Allosteric communication between protomers of dopamine class A GPCR dimers modulates activation

Nat Chem Biol. 2009 Sep;5(9):688-95. doi: 10.1038/nchembio.199. Epub 2009 Aug 2.


A major obstacle to understanding the functional importance of dimerization between class A G protein-coupled receptors (GPCRs) has been the methodological limitation in achieving control of the identity of the components comprising the signaling unit. We have developed a functional complementation assay that enables such control, and we demonstrate it here for the human dopamine D2 receptor. The minimal signaling unit, two receptors and a single G protein, is maximally activated by agonist binding to a single protomer, which suggests an asymmetrical activated dimer. Inverse agonist binding to the second protomer enhances signaling, whereas agonist binding to the second protomer blunts signaling. Ligand-independent constitutive activation of the second protomer also inhibits signaling. Thus, GPCR dimer function can be modulated by the activity state of the second protomer, which for a heterodimer may be altered in pathological states. Our new methodology also makes possible the characterization of signaling from a defined heterodimer unit.

Publication types

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

MeSH terms

  • Allosteric Regulation
  • Cell Line
  • Computational Biology
  • Dopamine D2 Receptor Antagonists
  • GTP-Binding Proteins / metabolism
  • Humans
  • Models, Biological
  • Models, Molecular
  • Promoter Regions, Genetic*
  • Protein Multimerization
  • Quinpirole / pharmacology
  • Receptors, Dopamine D2 / genetics
  • Receptors, Dopamine D2 / metabolism
  • Receptors, G-Protein-Coupled / antagonists & inhibitors
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism*
  • Signal Transduction* / drug effects


  • Dopamine D2 Receptor Antagonists
  • Receptors, Dopamine D2
  • Receptors, G-Protein-Coupled
  • Quinpirole
  • GTP-Binding Proteins

Associated data

  • PubChem-Substance/84970648
  • PubChem-Substance/84970649
  • PubChem-Substance/84970650
  • PubChem-Substance/84970651
  • PubChem-Substance/84970652
  • PubChem-Substance/84970653
  • PubChem-Substance/84970654
  • PubChem-Substance/84970655
  • PubChem-Substance/84970656