Abstract
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 Gi/o protein, Gβγ 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.
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Acknowledgements
The authors thank Jean-Philippe PIN and Philippe Rondard (Institut de Génomique Fonctionnelle, Montpellier, France) for their discussions and critical comments regarding the manuscript. This work was supported by the National Natural Science Foundation of China (NSFC grant nos. 31420103909, 31711530146, 31511130131), the Program of Introducing Talents of Discipline to the Universities of the Ministry of Education (grant no. B08029), Natural Science Foundation of Hubei Province (grant no. 2014CFA010), and NSFC grant (no. 31301163) to C-jX.
Author contributions
J-fL and C-jX conceived the project; Yong-jian Hu, QS, C-jX, and J-fL designed the experiments; Yong-jian Hu, QS, W-hZ, and Yu-jia Huo performed the experiments; Yong-jian Hu, QS, C-jX, and J-fL analyzed the data; and C-jX, J-fL, and Yong-jian Hu wrote the manuscript.
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Hu, Yj., Sun, Q., Zhang, Wh. et al. Specific activation of mGlu2 induced IGF-1R transactivation in vitro through FAK phosphorylation. Acta Pharmacol Sin 40, 460–467 (2019). https://doi.org/10.1038/s41401-018-0033-7
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DOI: https://doi.org/10.1038/s41401-018-0033-7
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