Cysteine accessibility analysis of the human alpha7 nicotinic acetylcholine receptor ligand-binding domain identifies L119 as a gatekeeper.

Neuropharmacology
Roger L PapkeNicole A Horenstein

Abstract

A large number of structurally diverse ligands have been produced to selectively target α7 nicotinic acetylcholine receptors (nAChRs). We applied the method of scanning cysteine accessibility mutations (SCAM) to the ligand-binding domain of the α7 nAChR to identify subdomains of particular importance to the binding and subsequent activation by select agonists. We evaluated the activity of four structurally distinct α7 agonists on wild-type human α7 and 44 targeted mutants expressed in Xenopus oocytes. Responses were measured prior and subsequent to the application of the sulfhydryl reagent methanethiosulfonate ethylammonium (MTSEA). One mutant (C116S) served as a Cys-null control, and the additional mutants were made in the C116S background. In many cases, the insertion of free cysteines into the agonist-binding site had a negative effect on function, with 12 of 44 mutants showing no detectable responses to ACh, and with only 19 of the 44 mutants showing sufficiently large responses to permit further study. Several of the cysteine mutations, including W55C, showed selectively reduced responses to the largest agonist tested, 2-methoxy,4-hydroxy-benzylidene anabaseine. Interestingly, although homology models suggest that most of ...Continue Reading

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Citations

Mar 30, 2011·The Journal of General Physiology·Dustin K WilliamsRoger L Papke
Nov 5, 2011·Critical Reviews in Toxicology·Alessio CardinalePatrizia Russo
Feb 16, 2017·British Journal of Pharmacology·Jingyi Wang, Jon Lindstrom
May 10, 2017·British Journal of Pharmacology·Roger L PapkeNicole A Horenstein
Jul 25, 2014·The Journal of Biological Chemistry·Ying WangHenry A Lester
Oct 1, 2015·Pharmacological Reviews·Daniel BertrandDiana Donnelly-Roberts
Apr 15, 2015·The Journal of Biological Chemistry·Jingyi WangJon Lindstrom

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