CAL与mGluR1相互作用抑制mGluR1过度激活诱导的细胞毒性作用  

The Interaction Between CAL and mGluR1 Alleviates Cytotoxicity Induced by mGluR1 Overactivation

作　　者：杨荟敏[1] 范景凯 朱萍 罗雯媛 张亚楠 张红[1] YANG Hui-Min;FAN Jing-Kai;ZHU Ping;LUO Wen-Yuan;ZHANG Ya-Nan;ZHANG Hong(Department of Neurobiology,School of Basic Medical Sciences,Capital Medical University,Beijing 100069,China;Department of Clinical Laboratory,Yantai Yuhuangding Hospital,Yantai 264000,Shandong,China)

机构地区：[1]首都医科大学基础医学院神经生物学系,北京100069 [2]烟台毓璜顶医院检验科,山东烟台264000

出　　处：《中国生物化学与分子生物学报》2022年第11期1493-1503,共11页Chinese Journal of Biochemistry and Molecular Biology

基　　金：国家自然科学基金项目(No.81972231)资助。

摘　　要：代谢型谷氨酸受体1(mGluR1)过度激活介导的谷氨酸兴奋性毒性是帕金森病(PD)的主要发病机制之一。在临床试验中应用mGluRs的负性变构调节剂缓解PD病人的运动障碍已有报道,但由于精确调控mGluRs表达或活性的局限性,目前,在PD的治疗中仍存在一些问题。因此,寻找能够精确调控mGluR1表达及活性的小分子药物或内源性基因,将有可能成为解决目前PD治疗中存在问题的有效方法。本文通过体内和体外实验,对囊性纤维跨膜调节器相关配体(CAL)在mGluR1过度激活诱导的细胞毒性中的作用和机制进行研究。研究结果显示,在工具细胞HEK293中,应用mGluR1的激动剂激活受体,CAL与mGluR1的相互作用明显增强(P<0.05),且CAL通过与mGluR1相互作用,抑制mGluR1过度激活诱导的细胞凋亡及其下游信号通路的激活。在鱼藤酮诱导的PD大鼠模型中,过表达CAL通过抑制mGluR1下游通路的激活,减少鱼藤酮引起的神经损伤(P<0.001)。本文揭示了一种调控mGluR1活性的新机制,希望为神经系统疾病的治疗和相关研究提供新思路。Glutamate excitotoxicity mediated by metabotropic glutamate receptor 1(mGluR1)overexpression or overactivation plays an important role in the development of Parkinson’s disease(PD).Although clinical trials support the therapeutic potential of certain mGluR negative allosteric modulators(NAMs),there are still some limitations of precise modulation of mGluR using NAMs.Thus,the identification of small molecules or endogenous genes that facilitate mGluR1 modulation might be potentially beneficial for PD treatment.We determined the role of interacting partner cystic fibrosis transmembrane conductance regulator-associated ligand(CAL)in overactivated mGluR1-mediated cell apoptosis and signaling pathway in vitro and in vivo.HEK293 cells were used as an experimental tool to directly examine the interaction between CAL and mGluR1.We found that agonist of mGluR1 significantly enhanced the interaction between CAL and mGluR1(P<0.05).Furthermore,CAL suppressed overactivated mGluR1-induced cell apoptosis and the activation of mGluR1 downstream signaling pathways.CAL overexpression relieved rotenone-induced neuron death(P<0.001)by inhibiting the activation of mGluR1-mediated signaling pathways in rotenone-induced rat model of PD.This study may reveal a new mechanism of mGluR1 activity regulation,and hopefully provide a novel molecular mechanism for the nervous system related diseases.

关 键 词：帕金森病 代谢型谷氨酸受体1 囊性纤维跨膜调节器相关配体 蛋白质相互作用 细胞凋亡 

分 类 号：Q2[生物学—细胞生物学]