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Molecular Pharmacology

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Research ArticleArticle

Efficient Binding of 4/7 α-Conotoxins to Nicotinic α4β2 Receptors Is Prevented by Arg185 and Pro195 in the α4 Subunit

Mirko Beissner, Sébastien Dutertre, Rudolf Schemm, Timm Danker, Annett Sporning, Helmut Grubmüller and Annette Nicke
Molecular Pharmacology October 2012, 82 (4) 711-718; DOI: https://doi.org/10.1124/mol.112.078683
Mirko Beissner
Department of Neurochemistry, Max Planck Institute for Brain Research, Frankfurt, Germany (M.B., A.N.); Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia (S.D.); Department of Theoretical and Computational Biophysics, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany (R.S., H.G.); NMI Technologie Transfer GmbH, Reutlingen, Germany (T.D.); and Department of Molecular Biology of Neuronal Signals, Max Planck Institute for Experimental Medicine, Göttingen, Germany (A.S., A.N.)
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Sébastien Dutertre
Department of Neurochemistry, Max Planck Institute for Brain Research, Frankfurt, Germany (M.B., A.N.); Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia (S.D.); Department of Theoretical and Computational Biophysics, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany (R.S., H.G.); NMI Technologie Transfer GmbH, Reutlingen, Germany (T.D.); and Department of Molecular Biology of Neuronal Signals, Max Planck Institute for Experimental Medicine, Göttingen, Germany (A.S., A.N.)
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Rudolf Schemm
Department of Neurochemistry, Max Planck Institute for Brain Research, Frankfurt, Germany (M.B., A.N.); Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia (S.D.); Department of Theoretical and Computational Biophysics, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany (R.S., H.G.); NMI Technologie Transfer GmbH, Reutlingen, Germany (T.D.); and Department of Molecular Biology of Neuronal Signals, Max Planck Institute for Experimental Medicine, Göttingen, Germany (A.S., A.N.)
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Timm Danker
Department of Neurochemistry, Max Planck Institute for Brain Research, Frankfurt, Germany (M.B., A.N.); Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia (S.D.); Department of Theoretical and Computational Biophysics, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany (R.S., H.G.); NMI Technologie Transfer GmbH, Reutlingen, Germany (T.D.); and Department of Molecular Biology of Neuronal Signals, Max Planck Institute for Experimental Medicine, Göttingen, Germany (A.S., A.N.)
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Annett Sporning
Department of Neurochemistry, Max Planck Institute for Brain Research, Frankfurt, Germany (M.B., A.N.); Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia (S.D.); Department of Theoretical and Computational Biophysics, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany (R.S., H.G.); NMI Technologie Transfer GmbH, Reutlingen, Germany (T.D.); and Department of Molecular Biology of Neuronal Signals, Max Planck Institute for Experimental Medicine, Göttingen, Germany (A.S., A.N.)
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Helmut Grubmüller
Department of Neurochemistry, Max Planck Institute for Brain Research, Frankfurt, Germany (M.B., A.N.); Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia (S.D.); Department of Theoretical and Computational Biophysics, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany (R.S., H.G.); NMI Technologie Transfer GmbH, Reutlingen, Germany (T.D.); and Department of Molecular Biology of Neuronal Signals, Max Planck Institute for Experimental Medicine, Göttingen, Germany (A.S., A.N.)
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Annette Nicke
Department of Neurochemistry, Max Planck Institute for Brain Research, Frankfurt, Germany (M.B., A.N.); Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia (S.D.); Department of Theoretical and Computational Biophysics, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany (R.S., H.G.); NMI Technologie Transfer GmbH, Reutlingen, Germany (T.D.); and Department of Molecular Biology of Neuronal Signals, Max Planck Institute for Experimental Medicine, Göttingen, Germany (A.S., A.N.)
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Abstract

α-Conotoxins are subtype-selective nicotinic acetylcholine receptor (nAChR) antagonists. Although potent α3β2 nAChR-selective α-conotoxins have been identified, currently characterized α-conotoxins show no or only weak affinity for α4β2 nAChRs, which are, besides α7 receptors, the most abundant nAChRs in the mammalian brain. To identify the determinants responsible for this difference, we substituted selected amino acid residues in the ligand-binding domain of the α4 subunit by the corresponding residues in the α3 subunit. Two-electrode voltage clamp analysis of these mutants revealed increased affinity of α-conotoxins MII, TxIA, and [A10L]TxIA at the α4(R185I)β2 receptor. Conversely, α-conotoxin potency was reduced at the reverse α3(I186R)β2 mutant. Replacement of α4Arg185 by alanine, glutamate, and lysine demonstrated that a positive charge in this position prevents α-conotoxin binding. Combination of the R185I mutation with a P195Q mutation outside the binding site but in loop C completely transferred high α-conotoxin potency to the α4β2 receptor. Molecular dynamics simulations of homology models with docked α-conotoxin indicate that these residues control access to the α-conotoxin binding site.

Footnotes

  • ↵Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

  • This work was supported by the Deutsche Forschungsgemeinschaft [Grants NI 592/3 and 592/5].

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    http://dx.doi.org/10.1124/mol.112.078683.

  • ABBREVIATIONS:

    ACh
    acetylcholine
    nAChR
    nicotinic acetylcholine receptor
    AChBP
    acetylcholine binding protein
    MD
    molecular dynamics
    wt
    wild-type
    TEVC
    two-electrode voltage clamp.

  • Received March 17, 2012.
  • Accepted July 16, 2012.
  • Copyright © 2012 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 82 (4)
Molecular Pharmacology
Vol. 82, Issue 4
1 Oct 2012
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Research ArticleArticle

α-Conotoxin Binding to α4β2 Receptors

Mirko Beissner, Sébastien Dutertre, Rudolf Schemm, Timm Danker, Annett Sporning, Helmut Grubmüller and Annette Nicke
Molecular Pharmacology October 1, 2012, 82 (4) 711-718; DOI: https://doi.org/10.1124/mol.112.078683

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Research ArticleArticle

α-Conotoxin Binding to α4β2 Receptors

Mirko Beissner, Sébastien Dutertre, Rudolf Schemm, Timm Danker, Annett Sporning, Helmut Grubmüller and Annette Nicke
Molecular Pharmacology October 1, 2012, 82 (4) 711-718; DOI: https://doi.org/10.1124/mol.112.078683
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