Cellular Signaling Laboratory, Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China.
Acta Pharmacol Sin. 2019 Apr;40(4):460-467. doi: 10.1038/s41401-018-0033-7. Epub 2018 Jun 26.
Metabotropic glutamate receptor 2 (mGlu2) belongs to the group-II metabotropic glutamate (mGlu) receptors and is a neurotransmitter G protein-coupled receptor. The group-II mGlu receptors are promising antipsychotic targets, but the specific role of mGlu2 signaling remains unclear. Receptor tyrosine kinases (RTKs) are also believed to participate in brain pathogenesis. To investigate whether there is any communication between mGlu2 and RTKs, we generated a CHO-mGlu2 cell line that stably expresses mGlu2 and showed that activation of mGlu2 by LY379268, a group II mGlu agonist, was able to transactivate insulin-like growth factor 1 receptor (IGF-1R). We further determined that the G protein, G subunits, phospholipase C, and focal adhesion kinase (FAK) were involved in the IGF-1R transactivation signaling axis, which further induced the phosphorylation of extracellular signal-regulated kinase1/2 (ERK1/2) and cAMP response element-binding protein. In primary mouse cortical neurons, similar signaling pathways were observed when mGlu2 were stimulated by LY487379, an mGlu2 positive allosteric modulator. Transactivation of IGF-1R through FAK in response to mGlu2 should provide a better understanding of the association of mGlu2 with brain disease.
代谢型谷氨酸受体 2（mGlu2）属于 II 组代谢型谷氨酸（mGlu）受体，是一种神经递质 G 蛋白偶联受体。II 组 mGlu 受体是很有前途的抗精神病靶点，但 mGlu2 信号的具体作用尚不清楚。受体酪氨酸激酶（RTKs）也被认为参与脑发病机制。为了研究 mGlu2 和 RTKs 之间是否存在任何通讯，我们生成了稳定表达 mGlu2 的 CHO-mGlu2 细胞系，并表明 II 组 mGlu 激动剂 LY379268 激活 mGlu2 能够转激活胰岛素样生长因子 1 受体（IGF-1R）。我们进一步确定 G 蛋白、G 亚基、磷脂酶 C 和粘着斑激酶（FAK）参与 IGF-1R 转激活信号轴，进一步诱导细胞外信号调节激酶 1/2（ERK1/2）和 cAMP 反应元件结合蛋白的磷酸化。在原代小鼠皮质神经元中，当 mGlu2 被 mGlu2 正变构调节剂 LY487379 刺激时，观察到类似的信号通路。mGlu2 通过 FAK 对 IGF-1R 的转激活应该有助于更好地理解 mGlu2 与脑部疾病的关联。
