Center for Molecular Recognition and Departments of Psychiatry and Pharmacology, College of Physicians and Surgeons, Columbia University, New York, New York, USA.
Nat Chem Biol. 2011 Jul 24;7(9):624-30. doi: 10.1038/nchembio.623.
Here we present a new method that combines protein complementation with resonance energy transfer to study conformational changes in response to activation of a defined G protein-coupled receptor heteromer, and we apply the approach to the putative dopamine D1-D2 receptor heteromer. Remarkably, the potency of the D2 dopamine receptor (D2R) agonist R-(-)-10,11-dihydroxy-N-n-propylnoraporphine (NPA) to change the Gα(i) conformation via the D2R protomer in the D1-D2 heteromer was enhanced ten-fold relative to its potency in the D2R homomer. In contrast, the potencies of the D2R agonists dopamine and quinpirole were the same in the homomer and heteromer. Thus, we have uncovered a molecular mechanism for functional selectivity in which a drug acts differently at a G protein-coupled receptor (GPCR) protomer depending on the identity of the second protomer participating in the formation of the signaling unit--opening the door to enhancing pharmacological specificity by targeting differences between homomeric and heteromeric signaling.
在这里，我们提出了一种新的方法，将蛋白质互补与共振能量转移相结合，研究在激活特定的 G 蛋白偶联受体异源二聚体时的构象变化，我们将该方法应用于假定的多巴胺 D1-D2 受体异源二聚体。值得注意的是，D2 多巴胺受体（D2R）激动剂 R-(-)-10,11-二羟基-N-正丙基-N-去甲阿朴啡（NPA）通过 D1-D2 异源二聚体中的 D2R 单体改变 Gα(i)构象的效力相对于其在 D2R 同源二聚体中的效力增强了十倍。相比之下，D2R 激动剂多巴胺和喹吡罗在同源二聚体和异源二聚体中的效力相同。因此，我们已经发现了一种功能选择性的分子机制，其中一种药物在 G 蛋白偶联受体（GPCR）单体上的作用取决于参与形成信号单元的第二个单体的身份不同——通过针对同源和异源信号之间的差异来提高药理学特异性，从而为这种作用提供了可能性。
