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J. Biol. Chem., Vol. 280, Issue 50, 41655-41666, December 16, 2005

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

From the Division of Chemistry and Chemical Engineering and Division of Biology, California Institute of Technology, Pasadena, California 91125

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 -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.

Received for publication, August 5, 2005 , and in revised form, October 6, 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.

¹ To whom correspondence should be addressed: Division of Chemistry and Chemical Engineering, California Institute of Technology, 164-30, Pasadena, CA 91125. Tel.: 626-395-6089; Fax: 626-564-9297; E-mail: dadougherty{at}caltech.edu.

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