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An open-channel blocker interacts with adjacent turns of α-helices in the nicotinic acetylcholine receptor

Charnet, Pierre and Labarca, Cesar and Leonard, Reid J. and Vogelaar, Nancy J. and Czyzyk, Linda and Gouin, Annie and Davidson, Norman and Lester, Henry A. (1990) An open-channel blocker interacts with adjacent turns of α-helices in the nicotinic acetylcholine receptor. Neuron, 4 (1). pp. 87-95. ISSN 0896-6273. doi:10.1016/0896-6273(90)90445-L.

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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.

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Lester, Henry A.0000-0002-5470-5255
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).
Funding AgencyGrant Number
Muscular Dystrophy AssociationUNSPECIFIED
NIH Postdoctoral FellowshipNS-8083
Bourse LavoiserUNSPECIFIED
Fondation pour la Recherche MédicaleUNSPECIFIED
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Record Number:CaltechAUTHORS:20170408-161145019
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Official Citation:Pierre Charnet, Cesar Labarca, Reid J. Leonard, Nancy J. Vogelaar, Linda Czyzyk, Annie Gouin, Norman Davidson, Henry A. Lester, An open-channel blocker interacts with adjacent turns of α-helices in the nicotinic acetylcholine receptor, Neuron, Volume 4, Issue 1, 1990, Pages 87-95, ISSN 0896-6273, (
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ID Code:76144
Deposited By: 1Science Import
Deposited On:22 Jun 2017 22:51
Last Modified:15 Nov 2021 16:57

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