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Research ArticleArticle

α-Conotoxin PeIA[S9H,V10A,E14N] Potently and Selectively Blocks α6β2β3 versus α6β4 Nicotinic Acetylcholine Receptors

Arik J. Hone, Mick'l Scadden, Joanna Gajewiak, Sean Christensen, Jon Lindstrom and J. Michael McIntosh
Molecular Pharmacology November 2012, 82 (5) 972-982; DOI: https://doi.org/10.1124/mol.112.080853
Arik J. Hone
Department of Biology (A.J.H., M.S., J.G., S.C., J.M.M.), Interdepartmental Program in Neuroscience (J.M.M.), and Department of Psychiatry (J.M.M.), University of Utah, Salt Lake City, Utah; and Department of Neuroscience, University of Pennsylvania Medical School, Philadelphia, Pennsylvania (J.L.)
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Mick'l Scadden
Department of Biology (A.J.H., M.S., J.G., S.C., J.M.M.), Interdepartmental Program in Neuroscience (J.M.M.), and Department of Psychiatry (J.M.M.), University of Utah, Salt Lake City, Utah; and Department of Neuroscience, University of Pennsylvania Medical School, Philadelphia, Pennsylvania (J.L.)
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Joanna Gajewiak
Department of Biology (A.J.H., M.S., J.G., S.C., J.M.M.), Interdepartmental Program in Neuroscience (J.M.M.), and Department of Psychiatry (J.M.M.), University of Utah, Salt Lake City, Utah; and Department of Neuroscience, University of Pennsylvania Medical School, Philadelphia, Pennsylvania (J.L.)
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Sean Christensen
Department of Biology (A.J.H., M.S., J.G., S.C., J.M.M.), Interdepartmental Program in Neuroscience (J.M.M.), and Department of Psychiatry (J.M.M.), University of Utah, Salt Lake City, Utah; and Department of Neuroscience, University of Pennsylvania Medical School, Philadelphia, Pennsylvania (J.L.)
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Jon Lindstrom
Department of Biology (A.J.H., M.S., J.G., S.C., J.M.M.), Interdepartmental Program in Neuroscience (J.M.M.), and Department of Psychiatry (J.M.M.), University of Utah, Salt Lake City, Utah; and Department of Neuroscience, University of Pennsylvania Medical School, Philadelphia, Pennsylvania (J.L.)
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J. Michael McIntosh
Department of Biology (A.J.H., M.S., J.G., S.C., J.M.M.), Interdepartmental Program in Neuroscience (J.M.M.), and Department of Psychiatry (J.M.M.), University of Utah, Salt Lake City, Utah; and Department of Neuroscience, University of Pennsylvania Medical School, Philadelphia, Pennsylvania (J.L.)
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Abstract

Nicotinic acetylcholine receptors (nAChRs) containing α6 and β2 subunits modulate dopamine release in the basal ganglia and are therapeutically relevant targets for treatment of neurological and psychiatric disorders including Parkinson's disease and nicotine dependence. However, the expression profile of β2 and β4 subunits overlap in a variety of tissues including locus ceruleus, retina, hippocampus, dorsal root ganglia, and adrenal chromaffin cells. Ligands that bind α6β2 nAChRs also potently bind the closely related α6β4 subtype. To distinguish between these two subtypes, we synthesized novel analogs of a recently described α-conotoxin, PeIA. PeIA is a peptide antagonist that blocks several nAChR subtypes, including α6/α3β2β3 and α6/α3β4 nAChRs, with low nanomolar potency. We systematically mutated PeIA and evaluated the resulting analogs for enhanced potency and/or selectivity for α6/α3β2β3 nAChRs expressed in Xenopus oocytes (α6/α3 is a subunit chimera that contains the N-terminal ligand-binding domain of the α6 subunit). On the basis of these results, second-generation analogs were then synthesized. The final analog, PeIA[S9H,V10A,E14N], potently blocked acetylcholine-gated currents mediated by α6/α3β2β3 and α6/α3β4 nAChRs with IC50 values of 223 pM and 65 nM, respectively, yielding a >290-fold separation between the two subtypes. Kinetic studies of ligand binding to α6/α3β2β3 nAChRs yielded a koff of 0.096 ± 0.001 min−1 and a kon of 0.23 ± 0.019 min−1 M−9. The synthesis of PeIA[S9H,V10A,E14N] demonstrates that ligands can be developed to discriminate between α6β2 and α6β4 nAChRs.

Footnotes

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

  • This work was supported by the National Institutes of Health National Institute of General Medical Sciences [Grants GM48677, GM103801]; and National Institutes of Health National Institute of Neurological Disorders and Stroke [Grant NS1132].

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

    http://dx.doi.org/10.1124/mol.112.080853.

  • ABBREVIATIONS:

    nAChR
    nicotinic acetylcholine receptor
    α-Ctx
    α-conotoxin
    ACh
    acetylcholine
    Fmoc
    9-fluorenylmethyloxycarbonyl
    HPLC
    high-performance liquid chromatography.

  • Received June 27, 2012.
  • Accepted August 17, 2012.
  • Copyright © 2012 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 82 (5)
Molecular Pharmacology
Vol. 82, Issue 5
1 Nov 2012
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Research ArticleArticle

PeIA[S9H,V10A,E14N] Blocks α6β2β3 Nicotinic Receptors

Arik J. Hone, Mick'l Scadden, Joanna Gajewiak, Sean Christensen, Jon Lindstrom and J. Michael McIntosh
Molecular Pharmacology November 1, 2012, 82 (5) 972-982; DOI: https://doi.org/10.1124/mol.112.080853

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Research ArticleArticle

PeIA[S9H,V10A,E14N] Blocks α6β2β3 Nicotinic Receptors

Arik J. Hone, Mick'l Scadden, Joanna Gajewiak, Sean Christensen, Jon Lindstrom and J. Michael McIntosh
Molecular Pharmacology November 1, 2012, 82 (5) 972-982; DOI: https://doi.org/10.1124/mol.112.080853
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