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

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 GABAA 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.