Multiple binding sites for the general anesthetic isoflurane identified in the nicotinic acetylcholine receptor transmembrane domain

Grace Brannigan, David N. LeBard, Jérôme Hénin, Roderic G. Eckenhoff, Michael L. Klein

Research output: Contribution to journalArticlepeer-review

96 Scopus citations

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 α 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.

Original languageEnglish (US)
Pages (from-to)14122-14127
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number32
DOIs
StatePublished - Aug 10 2010
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • General

Keywords

  • Anesthesia
  • Cys-loop receptor
  • Ligand-gated ion channel

Fingerprint

Dive into the research topics of 'Multiple binding sites for the general anesthetic isoflurane identified in the nicotinic acetylcholine receptor transmembrane domain'. Together they form a unique fingerprint.

Cite this