Philibert Clémentine Eva, Disdier Candice, Lafon Pierre-André, Bouyssou Alexandre, Oosterlaken Mathieu, Galant Sonya, Pizzoccaro Anne, Tuduri Pola, Ster Jeanne, Liu Jianfeng, Kniazeff Julie, Pin Jean-Philippe, Rondard Philippe, Marin Philippe, Vandermoere Franck
Institut de Génomique Fonctionnelle (IGF), Université de Montpellier, CNRS, INSERM, Montpellier, France.
Cellular Signaling Laboratory, Key Laboratory of Molecular Biophysics of MOE, International Research Centre for Sensory Biology and Technology of MOST, College of Life Science and Technology, Huazhong University of Science and Technology, 430074 Wuhan, China.
Sci Adv. 2024 Jan 26;10(4):eadg1679. doi: 10.1126/sciadv.adg1679.
Metabotropic glutamate receptor 2 (mGlu) attracts particular attention as a possible target for a new class of antipsychotics. However, the signaling pathways transducing the effects of mGlu in the brain remain poorly characterized. Here, we addressed this issue by identifying native mGlu interactome in mouse prefrontal cortex. Nanobody-based affinity purification and mass spectrometry identified 149 candidate mGlu partners, including the neurotrophin receptor TrkB. The later interaction was confirmed both in cultured cells and prefrontal cortex. mGlu activation triggers phosphorylation of TrkB on Tyr in primary cortical neurons and prefrontal cortex. Reciprocally, TrkB stimulation enhances mGlu-operated G protein activation. Furthermore, TrkB inhibition prevents the rescue of behavioral deficits by glutamatergic antipsychotics in phencyclidine-treated mice. Collectively, these results reveal a cross-talk between TrkB and mGlu, which is key to the behavioral response to glutamatergic antipsychotics.
代谢型谷氨酸受体2（mGlu）作为一类新型抗精神病药物的潜在靶点备受关注。然而，mGlu在大脑中传导效应的信号通路仍未得到充分表征。在此，我们通过鉴定小鼠前额叶皮质中的天然mGlu相互作用组来解决这一问题。基于纳米抗体的亲和纯化和质谱分析鉴定出149个候选mGlu相互作用伙伴，包括神经营养因子受体TrkB。随后在培养细胞和前额叶皮质中均证实了这种相互作用。mGlu激活可触发原代皮质神经元和前额叶皮质中TrkB酪氨酸位点的磷酸化。相反，TrkB刺激可增强mGlu介导的G蛋白激活。此外，TrkB抑制可阻止谷氨酸能抗精神病药物对苯环己哌啶处理小鼠行为缺陷的挽救作用。这些结果共同揭示了TrkB与mGlu之间的相互作用，这是对谷氨酸能抗精神病药物行为反应的关键。
