上海第六人民医院和上海交通大学医学院殷善开、时海波登近日取得一项新成果。经过不懈努力，他们揭示谷氨酸通过酸离子敏感通道加重缺血性脑损伤。这一研究成果于2024年7月10日发表在国际顶尖学术期刊《自然》上。

小组发现谷氨酸及其结构类似物，包括NMDAR拮抗剂L-AP5(也称为APV)，在中风中与酸中毒诱导的神经毒性相关的酸离子敏感通道(ASICs)介导的电流中有效地增强。谷氨酸增加酸离子敏感通道对质子的亲和力及其打开概率，在体外和体内模型中加重缺血性神经毒性。位点定向诱变、基于结构的建模和功能分析显示，ASIC1a的细胞外结构域存在真正的谷氨酸结合腔。

计算药物筛选鉴定出一种小分子LK-2，它与该空腔结合并消除谷氨酸依赖的酸离子敏感通道电流增强，但保留NMDARs。LK-2在缺血性中风的小鼠模型中减少梗死面积并改善感觉运动恢复，这与敲除Asic1a或敲除其他阳离子通道的小鼠中所见的情况相似。

该研究团队得出的结论是，谷氨酸作为酸离子敏感通道的正变构调节剂，可以加剧神经毒性，并且优先靶向酸离子敏感通道上的谷氨酸结合位点而不是NMDARs，可能是开发缺乏NMDAR拮抗剂精神病性副作用的中风治疗策略。

据悉，传统上，谷氨酸被认为是激活NMDAR (N-甲基-D-天冬氨酸受体)依赖的中风细胞死亡途径的第一个信使，但NMDAR拮抗剂不成功的临床试验暗示了其他机制的参与。

附：英文原文

Title: Glutamate acts on acid-sensing ion channels to worsen ischaemic brain injury

Author: Lai, Ke, Pritianac, Iva, Liu, Zhen-Qi, Liu, Han-Wei, Gong, Li-Na, Li, Ming-Xian, Lu, Jian-Fei, Qi, Xin, Xu, Tian-Le, Forman-Kay, Julie, Shi, Hai-Bo, Wang, Lu-Yang, Yin, Shan-Kai

Issue&Volume: 2024-07-10

Abstract: Glutamate is traditionally viewed as the first messenger to activate NMDAR (N-methyl-D-aspartate receptor)-dependent cell death pathways in stroke1,2, but unsuccessful clinical trials with NMDAR antagonists implicate the engagement of other mechanisms3,4,5,6,7. Here we show that glutamate and its structural analogues, including NMDAR antagonist L-AP5 (also known as APV), robustly potentiate currents mediated by acid-sensing ion channels (ASICs) associated with acidosis-induced neurotoxicity in stroke4. Glutamate increases the affinity of ASICs for protons and their open probability, aggravating ischaemic neurotoxicity in both in vitro and in vivo models. Site-directed mutagenesis, structure-based modelling and functional assays reveal a bona fide glutamate-binding cavity in the extracellular domain of ASIC1a. Computational drug screening identified a small molecule, LK-2, that binds to this cavity and abolishes glutamate-dependent potentiation of ASIC currents but spares NMDARs. LK-2 reduces the infarct volume and improves sensorimotor recovery in a mouse model of ischaemic stroke, reminiscent of that seen in mice with Asic1a knockout or knockout of other cation channels4,5,6,7. We conclude that glutamate functions as a positive allosteric modulator for ASICs to exacerbate neurotoxicity, and preferential targeting of the glutamate-binding site on ASICs over that on NMDARs may be strategized for developing stroke therapeutics lacking the psychotic side effects of NMDAR antagonists.

DOI: 10.1038/s41586-024-07684-7

Source: https://www.nature.com/articles/s41586-024-07684-7