title: Dual cooperative allosteric modulation of binding to ionotropic glycine receptors.
abstract: Glycine receptors (GlyRs) were studied via [(3)H]strychnine binding to synaptosomal membranes of rat spinal cord. A ternary allosteric model was applied for the effects of tropeines, alcohols, minaxolone, nitrendipine, Zn(2+), muscarinic and serotonin receptor ligands. It enabled us to determine the dissociation constants of the allosteric agents (K(A)) and their cooperativity factors affecting the dissociation constants of [(3)H]strychnine (alphaK(S)) and glycine (betaK(L)). Cooperativity with [(3)H]strychnine ranged from strong negative for tropeines to weak positive for nitrendipine. Displacement curves of glycine were examined in the presence of allosteric agents. Positive cooperativities with glycine were found for submicromolar concentrations of tropisetron, bemesetron, zatosetron and nitrendipine; for tubocurarine, propofol, butanol, minaxolone, cocaine and 10 microM Zn(2+). Micromolar concentrations of tropisetron and nitrendipine showed weaker cooperativities. Other allosteric agents and 1 mM Zn(2+) displayed negative cooperativity with glycine. Binding parameters K(A) and beta correlate excellently with the activities of the allosteric agents on GlyR-ionophores. Combined inhibitory effects of the allosteric agents suggest that there are different subgroups (tropeines, alcohols and dihydropyridines) binding to distinct sites on GlyRs exerting cooperativity with glycine via a common mechanism. This is the first quantitative analysis of allosteric binding interactions for GlyRs.
authors.affiliation: Department of Molecular Pharmacology, Chemical Research Center, Hungarian Academy of Sciences, POB 17, H-1525, Budapest, Hungary. maksay@chemres.hu
authors.forename: Gábor
authors.initials: G
authors.lastname: Maksay
authors.forename: Tímea
authors.initials: T
authors.lastname: Bíró
mesh_terms: D000494:Allosteric Regulation / Q000502:physiology; D000818:Animals; D001665:Binding Sites / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D005998:Glycine / Q000737:chemistry / Q000378:metabolism; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D018009:Receptors, Glycine / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013116:Spinal Cord / Q000378:metabolism; D013331:Strychnine / Q000737:chemistry / Q000378:metabolism
chemical_list: D018009:Receptors, Glycine; D013331:Strychnine; D005998:Glycine