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Research ArticleArticle

A Structure-Based Approach to Nicotinic Receptor Pharmacology

Stephen E. Ryan and John E. Baenziger
Molecular Pharmacology February 1999, 55 (2) 348-355; DOI: https://doi.org/10.1124/mol.55.2.348
Stephen E. Ryan
Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Canada
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John E. Baenziger
Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Canada
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Abstract

Infrared difference spectroscopy has been used to examine the structural effects of local anesthetic (LA) binding to the nicotinic acetylcholine receptor (nAChR). Several LAs induce subtle changes in the vibrational spectrum of the nAChR over a range of concentrations consistent with their reported nAChR-binding affinities. At concentrations of the desensitizing LAs prilocaine and lidocaine consistent with their binding to the ion channel pore, the vibrational changes suggest the stabilization of an intermediate conformation that shares structural features in common with both the resting and desensitized states. Higher concentrations of prilocaine and lidocaine, as well as the LA dibucaine, lead to additional binding to the neurotransmitter-binding site, the formation of physical interactions (most notably cation-tyrosine interactions) between LAs and neurotransmitter-binding-site residues, and the subsequent formation of a presumed desensitized nAChR. Although concentrations of the LA tetracaine consistent with binding to the ion channel pore elicit a reversed pattern of spectral changes suggestive of a resting state-like nAChR, higher concentrations also lead to neurotransmitter site binding and desensitization. Our results suggest that LAs stabilize multiple conformations of the nAChR by binding to at least two conformationally sensitive LA-binding sites. The spectra also reveal subtle differences in the strengths of the physical interactions that occur between LAs and binding-site residues. These differences correlate with LA potency at the nAChR.

Footnotes

    • Received May 6, 1998.
    • Accepted November 16, 1998.
  • Send reprint requests to: Dr. John E. Baenziger, Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, 451 Smyth Road Ottawa, Canada, K1H 8M5. E-mail: jebaenz{at}uottawa.ca

  • This work was supported by a grant from the Medical Research Council of Canada to J.E.B. S.E.R. is supported by a grant from the Natural Sciences and Engineering Research Council of Canada.

  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 55 (2)
Molecular Pharmacology
Vol. 55, Issue 2
1 Feb 1999
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Research ArticleArticle

A Structure-Based Approach to Nicotinic Receptor Pharmacology

Stephen E. Ryan and John E. Baenziger
Molecular Pharmacology February 1, 1999, 55 (2) 348-355; DOI: https://doi.org/10.1124/mol.55.2.348

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Research ArticleArticle

A Structure-Based Approach to Nicotinic Receptor Pharmacology

Stephen E. Ryan and John E. Baenziger
Molecular Pharmacology February 1, 1999, 55 (2) 348-355; DOI: https://doi.org/10.1124/mol.55.2.348
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