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

• 成果类型: Article
• 署名作者: Lai, Ke; Pritisanac, 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
• 署名单位: Shanghai Jiao Tong University; Shanghai Jiao Tong University; University of Toronto; Hospital for Sick Children (SickKids); University of Toronto; Shanghai Center for Brain Science & Brain-Inspired Technology; University of Toronto; Hospital for Sick Children (SickKids); University of Toronto; Medical University of Graz; Shanghai Jiao Tong University; University of Toronto
• 刊物名称: Nature
• ISSN/ISSBN: 0028-5901
• DOI: 10.1038/s41586-024-07684-7
• 发表日期: 2024-07-25
• 页码: 826-+
• 关键词: synaptic-transmission; nmda receptor; stroke; neuroprotection; contributes; aspartate; excitotoxicity; tolerability; selfotel; affinity

摘要

Glutamate is traditionally viewed as the first messenger to activate NMDAR (N-methyl-d-aspartate receptor)-dependent cell death pathways in stroke(1,2), but unsuccessful clinical trials with NMDAR antagonists implicate the engagement of other mechanisms(3-7). 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 stroke(4). 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 channels(4-7). 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.