title: Comparative pharmacology and computational modelling yield insights into allosteric modulation of human alpha7 nicotinic acetylcholine receptors.
abstract: The human alpha7 nicotinic acetylcholine receptor (nAChR) subunit and its Caenorhabditis elegans homolog, ACR-16, can generate functional recombinant homomeric receptors when expressed in Xenopus laevis oocytes. Both nAChRs express robustly in the presence of the co-injected chaperone, RIC-3, and show striking differences in the actions of a type I positive allosteric modulator (PAM), ivermectin (IVM). Type I PAMs are characterised by an increase in amplitude only of the response to acetylcholine (ACh), whereas type II PAMs exhibit, in addition, changes in time-course/desensitization of the ACh response. The type I PAMs, ivermectin, 5-hydroxyindole (5-HI), NS-1738 and genistein and the type II PAM, PNU-120596, are all active on human alpha7 but are without PAM activity on ACR-16, where they attenuate the amplitude of the ACh response. We used the published structure of avermectin B1a to generate a model of IVM, which was then docked into the candidate transmembrane allosteric binding site on alpha7 and ACR-16 in an attempt to gain insights into the observed differences in IVM actions. The new pharmacological findings and computational approaches being developed may inform the design of novel PAM drugs targeting major neurological disorders.
authors: MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3QX, UK. david.sattelle@dpag.ox.ac.uk
authors: David B
authors: DB
authors: Sattelle
authors: Steven D
authors: SD
authors: Buckingham
authors: Miki
authors: M
authors: Akamatsu
authors: Kazuhiko
authors: K
authors: Matsuda
authors: Ilse S
authors: IS
authors: Pienaar
authors: Ilse
authors: I
authors: Pienaar
authors: Andrew K
authors: AK
authors: Jones
authors: Benedict M
authors: BM
authors: Sattelle
authors: Andrew
authors: A
authors: Almond
authors: Charles D
authors: CD
authors: Blundell
mesh_terms: D000494:Allosteric Regulation; D000495:Allosteric Site; D000595:Amino Acid Sequence; D000818:Animals; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000502:physiology; D003198:Computer Simulation; D005260:Female; D019833:Genistein / Q000494:pharmacology; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology; D007559:Ivermectin / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009865:Oocytes / Q000502:physiology; D018408:Patch-Clamp Techniques; D010671:Phenylurea Compounds / Q000494:pharmacology; D011978:Receptors, Nicotinic / Q000737:chemistry* / Q000235:genetics / Q000502:physiology*; D017386:Sequence Homology, Amino Acid; D014982:Xenopus laevis; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: C508388:1-(5-chloro-2,4-dimethoxyphenyl)-3-(5-methylisoxazol-3-yl)urea; C523981:1-(5-chloro-2-hydroxyphenyl)-3-(2-chloro-5-trifluoromethylphenyl)urea; D029742:Caenorhabditis elegans Proteins; C579167:Chrna7 protein, human; D007555:Isoxazoles; D010671:Phenylurea Compounds; D011978:Receptors, Nicotinic; C099378:acr-16 protein, C elegans; D064569:alpha7 Nicotinic Acetylcholine Receptor; D007559:Ivermectin; D019833:Genistein