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Research ArticleArticle

Molecular Interaction of α-Conotoxin RgIA with the Rat α9α10 Nicotinic Acetylcholine Receptor

Layla Azam, Athanasios Papakyriakou, Marios Zouridakis, Petros Giastas, Socrates J. Tzartos and J. Michael McIntosh
Molecular Pharmacology May 2015, 87 (5) 855-864; DOI: https://doi.org/10.1124/mol.114.096511
Layla Azam
Departments of Biology (L.A., J.M.M.) and Psychiatry (J.M.M.), University of Utah, Salt Lake City, Utah; George E. Wahlen Veterans Affair Medical Center, Salt Lake City, Utah (J.M.M.); National Center for Scientific Research “Demokritos,” Athens, Greece (A.P.); and Department of Neurobiology, Hellenic Pasteur Institute, Athens, Greece (M.Z., P.G., S.J.T.)
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Athanasios Papakyriakou
Departments of Biology (L.A., J.M.M.) and Psychiatry (J.M.M.), University of Utah, Salt Lake City, Utah; George E. Wahlen Veterans Affair Medical Center, Salt Lake City, Utah (J.M.M.); National Center for Scientific Research “Demokritos,” Athens, Greece (A.P.); and Department of Neurobiology, Hellenic Pasteur Institute, Athens, Greece (M.Z., P.G., S.J.T.)
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Marios Zouridakis
Departments of Biology (L.A., J.M.M.) and Psychiatry (J.M.M.), University of Utah, Salt Lake City, Utah; George E. Wahlen Veterans Affair Medical Center, Salt Lake City, Utah (J.M.M.); National Center for Scientific Research “Demokritos,” Athens, Greece (A.P.); and Department of Neurobiology, Hellenic Pasteur Institute, Athens, Greece (M.Z., P.G., S.J.T.)
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Petros Giastas
Departments of Biology (L.A., J.M.M.) and Psychiatry (J.M.M.), University of Utah, Salt Lake City, Utah; George E. Wahlen Veterans Affair Medical Center, Salt Lake City, Utah (J.M.M.); National Center for Scientific Research “Demokritos,” Athens, Greece (A.P.); and Department of Neurobiology, Hellenic Pasteur Institute, Athens, Greece (M.Z., P.G., S.J.T.)
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Socrates J. Tzartos
Departments of Biology (L.A., J.M.M.) and Psychiatry (J.M.M.), University of Utah, Salt Lake City, Utah; George E. Wahlen Veterans Affair Medical Center, Salt Lake City, Utah (J.M.M.); National Center for Scientific Research “Demokritos,” Athens, Greece (A.P.); and Department of Neurobiology, Hellenic Pasteur Institute, Athens, Greece (M.Z., P.G., S.J.T.)
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J. Michael McIntosh
Departments of Biology (L.A., J.M.M.) and Psychiatry (J.M.M.), University of Utah, Salt Lake City, Utah; George E. Wahlen Veterans Affair Medical Center, Salt Lake City, Utah (J.M.M.); National Center for Scientific Research “Demokritos,” Athens, Greece (A.P.); and Department of Neurobiology, Hellenic Pasteur Institute, Athens, Greece (M.Z., P.G., S.J.T.)
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This article has a correction. Please see:

  • Corrections to “Molecular interaction of α-conotoxin RgIA with the rat α9α10 nicotinic acetylcholine receptor” - October 01, 2016

Abstract

The α9α10 nicotinic acetylcholine receptor (nAChR) was first identified in the auditory system, where it mediates synaptic transmission between efferent olivocochlear cholinergic fibers and cochlea hair cells. This receptor gained further attention due to its potential role in chronic pain and breast and lung cancers. We previously showed that α-conotoxin (α-CTx) RgIA, one of the few α9α10 selective ligands identified to date, is 300-fold less potent on human versus rat α9α10 nAChR. This species difference was conferred by only one residue in the (−), rather than (+), binding region of the α9 subunit. In light of this unexpected discovery, we sought to determine other interacting residues with α-CTx RgIA. A previous molecular modeling study, based on the structure of the homologous molluscan acetylcholine-binding protein, predicted that RgIA interacts with three residues on the α9(+) face and two residues on the α10(−) face of the α9α10 nAChR. However, mutations of these residues had little or no effect on toxin block of the α9α10 nAChR. In contrast, mutations of homologous residues in the opposing nAChR subunits (α10 Ε197, P200 and α9 T61, D121) resulted in 19- to 1700-fold loss of toxin activity. Based on the crystal structure of the extracellular domain (ECD) of human α9 nAChR, we modeled the rat α9α10 ECD and its complexes with α-CTx RgIA and acetylcholine. Our data support the interaction of α-CTx RgIA at the α10/α9 rather than the α9/α10 nAChR subunit interface, and may facilitate the development of selective ligands with therapeutic potential.

Footnotes

    • Received October 27, 2014.
    • Accepted March 2, 2015.
  • This work was supported by National Institutes of Health [Grants P01-GM48677, R01-GM103801] and European Commission Seventh Framework Programme ‘REGPOT-NeuroSign’ [Grant 264083].

  • dx.doi.org/10.1124/mol.114.096511.

  • ↵Embedded ImageThis article has supplemental material available at molpharm.aspetjournals.org.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 87 (5)
Molecular Pharmacology
Vol. 87, Issue 5
1 May 2015
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Research ArticleArticle

α-Conotoxin RgIA and α9α10 nAChR

Layla Azam, Athanasios Papakyriakou, Marios Zouridakis, Petros Giastas, Socrates J. Tzartos and J. Michael McIntosh
Molecular Pharmacology May 1, 2015, 87 (5) 855-864; DOI: https://doi.org/10.1124/mol.114.096511

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Research ArticleArticle

α-Conotoxin RgIA and α9α10 nAChR

Layla Azam, Athanasios Papakyriakou, Marios Zouridakis, Petros Giastas, Socrates J. Tzartos and J. Michael McIntosh
Molecular Pharmacology May 1, 2015, 87 (5) 855-864; DOI: https://doi.org/10.1124/mol.114.096511
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