Equilibrium and kinetic allosteric mechanisms for anesthetic and structure function studies of GABA_A receptors

摘要

GABAA receptors and related ligand-gated channels are allosteric proteins. Agonism of these channels has been described using classical Monod-Wyman-Changeux (MWC) models that couple ligand binding to the fundamental two-state (closed-open) equilibrium. A highly constrained MWC co-agonist model can also explain etomidate actions on GABA_A receptors, both in the absence and in presence of GABA. Importantly, this model provides mechanistic insight into etomidate binding and efficacy, and a strategy for interpreting the effects of structural alterations in the protein or ligand. Expanding MWC models to three fundamental states (closed-open-desensitized) and incorporating rate-constants and several empiric constraints allows simulation of receptor kinetic behavior. This model has been used to gain insight into anesthetic actions and several pore-domain mutations that alter macrocurrent kinetics.