An open-channel blocker interacts with adjacent turns of α-helices in the nicotinic acetylcholine receptor
Abstract
The binding site for an open-channel blocker, QX-222, at mouse muscle nicotinic acetylcholine receptors was probed using site-directed mutagenesis, oocyte expression, and elect rophysiologicaI analysis. The proposed cytoplasmic end of the M2 transmembrane helix is termed position 1′. At position 10′ (αS252, βT263, γA261, δA266), Ala residues yield stronger and longer binding of QX-222 than Ser or Thr residues. These effects are opposite and roughly equal (30%–50% per mutation) to previously reported effects at position 6′. The polar end of an anesthetic molecule seems to bind to the position 6′ OH groups, which provide a water-like region; the nonpolar moiety is near position 10′ and binds more strongly in a nonpolar environment. Interactions with adjacent OH-rich turns of an amphiphilic helix may explain the widespread blocking effects of local anesthetics at the conduction pore of ion channels.
Additional Information
© 1990 Cell Press. Received 17 August 1989, Revised 29 August 1989. We thank Dr. Bertil Takmann of Astra Pharmaceuticals for gifts of QX-222; Drs. Takmann and R. A. North for discussion; and W. J. Goddard for the use of computer modeling facilities. This work was supported by grants from the National Institutes of Health (NS-11756) and from the Muscular Dystrophy Association and by postdoctoral fellowships to R. J. L. (NS-8083) and P. C. (Bourse Lavoiser and Fondation pour la Recherche Médicale).Additional details
- Eprint ID
- 76144
- Resolver ID
- CaltechAUTHORS:20170408-161145019
- NIH
- NS-11756
- Muscular Dystrophy Association
- NIH Postdoctoral Fellowship
- NS-8083
- Bourse Lavoiser
- Fondation pour la Recherche Médicale
- Created
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2017-06-22Created from EPrint's datestamp field
- Updated
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2021-11-15Created from EPrint's last_modified field