Multiple Binding Sites for the General Anesthetic Isoflurane Identified in the Nicotinic Acetylcholine Receptor Transmembrane Domain

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2010 Jul 28

PMID 20660787

Citations 64

Authors

Grace Brannigan

David N LeBard

Jerome Henin

Roderic G Eckenhoff

Michael L Klein

Affiliations

Soon will be listed here.

Abstract

An extensive search for isoflurane binding sites in the nicotinic acetylcholine receptor (nAChR) and the proton gated ion channel from Gloebacter violaceus (GLIC) has been carried out based on molecular dynamics (MD) simulations in fully hydrated lipid membrane environments. Isoflurane introduced into the aqueous phase readily partitions into the lipid membrane and the membrane-bound protein. Specifically, isoflurane binds persistently to three classes of sites in the nAChR transmembrane domain: (i) An isoflurane dimer occludes the pore, contacting residues identified by previous mutagenesis studies; analogous behavior is observed in GLIC. (ii) Several nAChR subunit interfaces are also occupied, in a site suggested by photoaffinity labeling and thought to positively modulate the receptor; these sites are not occupied in GLIC. (iii) Isoflurane binds to the subunit centers of both nAChR alpha chains and one of the GLIC chains, in a site that has had little experimental targeting. Interpreted in the context of existing structural and physiological data, the present MD results support a multisite model for the mechanism of receptor-channel modulation by anesthetics.

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