Monod-Wyman-Changeux Allosteric Mechanisms of Action and the Pharmacology of Etomidate

Curr Opin Anaesthesiol. 2012 Aug;25(4):411-8. doi: 10.1097/ACO.0b013e328354feea.

Abstract

Purpose of review: 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.

Recent findings: 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.

Summary: 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Allosteric Regulation
  • Anesthetics, Intravenous / pharmacology*
  • Animals
  • Etomidate / pharmacology*
  • GABA Agonists / pharmacology
  • Humans
  • Models, Biological
  • Mutation
  • Receptors, GABA-A / chemistry
  • Receptors, GABA-A / drug effects*
  • Structure-Activity Relationship

Substances

  • Anesthetics, Intravenous
  • GABA Agonists
  • Receptors, GABA-A
  • Etomidate