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Research ArticleArticle

Determinants of Channel Gating Located in the N-Terminal Extracellular Domain of Nicotinic α7 Receptor

René Anand, Mark E. Nelson, Volodymyr Gerzanich, Gregg B. Wells and Jon Lindstrom
Journal of Pharmacology and Experimental Therapeutics November 1998, 287 (2) 469-479;
René Anand
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Mark E. Nelson
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Volodymyr Gerzanich
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Gregg B. Wells
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Jon Lindstrom
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Abstract

We identified regions within the N-terminal extracellular domain of α7 nicotinic acetylcholine receptors that affect channel gating. By single-channel analysis of α7 nicotinic acetylcholine receptors currents, we show that the difference in efficacy between the two agonists acetylcholine and 1,1-dimethyl-4-phenylpiperazinium (DMPP) is due to a slower channel activation rate by DMPP. The partial efficacy of DMPP was not caused by channel block or faster desensitization of α7 AChRs by DMPP. In addition, the efficacy and, by inference, the activation rate were found to be voltage dependent. Using chimeras of the two closely related subunits α7 and α8, we map residues that affect channel activation rate and agonist affinity to two different regions of the extracellular domain. Residues that affect channel activation rate are within the sequence 1–179, whereas residues that affect agonist affinity are within the sequence 180–208.

Footnotes

  • Send reprint requests to: Dr. Jon Lindstrom, Department of Neuroscience, 217 Stemmler Hall, 36th and Hamilton Walk, University of Pennsylvania Medical School, Philadelphia, PA 19104-6074. E-mail:jslkk{at}mail.med.upenn.edu

  • ↵1 This work was supported by National Institutes of Health Grants NS33625 (R.A.), NS01903 (G.B.W.), NS10333 (M.E.N.) and NS11323 (J.L.) and by grants from the Muscular Dystrophy Association (J.L.), Council for Tobacco Research, USA, Inc. (J.L.), Smokeless Tobacco Research Council (J.L.) and the Pittsburgh Supercomputing Center through NIH National Center for Research Resources cooperative agreement 2 p41 RR06009. Portions of this work have appeared in abstract form (annual meetings of the Society for Neuroscience, Washington, D.C., 1994; New Orleans, LA, 1997).

  • Abbreviations:
    ACh
    acetylcholine
    AChR
    nicotinic acetylcholine receptor
    BAPTA AM
    1,2-bis (2-aminophenoxy)-ethane-N,N,N′,N′-tetraacetic acid tetrakis (acetyoxymethyl) ester
    DMPP
    1,1-dimethyl-4-phenylpiperazinium
    EC50
    half-maximally effective concentration of agonist
    EGTA
    ethyleneglycol-bis-(βaminoethyl ether)-N,N,N′,N′-tetraacetic acid
    fc
    filter cut off frequency ≈3 dB
    5-HT3
    serotonin receptor type 3
    Imax
    peak current maximum
    fc
    filter corner frequency
    HEPES
    N-[2-hydroxyethyl]piperazine-N′-2-ethane sulfonic acid
    MgATP
    adenosine-5′-triphosphate (magnesium salt)
    nH
    Hill coefficient
    M1–M4
    transmembrane domains 1–4
    Tr
    filter rise time
    • Received March 27, 1998.
    • Accepted June 5, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 287, Issue 2
1 Nov 1998
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Research ArticleArticle

Determinants of Channel Gating Located in the N-Terminal Extracellular Domain of Nicotinic α7 Receptor

René Anand, Mark E. Nelson, Volodymyr Gerzanich, Gregg B. Wells and Jon Lindstrom
Journal of Pharmacology and Experimental Therapeutics November 1, 1998, 287 (2) 469-479;

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Research ArticleArticle

Determinants of Channel Gating Located in the N-Terminal Extracellular Domain of Nicotinic α7 Receptor

René Anand, Mark E. Nelson, Volodymyr Gerzanich, Gregg B. Wells and Jon Lindstrom
Journal of Pharmacology and Experimental Therapeutics November 1, 1998, 287 (2) 469-479;
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