The intra-molecular activation mechanisms of the dimeric metabotropic glutamate receptor 1 differ depending on the type of G proteins
The intra-molecular activation mechanisms of the dimeric metabotropic glutamate receptor 1 differ depending on the type of G proteins
复制标题
二聚体代谢型谷氨酸受体1的分子内激活机制根据G蛋白的类型而不同
DOI：
10.1016/j.neuropharm.2011.05.031
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发表时间：
2011
期刊：
影响因子：
--
通讯作者：
Y
中科院分区：
文献类型：
--
作者：
Tateyama;M.;Kubo;Y
代谢型谷氨酸受体1（mGlu 1）作为同型二聚体发挥功能，不仅激活Gq，而且激活Gi/o和Gs通路。由于二聚体构型，不同的途径可以通过谷氨酸结合的亚基（顺式激活）和/或另一个（反式激活）被激活。我们在这里检查是否在mGlu 1的分子内激活机制不同，这取决于耦合G蛋白的类型，使用各种组合的mGlu 1结构，缺乏谷氨酸结合和/或G-蛋白耦合。证实单独的顺式或反式激活触发Gq偶联的细胞内Ca 2+瞬变。相反，Gi/o偶联的G蛋白依赖性内向整流钾（GIRK）通道不通过单独的顺式或反式激活激活。当二聚体mGlu 1的一个亚基缺乏G-蛋白偶联时，也观察到谷氨酸诱导的GIRK电流密度显著降低。由于G蛋白偶联缺陷亚基没有降低mGlu 1的细胞表面表达和Gq偶联的Ca 2+瞬变，因此建议mGlu 1的一个亚基中的偶联缺陷减弱Gi/o而不是Gq偶联。总之，多种G-蛋白信号被不同的二聚体mGlu 1的分子内激活机制差异激活。
Metabotropic glutamate receptor 1 (mGlu1) functions as a homodimer and activates not only the Gq but also the Gi/o and Gs pathways. Because of the dimeric configuration, different pathways could be activated either through the glutamate-bound subunit (cis-activation) and/or the other one (trans-activation). We here examined whether the intra-molecular activation mechanisms in the mGlu1 differ depending on the type of coupling G proteins, using various combinations of mGlu1 constructs that lack glutamate binding and/or G-protein coupling. The cis- or trans-activation alone was confirmed to trigger the Gq-coupled intracellular Ca2+transient. In contrast, the Gi/o-coupled G protein-dependent inward rectifying potassium (GIRK) channels were not activated either through the cis- or trans-activation alone. When one subunit of dimeric mGlu1 lacked the G-protein coupling, a significant decrease in the glutamate-induced GIRK current density was also observed. As the G protein-coupling-deficient subunit did not decrease the cell surface expression of mGlu1 and the Gq-coupled Ca2+transient, it was suggested that the coupling deficiency in one subunit of mGlu1 attenuates the Gi/o but not Gq coupling. In conclusion, multiple G-protein signaling was differentially activated by different intra-molecular activation mechanisms of the dimeric mGlu1.