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

Ke Lai, Iva Pritišanac, Zhen-Qi Liu, Han-Wei Liu, Li-Na Gong, Ming-Xian Li, Jian-Fei Lu, Xin Qi, Tian-Le Xu, Julie Forman-Kay, Hai-Bo Shi (), Lu-Yang Wang () and Shan-Kai Yin ()
Additional contact information
Ke Lai: Shanghai Sixth People’s Hospital and Shanghai Jiao Tong University School of Medicine
Iva Pritišanac: SickKids Research Institute
Zhen-Qi Liu: Shanghai Sixth People’s Hospital and Shanghai Jiao Tong University School of Medicine
Han-Wei Liu: Shanghai Sixth People’s Hospital and Shanghai Jiao Tong University School of Medicine
Li-Na Gong: Shanghai Sixth People’s Hospital and Shanghai Jiao Tong University School of Medicine
Ming-Xian Li: Shanghai Sixth People’s Hospital and Shanghai Jiao Tong University School of Medicine
Jian-Fei Lu: Shanghai Jiao Tong University School of Medicine
Xin Qi: Shanghai Jiao Tong University School of Medicine
Tian-Le Xu: Shanghai Jiao Tong University School of Medicine
Julie Forman-Kay: SickKids Research Institute
Hai-Bo Shi: Shanghai Sixth People’s Hospital and Shanghai Jiao Tong University School of Medicine
Lu-Yang Wang: SickKids Research Institute
Shan-Kai Yin: Shanghai Sixth People’s Hospital and Shanghai Jiao Tong University School of Medicine

Nature, 2024, vol. 631, issue 8022, 826-834

Abstract: 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 mechanisms3–7. 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 channels4–7. 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.

Date: 2024
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DOI: 10.1038/s41586-024-07684-7

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