期刊
NATURE CHEMICAL BIOLOGY
卷 5, 期 9, 页码 688-695出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nchembio.199
关键词
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资金
- US National Institutes of Health [DA022413, MH054137, DA012923]
- Lieber Center
- European Molecular Biology Organization
- David A. Cofrin Center for Biomedical Information (Institute for Computational Biomedicine, Weill Cornell Medical College of Cornell University)
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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