ronald A.} and Tomaselli, {Gordon F.}",
year = "2006",
month = "11",
day = "1",
doi = "10.1113/jphysiol.2006.115105",
language = "English (US)",
volume = "576",
pages = "739--754",
journal = "Journal of Physiology",
issn = "0022-3751",
publisher = "Wiley-Blackwell",
number = "3",

}

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 - 2006/11/1

Y1 - 2006/11/1

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.

UR - http://www.scopus.com/inward/record.url?scp=33750402366&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33750402366&partnerID=8YFLogxK

U2 - 10.1113/jphysiol.2006.115105

DO - 10.1113/jphysiol.2006.115105

M3 - Article

C2 - 16873407

AN - SCOPUS:33750402366

VL - 576

SP - 739

EP - 754

JO - Journal of Physiology

JF - Journal of Physiology

SN - 0022-3751

IS - 3

ER -