Hyperekplexia mutation of glycine receptors: Decreased gating efficacy with altered binding thermodynamics

Gábor Maksay, Tímea Bíró, Bodo Laube

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Abstract

[3H]Strychnine binding was studied to recombinant human α1 and the hyperekplexia mutant α1R271L glycine receptors (GlyRs) transiently expressed in human embryonic kidney (HEK)-293 cell cultures at 0, 18 and 37°. The α1R271L mutation did not affect the linear van't Hoff plots of the exothermic binding of the antagonist [3H]strychnine while it turned taurine into an antagonist with exothermic binding. The inhibition constants of the agonist glycine showed opposite temperature dependence on α1 GlyRs, corresponding to endothermic binding driven by large entropic increases. The temperature dependence of displacement by the partial agonists taurine on α1 GlyRs and glycine on α1R271L GlyRs was biphasic reflecting negative heat capacity changes, dehydration changes and/or a complex binding mechanism. The thermodynamic discrimination of efficacy is valid for native rat spinal and recombinant human GlyRs. The α1R271L mutation impairs the transduction mechanism and distorts gating of GlyRs. Thereby it reduces the potency and efficacy of agonists and affects their thermodynamic parameters of binding. The hyperekplexia mutation offers a model system to demonstrate the correlation among pathophysiology, gating efficacy and binding thermodynamics of GlyRs.

Original languageEnglish
Pages (from-to)285-288
Number of pages4
JournalBiochemical Pharmacology
Volume64
Issue number2
DOIs
Publication statusPublished - Jul 15 2002

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Keywords

  • Hyperekplexia mutation
  • Partial agonists
  • Recombinant glycine receptors
  • Strychnine
  • Taurine
  • Thermodynamics of binding

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology

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