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

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

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Center for Molecular Recognition, Columbia University College of Physicians and Surgeons, New York, NY, USA.


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.

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