Movement of 'gating charge' is coupled to ligand binding in a G-protein-coupled receptor

Nature. 2006 Nov 2;444(7115):106-9. doi: 10.1038/nature05259. Epub 2006 Oct 25.


Activation by agonist binding of G-protein-coupled receptors (GPCRs) controls most signal transduction processes. Although these receptors span the cell membrane, they are not considered to be voltage sensitive. Recently it was shown that both the activity of GPCRs and their affinity towards agonists are regulated by membrane potential. However, it remains unclear whether GPCRs intrinsically respond to changes in membrane potential. Here we show that two prototypical GPCRs, the m2 and m1 muscarinic receptors (m2R and m1R), display charge-movement-associated currents analogous to 'gating currents' of voltage-gated channels. The gating charge-voltage relationship of m2R correlates well with the voltage dependence of the affinity of the receptor for acetylcholine. The loop that couples m2R and m1R to their G protein has a crucial function in coupling voltage sensing to agonist-binding affinity. Our data strongly indicate that GPCRs serve as sensors for both transmembrane potential and external chemical signals.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholine / metabolism
  • Animals
  • Electric Conductivity
  • Ion Channel Gating
  • Ligands
  • Membrane Potentials / physiology
  • Movement
  • Mutant Proteins / agonists
  • Mutant Proteins / genetics
  • Mutant Proteins / metabolism
  • Mutation / genetics
  • Oocytes / metabolism
  • Protein Binding
  • Receptor, Muscarinic M1 / agonists
  • Receptor, Muscarinic M1 / genetics
  • Receptor, Muscarinic M1 / metabolism
  • Receptor, Muscarinic M2 / agonists
  • Receptor, Muscarinic M2 / genetics
  • Receptor, Muscarinic M2 / metabolism
  • Receptors, G-Protein-Coupled / agonists
  • Receptors, G-Protein-Coupled / chemistry
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism*
  • Signal Transduction
  • Xenopus


  • Ligands
  • Mutant Proteins
  • Receptor, Muscarinic M1
  • Receptor, Muscarinic M2
  • Receptors, G-Protein-Coupled
  • Acetylcholine