Activation of ionotropic receptors and thermodynamics of binding

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The structure, thermodynamics and activation mechanism of Cys-loop ionotropic receptors such as glycine, nicotinic acetylcholine, 5-HT 3-type serotonin and A-type γ-aminobutyric acid receptors are discussed. Based on the interrelationship of receptor binding and ionophore function, a ternary displacement mechanism of binding including the activation of ionophores is outlined. This displacement model can explain the enigmatic thermodynamic discrimination of agonists versus antagonists of Cys-loop ionotropic receptors. Binding of both agonists and antagonists is exothermic while activation is endothermic driven by large increases in entropy. Closure of the binding cavities around agonists in concert with subunit rotations and/or removal of water-filled crevices between transmembrane (TM) regions can account for entropy increases. Recombinant glycine and γ-aminobutyric acid A receptors and their point mutations support the predominant role of entropy in receptor activation.

Original languageEnglish
Pages (from-to)281-291
Number of pages11
JournalNeurochemistry international
Issue number4
Publication statusPublished - Mar 2005


  • Cys-loop ionotropic receptors
  • Mechanism of receptor activation
  • Point mutations
  • Recombinant receptors
  • Ternary mechanism of binding displacement
  • Thermodynamic discrimination

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Cell Biology

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