Molecular determinants of A2AR-D2R allosterism: role of the intracellular loop 3 of the D2R
Molecular determinants of A2AR-D2R allosterism: role of the intracellular loop 3 of the D2R
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DOI：
10.1111/j.1471-4159.2012.07956.x
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发表时间：
2012-11-01
影响因子：
4.7
通讯作者：
Ciruela, Francisco
中科院分区：
文献类型：
--
作者：
Fernandez-Duenas, Victor;Gomez-Soler, Maricel;Ciruela, Francisco
在CNS中，已经显示腺苷A2 A和多巴胺D2受体（A2 AR和D2 R）之间的拮抗相互作用，其可能与正常和病理状况（即，帕金森氏病）。因此，介导这种受体-受体相互作用的分子决定簇最近已被探索，因为该靶点（即A2 AR/D2 R寡聚体）的微调可能改善某些CNS疾病的治疗。在这里，我们使用了荧光共振能量转移为基础的方法来检查的变构调制的D2 R内的A2 AR/D2 R寡聚体和依赖性的受体受体相互作用的两个地区丰富的正电荷的细胞内环3的D2 R。有趣的是，我们观察到D2 R激动剂喹吡罗对A2 AR配体结合和活化的负变构效应。然而，这些变构效应被废除后，特定的精氨酸残基（217222和267269）的D2 R细胞内环3突变，从而证明了这些带正电荷的残基介导所观察到的receptorreceptor相互作用的主要作用。总的来说，这些结果提供了结构上的见解，以更好地了解A2 AR/D2 R寡聚体在活细胞中的功能。
In the CNS, an antagonistic interaction has been shown between adenosine A2A and dopamine D2 receptors (A2ARs and D2Rs) that may be relevant both in normal and pathological conditions (i.e., Parkinson's disease). Thus, the molecular determinants mediating this receptorreceptor interaction have recently been explored, as the fine tuning of this target (namely the A2AR/D2R oligomer) could possibly improve the treatment of certain CNS diseases. Here, we used a fluorescence resonance energy transfer-based approach to examine the allosteric modulation of the D2R within the A2AR/D2R oligomer and the dependence of this receptorreceptor interaction on two regions rich in positive charges on intracellular loop 3 of the D2R. Interestingly, we observed a negative allosteric effect of the D2R agonist quinpirole on A2AR ligand binding and activation. However, these allosteric effects were abolished upon mutation of specific arginine residues (217222 and 267269) on intracellular loop 3 of the D2R, thus demonstrating a major role of these positively charged residues in mediating the observed receptorreceptor interaction. Overall, these results provide structural insights to better understand the functioning of the A2AR/D2R oligomer in living cells.