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Research ArticleArticle

The E Loop of the Transmitter Binding Site Is a Key Determinant of the Modulatory Effects of Physostigmine on Neuronal Nicotinic α4β2 Receptors

Xiaochun Jin, Megan M. McCollum, Allison L. Germann, Gustav Akk and Joe Henry Steinbach
Molecular Pharmacology February 2017, 91 (2) 100-109; DOI: https://doi.org/10.1124/mol.116.106484
Xiaochun Jin
Department of Anesthesiology (X.J., M.M.C., A.L.G., G.A., J.H.S.) and Taylor Family Institute for Innovative Psychiatric Research (G.A., J.H.S.), Washington University School of Medicine, St. Louis, Missouri
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Megan M. McCollum
Department of Anesthesiology (X.J., M.M.C., A.L.G., G.A., J.H.S.) and Taylor Family Institute for Innovative Psychiatric Research (G.A., J.H.S.), Washington University School of Medicine, St. Louis, Missouri
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Allison L. Germann
Department of Anesthesiology (X.J., M.M.C., A.L.G., G.A., J.H.S.) and Taylor Family Institute for Innovative Psychiatric Research (G.A., J.H.S.), Washington University School of Medicine, St. Louis, Missouri
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Gustav Akk
Department of Anesthesiology (X.J., M.M.C., A.L.G., G.A., J.H.S.) and Taylor Family Institute for Innovative Psychiatric Research (G.A., J.H.S.), Washington University School of Medicine, St. Louis, Missouri
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Joe Henry Steinbach
Department of Anesthesiology (X.J., M.M.C., A.L.G., G.A., J.H.S.) and Taylor Family Institute for Innovative Psychiatric Research (G.A., J.H.S.), Washington University School of Medicine, St. Louis, Missouri
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Abstract

Physostigmine is a well known inhibitor of acetylcholinesterase, which can also activate, potentiate, and inhibit acetylcholine receptors, including neuronal nicotinic receptors comprising α4 and β2 subunits. We have found that the two stoichiometric forms of this receptor differ in the effects of physostigmine. The form containing three copies of α4 and two of β2 was potentiated at low concentrations of acetylcholine chloride (ACh) and physostigmine, whereas the form containing two copies of α4 and three of β2 was inhibited. Chimeric constructs of subunits indicated that the presence of inhibition or potentiation depended on the source of the extracellular ligand binding domain of the subunit. Further sets of chimeric constructs demonstrated that a portion of the ACh binding domain, the E loop, is a key determinant. Transferring the E loop from the β2 subunit to the α4 subunit resulted in strong inhibition, whereas the reciprocal transfer reduced inhibition. To control the number and position of the incorporated chimeric subunits, we expressed chimeric constructs with subunit dimers. Surprisingly, incorporation of a subunit with an altered E loop had similar effects whether it contributed either to an intersubunit interface containing a canonical ACh binding site or to an alternative interface. The observation that the α4 E loop is involved suggests that physostigmine interacts with regions of subunits that contribute to the ACh binding site, whereas the lack of interface specificity indicates that interaction with a particular ACh binding site is not the critical factor.

Footnotes

    • Received August 11, 2016.
    • Accepted November 23, 2016.
  • This research was supported by the National Institutes of Health National Institute of Neurological Disorders and Stroke [Grant R01 NS22356].

  • dx.doi.org/10.1124/mol.116.106484.

  • Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 91 (2)
Molecular Pharmacology
Vol. 91, Issue 2
1 Feb 2017
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Research ArticleArticle

The E Loop Is a Key Determinant for Physostigmine Action

Xiaochun Jin, Megan M. McCollum, Allison L. Germann, Gustav Akk and Joe Henry Steinbach
Molecular Pharmacology February 1, 2017, 91 (2) 100-109; DOI: https://doi.org/10.1124/mol.116.106484

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Research ArticleArticle

The E Loop Is a Key Determinant for Physostigmine Action

Xiaochun Jin, Megan M. McCollum, Allison L. Germann, Gustav Akk and Joe Henry Steinbach
Molecular Pharmacology February 1, 2017, 91 (2) 100-109; DOI: https://doi.org/10.1124/mol.116.106484
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