A Monod-Wyman-Changeux mechanism can explain G protein-coupled receptor (GPCR) allosteric modulation

J Biol Chem. 2012 Jan 2;287(1):650-659. doi: 10.1074/jbc.M111.314278. Epub 2011 Nov 15.

Abstract

The Monod-Wyman-Changeux (MWC) model was initially proposed to describe the allosteric properties of regulatory enzymes and subsequently extended to receptors. Yet despite GPCRs representing the largest family of receptors and drug targets, no study has systematically evaluated the MWC mechanism as it applies to GPCR allosteric ligands. We reveal how the recently described allosteric modulator, benzyl quinolone carboxylic acid (BQCA), behaves according to a strict, two-state MWC mechanism at the M1 muscarinic acetylcholine receptor (mAChR). Despite having a low affinity for the M1 mAChR, BQCA demonstrated state dependence, exhibiting high positive cooperativity with orthosteric agonists in a manner that correlated with efficacy but negative cooperativity with inverse agonists. The activity of BQCA was significantly increased at a constitutively active M1 mAChR but abolished at an inactive mutant. Interestingly, BQCA possessed intrinsic signaling efficacy, ranging from near-quiescence to full agonism depending on the coupling efficiency of the chosen intracellular pathway. This latter cellular property also determined the difference in magnitude of positive cooperativity between BQCA and the orthosteric agonist, carbachol, across pathways. The lack of additional, pathway-biased, allosteric modulation by BQCA was confirmed in genetically engineered yeast strains expressing different chimeras between the endogenous yeast G(pa1) protein and human Gα subunits. These findings define a chemical biological framework that can be applied to the study and classification of allosteric modulators across different GPCR families.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholine / metabolism
  • Allosteric Regulation / drug effects
  • Animals
  • CHO Cells
  • Cricetinae
  • Cricetulus
  • Drug Inverse Agonism
  • Humans
  • Ligands
  • Models, Biological*
  • Mutation
  • Quinolones / chemistry
  • Quinolones / metabolism
  • Quinolones / pharmacology
  • Receptor, Muscarinic M1 / agonists
  • Receptor, Muscarinic M1 / antagonists & inhibitors
  • Receptor, Muscarinic M1 / genetics
  • Receptor, Muscarinic M1 / metabolism*
  • Signal Transduction / drug effects

Substances

  • Ligands
  • Quinolones
  • Receptor, Muscarinic M1
  • Acetylcholine