Dual cooperative allosteric modulation of binding to ionotropic glycine receptors

Gábor Maksay, Tímea Bíró

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Glycine receptors (GlyRs) were studied via [3H]strychnine binding to synaptosomal membranes of rat spinal cord. A ternary allosteric model was applied for the effects of tropeines, alcohols, minaxolone, nitrendipine, Zn2+, muscarinic and serotonin receptor ligands. It enabled us to determine the dissociation constants of the allosteric agents (KA) and their cooperativity factors affecting the dissociation constants of [3H]strychnine (αKS) and glycine (βKL). Cooperativity with [3H]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 μM Zn2+. Micromolar concentrations of tropisetron and nitrendipine showed weaker cooperativities. Other allosteric agents and 1 mM Zn2+ displayed negative cooperativity with glycine. Binding parameters KA and β 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.

Original languageEnglish
Pages (from-to)1087-1098
Number of pages12
JournalNeuropharmacology
Volume43
Issue number7
DOIs
Publication statusPublished - Dec 2002

Keywords

  • Glycine receptor-ionophore
  • Mianserin
  • Minaxolone
  • Nitrendipine
  • Propofol
  • Ternary allosteric model
  • Tropeines
  • [H]strychnine binding

ASJC Scopus subject areas

  • Pharmacology
  • Cellular and Molecular Neuroscience

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