D1-D2 dopamine receptor heterooligomers with unique pharmacology are coupled to rapid activation of Gq/11 in the striatum
D1-D2 dopamine receptor heterooligomers with unique pharmacology are coupled to rapid activation of Gq/11 in the striatum
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DOI：
10.1073/pnas.0604049104
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发表时间：
2007-01-09
影响因子：
11.1
通讯作者：
George, Susan R.
中科院分区：
文献类型：
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作者：
Rashid, Asim J.;So, Christopher H.;George, Susan R.
我们证明了在大脑中存在一个与G(Q)/11偶联的异构体D1-D2多巴胺受体信号复合体，它需要激动剂与这两个受体结合才能激活G蛋白和细胞内钙释放。D_1激动剂SKF83959被鉴定为激活G(Q)/11的异构体的特异性激动剂，其作用是作为D_1受体的完全激动剂和高亲和力的抗百日咳毒素的D_2受体的部分激动剂。我们提供的证据表明，与3个月大的动物相比，8个月大的小鼠更容易检测到d1-d2信号复合体，这表明通过d1-d2多巴胺受体复合体的钙信号与青春期后大脑的功能有关。通过异构体激活G(Q)/11可以增加伏隔核内钙/钙调素依赖的蛋白激酶IIα的水平，这与激活G(S)/OF偶联的D1受体不同，这表明了D1-D2多巴胺受体复合体可能有助于突触可塑性的机制。
We demonstrate a heteromeric D1-D2 dopamine receptor signaling complex in brain that is coupled to G(q)/11 and requires agonist binding to both receptors for G protein activation and intracellular calcium release. The D1 agonist SKF83959 was identified as a specific agonist for the heteromer that activated G(q)/11 by functioning as a full agonist for the D1 receptor and a high-affinity partial agonist for a pertussis toxin-resistant D2 receptor within the complex. We provide evidence that the D1-D2 signaling complex can be more readily detected in mice that are 8 months in age compared with animals that are 3 months old, suggesting that calcium signaling through the D1-D2 dopamine receptor complex is relevant for function in the postadolescent brain. Activation of G(q)/11 through the heteromer increases levels of calcium/calmodulin-dependent protein kinase II alpha in the nucleus accumbens, unlike activation of G(s)/olf-coupled D1 receptors, indicating a mechanism by which D1-D2 dopamine receptor complexes may contribute to synaptic plasticity.