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 illustrate it 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 novel methodology also makes possible the characterization of signaling from a defined heterodimer unit.

• Publication year

  2009

• Venue

  Nature Chemical Biology

• Publication date

  2009-05-13

• Fields of study

  Biology, Medicine, Chemistry

• Identifiers
  DOI 10.1038/nchembio.199PMID 19648932PMCID 2817978
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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