FROM KINETICS AND THERMODYNAMICS OF GABA A RECEPTOR BINDING TO IONOPHORE FUNCTION

Abstract

The time- and temperature-dependencies of binding are overviewed for the benzodiazepine, GABA and convulsant binding sites of the GABA A receptor-ionophore complex. Kinetic separation of the dissociation phases of a ≌-carboline inverse agonist demonstrated the heterogeneity of its binding sites. The kinetics and thermodynamics of benzodiazepine binding alone do not correlate with ionophore function. The majority of the data suggest that agonist- and antagonist-preferring conformation exist for GABA A receptors. The high affinity binding of GABA A antagonists (SR 95531 and bicuculline) corresponds to the (super) low affinity binding of GABA. The correlation between the thermodynamic parameters of binding and efficacies common for GABA A and glycine receptor agonists and antagonists supports the functional similarities of these anionophore complexes. Binding kinetics of the bicyclic cage convulsants show several correlations with ionophore function because the convulsant sites are most intimately coupled to the ion channels. Kinetic interactions of the convulsant sites with the binding sites of benzodiazepines, GABA and central depressants have revealed several pharmacologically relevant allosteric GABAergic modulatory effects. Arrhenius analysis, Hammond's postulate and transition state theory were applied for the dissociation of convulsants. A kinetic model of interconvertible multiaffinity states of the convulsant sites shows correlations with the functional states of the GABA A ionophore. Copyright © 1996 Elsevier Science Ltd.