Monod-Wyman-Changeux allosteric mechanisms of action and the pharmacology of etomidate.

Formal Monod-Wyman-Changeux allosteric mechanisms have proven valuable in framing research on the mechanism of etomidate action on its major molecular targets, γ-aminobutyric acid type A (GABAA) receptors. However, the mathematical formalism of these mechanisms makes them difficult to comprehend. We illustrate how allosteric models represent shifting equilibria between various functional receptor states (closed versus open) and how co-agonism can be readily understood as simply addition of gating energy associated with occupation of distinct agonist sites. We use these models to illustrate how the functional effects of a point mutation, α1M236W, in GABAA receptors can be translated into an allosteric model phenotype. Allosteric co-agonism provides a robust framework for design and interpretation of structure-function experiments aimed at understanding where and how etomidate affects its GABAA receptor target molecules.