Isoform-specific uncoupling of the D2 dopamine receptors subtypes.
Isoform-specific uncoupling of the D2 dopamine receptors subtypes.
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D2 多巴胺受体亚型的异构体特异性解偶联。
DOI：
10.1016/j.neuropharm.2010.09.018
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发表时间：
2011
影响因子：
4.7
通讯作者：
Senogles,SusanE
中科院分区：
文献类型：
--
作者：
Kendall,RyanT;Senogles,SusanE
多巴胺能传递是许多临床感兴趣的神经通路的基础。我们分析了d2多巴胺受体的选择性剪接异构体，D2long （D2l）和D2short (D2s)，它们的区别只是在第三细胞质环中插入了29个氨基酸。众所周知，GPCR信号转导的决定因素——第三个细胞内环区——与野生型受体共同表达，以测试它们拮抗亲本受体功能的能力。我们发现D2l介导的对福斯克林刺激的腺苷酸环化酶的抑制被D2l细胞质第三环的共同表达所阻断。然而，d2s3细胞质环的表达并不抑制d2l介导的信号转导。相反，d23rd细胞质环的表达可以拮抗d2s受体的功能，而d23rd细胞质环则没有。相反，当与任一野生型受体异构体共表达时，交替剪接插入区域的表达没有影响。这些结果表明，每个受体的第三细胞质环具有独特的构象，并且插入区域的初级序列不是D2l和D2l之间信号传导差异的基础。这些发现进一步支持了先前的研究，表明D2受体同种异构体使用不同的信号转导机制。
Dopaminergic transmission is fundamental to many neural pathways of clinical interest. We have analyzed the alternatively-spliced isoforms of the D2dopamine receptor, D2long (D2l) and D2short (D2s), which differ only by a 29-amino acid insertion in the third cytoplasmic loop. Well-known determinants for GPCR signal transduction—the third intracellular loop regions—were co-expressed with the wild-type receptors to test for their ability to antagonize parent receptor function. We found that the D2l-mediated inhibition of forskolin-stimulated adenylyl cyclase was blocked by the co-expression of the third cytoplasmic loop of D2l. However, expression of the third cytoplasmic loop of D2sdid not inhibit D2l-mediated signal transduction. Conversely, expression of the D2sthird cytoplasmic loop antagonized the D2sreceptor’s function and the D2lthird cytoplasmic loop did not. In contrast, expression of the alternatively-spliced insert region had no effect when co-expressed with either wild-type receptor isoform. These results suggest that the third cytoplasmic loops of each receptor adopt unique conformations and that the primary sequence of the insert region is not the basis for differences in signaling between D2sand D2l. These findings further support previous studies suggesting that the D2 receptor isoforms use distinct signal transduction mechanisms.