Allosteric communication between protomers of dopamine class A GPCR dimers modulates activation.
Allosteric communication between protomers of dopamine class A GPCR dimers modulates activation.
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DOI：
10.1038/nchembio.199
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发表时间：
2009-09
影响因子：
14.8
通讯作者：
Javitch, Jonathan A.
中科院分区：
文献类型：
--
作者：
Han, Yang;Moreira, Irina S.;Urizar, Eneko;Weinstein, Harel;Javitch, Jonathan A.
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.
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