2. Academic Validation
  3. Glutamate acts on acid-sensing ion channels to worsen ischaemic brain injury

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

  • Nature. 2024 Jul;631(8022):826-834. doi: 10.1038/s41586-024-07684-7.
Ke Lai # 1 2 3 4,  Iva Pritišanac 5 6 7,  Zhen-Qi Liu # 1,  Han-Wei Liu 1,  Li-Na Gong 1,  Ming-Xian Li 1,  Jian-Fei Lu 8,  Xin Qi 8,  Tian-Le Xu 8,  Julie Forman-Kay 5 9,  Hai-Bo Shi 10,  Lu-Yang Wang 11 12,  Shan-Kai Yin 13
Affiliations

Affiliations

  • 1 Department of Otorhinolaryngology, Shanghai Sixth People's Hospital and Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 2 Program in Neuroscience and Mental Health, SickKids Research Institute, Toronto, Ontario, Canada.
  • 3 Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
  • 4 Shanghai Center for Brain Science and Brain-Inspired Technology, Shanghai, China.
  • 5 Program in Molecular Medicine, SickKids Research Institute, Toronto, Ontario, Canada.
  • 6 Department of Cell & Systems Biology, University of Toronto, Toronto, Ontario, Canada.
  • 7 Department of Medicinal Chemistry, Otto Loewi Research Center, Medical University of Graz, Graz, Austria.
  • 8 Department of Anatomy and Physiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 9 Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada.
  • 10 Department of Otorhinolaryngology, Shanghai Sixth People's Hospital and Shanghai Jiao Tong University School of Medicine, Shanghai, China. hbshi@sjtu.edu.cn.
  • 11 Program in Neuroscience and Mental Health, SickKids Research Institute, Toronto, Ontario, Canada. luyang.wang@utoronto.ca.
  • 12 Department of Physiology, University of Toronto, Toronto, Ontario, Canada. luyang.wang@utoronto.ca.
  • 13 Department of Otorhinolaryngology, Shanghai Sixth People's Hospital and Shanghai Jiao Tong University School of Medicine, Shanghai, China. skyin@sjtu.edu.cn.
  • # Contributed equally.
PMID: 38987597 DOI: 10.1038/s41586-024-07684-7
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.

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