Ivermectin: A Positive Allosteric Effector of the α7 Neuronal Nicotinic Acetylcholine Receptor

  1. Ryoko M. Krause1,
  2. Bruno Buisson1,
  3. Sonia Bertrand1,
  4. Pierre-Jean Corringer2,
  5. Jean-Luc Galzi1,2,
  6. Jean-Pierre Changeux2 and
  7. Daniel Bertrand1
  1. 1Department of Physiology, University Medical Center, 1211 Geneva 4, Switzerland (R.M.K., B.B., S.B., D.B.), and 2URA Centre National de la Recherche Scientifique D1284, Neurobiologie Moléculaire, Institut Pasteur, 75724 Paris Cedex 15, France (P.-J.C., J.-L.G., J.-P.C.)

    Abstract

    We report that preapplication of ivermectin, in the micromolar range, strongly enhances the subsequent acetylcholine-evoked current of the neuronal chick or human α7 nicotinic acetylcholine receptors reconstituted in Xenopus laevis oocytes and K-28 cells. This potentiation does not result from nonspecific Cl−currents. The concomitant increase in apparent affinity and cooperativity of the dose-response curve suggest that ivermectin acts as a positive allosteric effector. This interpretation is supported by the observation of an increase in efficiency of a partial agonist associated with the potentiation and by the differential effect of ivermectin on mutants within the M2 channel domain. Ivermectin effects reveal a novel allosteric site for pharmacological agents on neuronal α7 nicotinic acetylcholine receptors.

    Footnotes

    • Send reprint requests to: D. Bertrand, Department of Physiology, University Medical Center, 1211 Geneva 4, Switzerland. E-mail: bertrand{at}cmu.unige.ch

    • ↵1 Current affiliation: Centre National de la Recherche Scientifique, 67400 Illkirch, France.

    • This work was supported by the Swiss National Foundation and the Office Fédéral de l’Education et des Sciences (D.B.) and Collège de France, Association Française contre la Myopathie, Institut de la Santé et de la Recherche Médicale, Direction de la Recherche Etudes et Techniques, and Commission of the European Communities (Biotech, Biomed) (J.P.C.).

    • Abbreviations:
      ACh
      acetylcholine
      nAChR
      nicotinic acetylcholine receptor
      GABA
      γ-aminobutyric acid
      GABAAR
      γ-aminobutyric acid receptor
      HEPES
      4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid
      IVM-PO4
      22,23-dihydroavermectin B1a4"-O-phosphate
      BAPTA
      1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid
      I-V
      current/voltage
      DMPP
      1,1-dimethyl-4-phenylpiperazinium
      MLA
      methyllycaconitine
      IVM
      ivermectin
      • Received June 26, 1997.
      • Accepted October 14, 1997.
    « Previous | Next Article »Table of Contents

    This Article

    1. Molecular Pharmacology February 1, 1998 vol. 53 no. 2 283-294
    1. » Abstract
    2. Full Text
    3. Full Text (PDF)

    Classifications

    Responses

    1. Submit a response
    2. No responses published

    Current Issue

    1. November 2009, 76 (5)
    1. Current Issue
    1. Alert me to new issues of Molecular Pharmacology