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    Diversity of nicotinic acetylcholine receptor positive allosteric modulators revealed by mutagenesis and a revised structural model

    Newcombe, J. and Chatzidaki, A. and Sheppard, T.D. and Topf, Maya and Millar, N.S. (2017) Diversity of nicotinic acetylcholine receptor positive allosteric modulators revealed by mutagenesis and a revised structural model. Molecular Pharmacology 93 (2), pp. 128-140. ISSN 0026-895X.

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    By combining electrophysiological and computational approaches we have examined a series of positive allosteric modulators (PAMs) acting on the human α7 nicotinic acetylcholine receptor (nAChR). Electrophysiological studies have focussed on three α7-selective PAMs (A-867744, TBS-516 and TQS) that display similar effects on wild-type α7 nAChRs. In addition to potentiating agonist-evoked responses, all three compounds reduce receptor desensitisation and, consequently, are classed as type II PAMs. Despite having similar effects on wild-type receptors, A-867744 was found to have profoundly differing effects to TBS-516 and TQS on mutated receptors, a finding that is consistent with previous studies indicating that A-867744 may have a different mechanism of action to other α7-selective type II PAMs. Due to evidence that these PAMs bind within the α7 nAChR transmembrane region, we generated and validated new structural models of α7. Importantly, we have corrected a previously identified error in the transmembrane region of the original cryo-EM Torpedo model; the only pentameric ligand-gated ion channel imaged in a native lipid membrane. Real-space refinement was used to generate closed and open conformations on which the α7 models were based. Consensus docking with an extended series of PAMs with chemical similarity to A-867744, TBS-516 and TQS suggests that all bind to a broadly similar inter-subunit transmembrane site. However, differences in the predicted binding of A-867744, compared with TBS-516 and TQS, may help to explain the distinct functional effects of A-867744. Thus, our revised structural models may provide a useful tool for interpreting functional effects of PAMs.


    Item Type: Article
    Keyword(s) / Subject(s): Acetylcholine receptors, Ion channels, Ligand-gated ion channels, Nicotinic cholinergic receptors, Receptor structure
    School: School of Science > Biological Sciences
    Depositing User: Administrator
    Date Deposited: 14 Dec 2017 15:27
    Last Modified: 12 Jun 2021 01:23


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