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Molecular Pharmacology

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Research ArticleArticle

Positive Allosteric Modulation of the α7 Nicotinic Acetylcholine Receptor: Ligand Interactions with Distinct Binding Sites and Evidence for a Prominent Role of the M2-M3 Segment

Daniel Bertrand, Sonia Bertrand, Steven Cassar, Earl Gubbins, Jinhe Li and M. Gopalakrishnan
Molecular Pharmacology November 2008, 74 (5) 1407-1416; DOI: https://doi.org/10.1124/mol.107.042820
Daniel Bertrand
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Sonia Bertrand
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Steven Cassar
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Earl Gubbins
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Jinhe Li
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M. Gopalakrishnan
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Abstract

The α7 nicotinic acetylcholine receptor (nAChR), a homopentameric, rapidly activating and desensitizing ligand-gated ion channel with relatively high degree of calcium permeability, is expressed in the mammalian central nervous system, including regions associated with cognitive processing. Selective agonists targeting the α7 nAChR have shown efficacy in animal models of cognitive dysfunction. Use of positive allosteric modulators selective for the α7 receptor is another strategy that is envisaged in the design of active compounds aiming at improving attention and cognitive dysfunction. The recent discovery of novel positive allosteric modulators such as 1-(5-chloro-2-hydroxyphenyl)-3-(2-chloro-5-trifluoromethylphenyl)urea (NS-1738) and 1-(5-chloro-2,4-dimethoxyphenyl)-3-(5-methylisoxazol-3-yl)urea (PNU-120596) that are selective for the α7 nAChRs but display significant phenotypic differences in their profile of allosteric modulation, suggests that these molecules may act at different sites on the receptor. Taking advantage of the possibility to obtain functional receptors by the fusion of proteins domains from the α7 and the 5-HT3 receptor, we examined the structural determinants required for positive allosteric modulation. This strategy revealed that the extracellular N-terminal domain of α7 plays a critical role in allosteric modulation by NS-1738. In addition, α7-5HT3 chimeras harboring the M2-M3 segment showed that spontaneous activity in response to NS-1738, which confirmed the critical contribution of this small extracellular segment in the receptor gating. In contrast to NS-1738, positive allosteric modulation by PNU-120596 could not be restored in the α7-5HT3 chimeras but was selectively observed in the reverse 5HT3-α7 chimera. All together, these data illustrate the existence of distinct allosteric binding sites with specificity of different profiles of allosteric modulators and open new possibilities to investigate the α7 receptor function.

Footnotes

  • This work was supported by the Swiss National Science Foundation to DB.

  • ABBREVIATIONS: nAChR, nicotinic acetylcholine receptor; PNU-282987, N-((3R)-1-azabicyclo(2.2.2)oct-3-yl)-4-chlorobenzamide hydrochloride; AR-R 17779, spiro(1-azabicyclo(2.2.2)octane-3,5′-oxazolidin-2′-one); PHA-543613, N-(1-azabicyclo(2.2.2)oct-3-yl)furo(2,3-c)pyridine-5-carboxamide; SSR-180711, 4-bromophenyl-1,4-diazabicyclo(3.2.2) nonane-4-carboxylate, monohydrochloride; A-582941, 2-methyl-5-(6-phenyl-pyridazin-3-yl)octahydro-pyrrolo(3,4-c)pyrrole; ACh, acetylcholine; PAM, positive allosteric modulator; NS-1738, 1-(5-chloro-2-hydroxyphenyl)-3-(2-chloro-5-trifluoromethylphenyl)urea; PNU-120596, 1-(5-chloro-2,4-dimethoxyphenyl)-3-(5-methylisoxazol-3-yl)urea; IVM, ivermectin; 5-HI, 5-hydroxy-indole; TM, transmembrane domain; Chim, chimera receptor.

    • Received October 19, 2007.
    • Accepted August 1, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 74 (5)
Molecular Pharmacology
Vol. 74, Issue 5
1 Nov 2008
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Research ArticleArticle

Positive Allosteric Modulation of the α7 Nicotinic Acetylcholine Receptor: Ligand Interactions with Distinct Binding Sites and Evidence for a Prominent Role of the M2-M3 Segment

Daniel Bertrand, Sonia Bertrand, Steven Cassar, Earl Gubbins, Jinhe Li and M. Gopalakrishnan
Molecular Pharmacology November 1, 2008, 74 (5) 1407-1416; DOI: https://doi.org/10.1124/mol.107.042820

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Research ArticleArticle

Positive Allosteric Modulation of the α7 Nicotinic Acetylcholine Receptor: Ligand Interactions with Distinct Binding Sites and Evidence for a Prominent Role of the M2-M3 Segment

Daniel Bertrand, Sonia Bertrand, Steven Cassar, Earl Gubbins, Jinhe Li and M. Gopalakrishnan
Molecular Pharmacology November 1, 2008, 74 (5) 1407-1416; DOI: https://doi.org/10.1124/mol.107.042820
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