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Research ArticleArticle

Human α6β4 Nicotinic Acetylcholine Receptor: Heterologous Expression and Agonist Behavior Provide Insights into the Immediate Binding Site

María Constanza Maldifassi, Hugo Rego Campello, Timothy Gallagher, Henry A. Lester and Dennis A. Dougherty
Molecular Pharmacology June 2023, 103 (6) 339-347; DOI: https://doi.org/10.1124/molpharm.123.000672
María Constanza Maldifassi
Divisions of Chemistry and Chemical Engineering (M.C.M., D.A.D.) and Biology and Biological Engineering (H.A.L.), California Institute of Technology, Pasadena, California; and School of Chemistry, University of Bristol, Bristol, United Kingdom (H.R.C., T.G.)
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Hugo Rego Campello
Divisions of Chemistry and Chemical Engineering (M.C.M., D.A.D.) and Biology and Biological Engineering (H.A.L.), California Institute of Technology, Pasadena, California; and School of Chemistry, University of Bristol, Bristol, United Kingdom (H.R.C., T.G.)
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Timothy Gallagher
Divisions of Chemistry and Chemical Engineering (M.C.M., D.A.D.) and Biology and Biological Engineering (H.A.L.), California Institute of Technology, Pasadena, California; and School of Chemistry, University of Bristol, Bristol, United Kingdom (H.R.C., T.G.)
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Henry A. Lester
Divisions of Chemistry and Chemical Engineering (M.C.M., D.A.D.) and Biology and Biological Engineering (H.A.L.), California Institute of Technology, Pasadena, California; and School of Chemistry, University of Bristol, Bristol, United Kingdom (H.R.C., T.G.)
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Dennis A. Dougherty
Divisions of Chemistry and Chemical Engineering (M.C.M., D.A.D.) and Biology and Biological Engineering (H.A.L.), California Institute of Technology, Pasadena, California; and School of Chemistry, University of Bristol, Bristol, United Kingdom (H.R.C., T.G.)
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Abstract

Study of α6β4 nicotinic acetylcholine receptors (nAChRs) as a pharmacological target has recently gained interest because of their involvement in analgesia, control of catecholamine secretion, dopaminergic pathways, and aversive pathways. However, an extensive characterization of the human α6β4 nAChRs has been vitiated by technical difficulties resulting in poor receptor expression. In 2020, Knowland and collaborators identified BARP (β-anchoring and regulatory protein), a previously known voltage-gated calcium channel suppressor, as a novel human α6β4 chaperone. Here, we establish that co-expression of human BARP with human α6β4 in Xenopus oocytes, resulted in the functional expression of human α6β4 receptors with acetylcholine-elicited currents that allow an in-depth characterization of the receptor using two electrode voltage-clamp electrophysiology together with diverse agonists and receptor mutations. We report: 1) an extended pharmacological characterization of the receptor, and 2) key residues for agonist-activity located in or near the first shell of the binding pocket.

SIGNIFICANCE STATEMENT The human α6β4 nicotinic acetylcholine receptor has attained increased interest because of its involvement in diverse physiological processes and diseases. Although recognized as a pharmacological target, development of specific agonists has been hampered by limited knowledge of its structural characteristics and by challenges in expressing the receptor. By including the chaperone β-anchoring and regulatory protein for enhanced expression and employing different ligands, we have studied the pharmacology of α6β4, providing insight into receptor residues and structural requirements for ligands important to consider for agonist-induced activation.

Footnotes

    • Received January 9, 2023.
    • Accepted March 15, 2023.
  • This work was supported by The Regents of the University of California, Research Grants Program Office, Tobacco-Related Disease Research Program [Grant T29IR0455] (to D.A.D.).

  • ↵1Current affiliation: Institute of Biochemistry and Molecular Medicine, University of Bern, Bern, Switzerland.

  • No author has an actual or perceived conflict of interest with the contents of this article.

  • dx.doi.org/10.1124/molpharm.123.000672.

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

  • Copyright © 2023 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 103 (6)
Molecular Pharmacology
Vol. 103, Issue 6
1 Jun 2023
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Research ArticleArticle

Pharmacological Characterization of the Human α6β4 nAChR

María Constanza Maldifassi, Hugo Rego Campello, Timothy Gallagher, Henry A. Lester and Dennis A. Dougherty
Molecular Pharmacology June 1, 2023, 103 (6) 339-347; DOI: https://doi.org/10.1124/molpharm.123.000672

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Research ArticleArticle

Pharmacological Characterization of the Human α6β4 nAChR

María Constanza Maldifassi, Hugo Rego Campello, Timothy Gallagher, Henry A. Lester and Dennis A. Dougherty
Molecular Pharmacology June 1, 2023, 103 (6) 339-347; DOI: https://doi.org/10.1124/molpharm.123.000672
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