title: A single residue contributes sensitivity to allosteric modulation of AMPA receptors by LY395153.
abstract: Previous studies have shown that a single point mutation (S(750)Q) in the splice variant region of rat Glu(1) subunits can eliminate positive allosteric modulation by cyclothiazide. The present study investigated the effects of mutating the equivalent residue (S(776)Q) in the human Glu(4) subunit on the activity and binding of a novel AMPA receptor potentiator, LY395153 (N-2-(4-benzamidophenylpropyl-2-propanesulfonamide)). The mutation markedly attenuated, but did not eliminate, potentiation by LY395153 and cyclothiazide. In addition, binding of [3H]LY395153 was significantly reduced by this mutation. These effects occurred in the absence of any change in the response to glutamate or the binding of a competitive AMPA receptor antagonist, [3H]Ro 48-8587 ([2,4,5-3H]9-imidazol-1-yl-8-nitro-2,3,5,6-tetrahydro[1,2,4]-triazolo[1,5-c]quinazoline-2,5-dione triethylammonium salt). Collectively, these results demonstrate that structurally diverse classes of potentiators are sensitive to mutations of this single Ser residue, suggesting that binding to this residue may be necessary for positive allosteric modulation of AMPA receptors.
authors.affiliation: Neuroscience Division, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285-0510, USA.
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Quirk
authors.forename: Anni-Maija
authors.initials: AM
authors.lastname: Linden
authors.forename: Marina
authors.initials: M
authors.lastname: Strakhova
authors.forename: Hong
authors.initials: H
authors.lastname: Yu
authors.forename: Phil
authors.initials: P
authors.lastname: Skolnick
authors.forename: Eric S
authors.initials: ES
authors.lastname: Nisenbaum
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects / Q000502:physiology; D001549:Benzamides / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D006801:Humans; D017354:Point Mutation / Q000187:drug effects / Q000502:physiology*; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D018091:Receptors, AMPA / Q000819:agonists / Q000235:genetics* / Q000378:metabolism*; D013449:Sulfonamides / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D001549:Benzamides; C434044:N-2-(4-benzamidophenylpropyl-2-propanesulfonamide); D018091:Receptors, AMPA; D013449:Sulfonamides