Department of Neuroscience, Washington University School of Medicine, St Louis, Missouri, USA.
Department of Psychiatry, Washington University School of Medicine, St Louis, Missouri, USA; The Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, St Louis, Missouri, USA.
J Biol Chem. 2023 Aug;299(8):104949. doi: 10.1016/j.jbc.2023.104949. Epub 2023 Jun 22.
Metabotropic glutamate receptor 5 (mGlu) is widely expressed throughout the central nervous system and is involved in neuronal function, synaptic transmission, and a number of neuropsychiatric disorders such as depression, anxiety, and autism. Recent work from this lab showed that mGlu is one of a growing number of G protein-coupled receptors that can signal from intracellular membranes where it drives unique signaling pathways, including upregulation of extracellular signal-regulated kinase (ERK1/2), ETS transcription factor Elk-1, and activity-regulated cytoskeleton-associated protein (Arc). To determine the roles of cell surface mGlu as well as the intracellular receptor in a well-known mGlu synaptic plasticity model such as long-term depression, we used pharmacological isolation and genetic and physiological approaches to analyze spatially restricted pools of mGlu in striatal cultures and slice preparations. Here we show that both intracellular and cell surface receptors activate the phosphatidylinositol-3-kinase-protein kinase B-mammalian target of rapamycin (PI3K/AKT/mTOR) pathway, whereas only intracellular mGlu activates protein phosphatase 2 and leads to fragile X mental retardation protein degradation and de novo protein synthesis followed by a protein synthesis-dependent increase in Arc and post-synaptic density protein 95. However, both cell surface and intracellular mGlu activation lead to α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor GluA2 internalization and chemically induced long-term depression albeit via different signaling mechanisms. These data underscore the importance of intracellular mGlu in the cascade of events associated with sustained synaptic transmission in the striatum.
代谢型谷氨酸受体 5（mGlu）广泛表达于中枢神经系统，参与神经元功能、突触传递以及多种神经精神疾病，如抑郁症、焦虑症和自闭症。本实验室最近的工作表明，mGlu 是越来越多的 G 蛋白偶联受体之一，它可以从细胞内膜发出信号，驱动独特的信号通路，包括细胞外信号调节激酶（ERK1/2）、ETS 转录因子 Elk-1 和活性调节细胞骨架相关蛋白（Arc）的上调。为了确定细胞表面 mGlu 以及细胞内受体在长时程抑郁等著名的 mGlu 突触可塑性模型中的作用，我们使用药理学分离和遗传及生理方法来分析纹状体培养物和切片制备中细胞内 mGlu 的空间限制池。在这里，我们证明细胞内和细胞表面受体都可以激活磷脂酰肌醇-3-激酶-蛋白激酶 B-雷帕霉素靶蛋白（PI3K/AKT/mTOR）通路，而只有细胞内 mGlu 可以激活蛋白磷酸酶 2，导致脆性 X 智力低下蛋白降解和从头蛋白质合成，随后蛋白质合成依赖性的 Arc 和突触后密度蛋白 95 增加。然而，细胞表面和细胞内 mGlu 的激活都会导致α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体 GluA2 内化和化学诱导的长时程抑郁，尽管这是通过不同的信号机制。这些数据强调了细胞内 mGlu 在纹状体中与持续突触传递相关的一系列事件中的重要性。
