Allosteric communication between protomers of dopamine class A GPCR dimers modulates activation.
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.
Han
Yang
Y
Center for Molecular Recognition, Columbia University College of Physicians and Surgeons, New York, NY, USA.
Moreira
Irina S
IS
Urizar
Eneko
E
Weinstein
Harel
H
Javitch
Jonathan A
JA
D000494:Allosteric Regulation; D002460:Cell Line; D019295:Computational Biology; D065127:Dopamine D2 Receptor Antagonists; D019204:GTP-Binding Proteins / Q000378:metabolism; D006801:Humans; D008954:Models, Biological; D008958:Models, Molecular; D011401:Promoter Regions, Genetic; D055503:Protein Multimerization; D019257:Quinpirole / Q000494:pharmacology; D017448:Receptors, Dopamine D2 / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
D065127:Dopamine D2 Receptor Antagonists; D017448:Receptors, Dopamine D2; D043562:Receptors, G-Protein-Coupled; D019257:Quinpirole; D019204:GTP-Binding Proteins