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A Unified View of the Role of Electrostatic Interactions in Modulating the Gating of Cys Loop Receptors

Xiu, Xinan and Hanek, Ariele P. and Wang, Jinti and Lester, Henry A. and Dougherty, Dennis A. (2005) A Unified View of the Role of Electrostatic Interactions in Modulating the Gating of Cys Loop Receptors. Journal of Biological Chemistry, 280 (50). pp. 41655-41666. ISSN 0021-9258. http://resolver.caltech.edu/CaltechAUTHORS:XIUjbc05

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Abstract

In the Cys loop superfamily of ligand-gated ion channels, a global conformational change, initiated by agonist binding, results in channel opening and the passage of ions across the cell membrane. The detailed mechanism of channel gating is a subject that has lent itself to both structural and electrophysiological studies. Here we defined a gating interface that incorporates elements from the ligand binding domain and transmembrane domain previously reported as integral to proper channel gating. An overall analysis of charged residues within the gating interface across the entire superfamily showed a conserved charging pattern, although no specific interacting ion pairs were conserved. We utilized a combination of conventional mutagenesis and the high precision methodology of unnatural amino acid incorporation to study extensively the gating interface of the mouse muscle nicotinic acetylcholine receptor. We found that charge reversal, charge neutralization, and charge introduction at the gating interface are often well tolerated. Furthermore, based on our data and a reexamination of previously reported data on {gamma}-aminobutyric acid, type A, and glycine receptors, we concluded that the overall charging pattern of the gating interface, and not any specific pairwise electrostatic interactions, controls the gating process in the Cys loop superfamily.


Item Type:Article
Additional Information:Copyright © 2005 by the American Society for Biochemistry and Molecular Biology. Received for publication, August 5, 2005, and in revised form, October 6, 2005. Originally published In Press as doi:10.1074/jbc.M508635200 on October 10, 2005 This work was supported by the National Institutes of Health Grants NS-34407 and NS-11756. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. The on-line version of this article (available at http://www.jbc.org) contains Figs. i-v and Table 1.
Record Number:CaltechAUTHORS:XIUjbc05
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:XIUjbc05
Alternative URL:http://dx.doi.org/10.1074/jbc.M508635200
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:3329
Collection:CaltechAUTHORS
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Deposited On:30 May 2006
Last Modified:26 Dec 2012 08:53

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