Glutamate acts on acid-sensing ion channels to worsen ischaemic brain injury.
Ke LaiIva PritišanacZhen-Qi LiuHan-Wei LiuLi-Na GongMing-Xian LiJian-Fei LuXin QiTian-Le XuJulie Deborah Forman-KayHai-Bo ShiLu-Yang WangShan-Kai YinPublished in: Nature (2024)
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.
Keyphrases
- small molecule
- brain injury
- cell death
- clinical trial
- atrial fibrillation
- mouse model
- subarachnoid hemorrhage
- transcription factor
- cerebral ischemia
- metabolic syndrome
- gene expression
- crispr cas
- social media
- functional connectivity
- skeletal muscle
- randomized controlled trial
- mass spectrometry
- insulin resistance
- binding protein
- high fat diet induced
- genome wide
- coronary artery disease
- molecular docking
- open label
- wild type
- percutaneous coronary intervention
- high glucose
- cancer therapy
- left ventricular