Activation of G protein-coupled receptors: beyond two-state models and tertiary conformational changes

Annu Rev Pharmacol Toxicol. 2008;48:107-41. doi: 10.1146/annurev.pharmtox.48.113006.094630.


Transformation of G protein-coupled receptors (GPCRs) from a quiescent to an active state initiates signal transduction. All GPCRs share a common architecture comprising seven transmembrane-spanning alpha-helices, which accommodates signal propagation from a diverse repertoire of external stimuli across biological membranes to a heterotrimeric G protein. Signal propagation through the transmembrane helices likely involves mechanistic features common to all GPCRs. The structure of the light receptor rhodopsin may serve as a prototype for the transmembrane architecture of GPCRs. Early biochemical, biophysical, and pharmacological studies led to the conceptualization of receptor activation based on the context of two-state equilibrium models and conformational changes in protein structure. More recent studies indicate a need to move beyond these classical paradigms and to consider additional aspects of the molecular character of GPCRs, such as the oligomerization and dynamics of the receptor.

Publication types

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

MeSH terms

  • Binding Sites
  • Humans
  • Ligands
  • Models, Molecular*
  • Molecular Structure
  • Protein Structure, Tertiary*
  • Receptors, G-Protein-Coupled / metabolism*
  • Rhodopsin / metabolism
  • Signal Transduction


  • Ligands
  • Receptors, G-Protein-Coupled
  • Rhodopsin