德国海德堡大学Hilmar Bading课题组取得最新进展。他们发现NMDA受体（NMDAR）和TRPM4的耦联指导非常规神经保护剂的发现。该项研究成果发表在2020年10月9日出版的《科学》杂志上。

NMDAR诱导的兴奋性毒性被认为与高细胞内钙负荷密切相关。出乎意料的是，可以消除NMDAR介导的毒性而不影响NMDAR诱导的钙信号。相反，兴奋性毒性需要将NMDAR与TRPM4物理偶联。这种相互作用是由位于受体近膜部分的细胞内结构域介导的。使用TRPM4与NMDARs相互作用界面进行的基于结构的计算药物筛选，鉴定出的小分子可以省去NMDAR诱导的钙信号转导，但会破坏NMDAR / TRPM4复合物。

这些相互作用界面抑制剂可大大降低NMDA触发的毒性和线粒体功能障碍，消除环状单磷酸腺苷反应性元件结合蛋白（CREB）的封闭，增强基因诱导作用，并减少中风和视网膜变性小鼠模型的神经元丢失。重组或小分子NMDAR / TRPM4界面抑制剂可减轻目前无法治愈的人类神经退行性疾病。

附：英文原文

Title: Coupling of NMDA receptors and TRPM4 guides discovery of unconventional neuroprotectants

Author: Jing Yan, C. Peter Bengtson, Bettina Buchthal, Anna M. Hagenston, Hilmar Bading

Issue&Volume: 2020/10/09

Abstract: Excitotoxicity induced by NMDA receptors (NMDARs) is thought to be intimately linked to high intracellular calcium load. Unexpectedly, NMDAR-mediated toxicity can be eliminated without affecting NMDAR-induced calcium signals. Instead, excitotoxicity requires physical coupling of NMDARs to TRPM4. This interaction is mediated by intracellular domains located in the near-membrane portions of the receptors. Structure-based computational drug screening using the interaction interface of TRPM4 in complex with NMDARs identified small molecules that spare NMDAR-induced calcium signaling but disrupt the NMDAR/TRPM4 complex. These interaction interface inhibitors strongly reduce NMDA-triggered toxicity and mitochondrial dysfunction, abolish cyclic adenosine monophosphate–responsive element–binding protein (CREB) shutoff, boost gene induction, and reduce neuronal loss in mouse models of stroke and retinal degeneration. Recombinant or small-molecule NMDAR/TRPM4 interface inhibitors may mitigate currently untreatable human neurodegenerative diseases.

DOI: 10.1126/science.aay3302

Source: https://science.sciencemag.org/content/370/6513/eaay3302