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 collapse

### 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](https://pubmed.ncbi.nlm.nih.gov/38987597) DOI: [10.1038/s41586-024-07684-7](https://doi.org/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](https://www.medchemexpress.cn/Targets/radionuclide-drug-conjugates-rdcs/other.html) 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](https://www.medchemexpress.cn/Targets/radionuclide-drug-conjugates-rdcs/other.html) 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.

Figures

Products

- Cat. No.

Product Name

Description

Target

Research Area

- HY-15068

[NBQX](https://www.medchemexpress.cn/NBQX.html)

99.82%, AMPA Receptor Antagonist

[iGluR](https://www.medchemexpress.cn/Targets/iGluR.html)

[Neurological Disease](https://www.medchemexpress.cn/ResearchArea/Neurological%20Disease.html)

- HY-70059

[LY341495](https://www.medchemexpress.cn/LY341495.html)

99.50%, mGluR拮抗剂

[mGluR](https://www.medchemexpress.cn/Targets/mGluR.html)

[Neurological Disease](https://www.medchemexpress.cn/ResearchArea/Neurological%20Disease.html)

- HY-15754

[CGP37157](https://www.medchemexpress.cn/CGP37157.html)

99.87%, Na+/Ca2+ Exchanger抑制剂

[Na+/Ca2+ Exchanger](https://www.medchemexpress.cn/Targets/Na+_Ca2+%20Exchanger.html)

[Neurological Disease](https://www.medchemexpress.cn/ResearchArea/Neurological%20Disease.html); [Cancer](https://www.medchemexpress.cn/ResearchArea/Cancer.html)

- HY-113618B

[RO2959 monohydrochloride](https://www.medchemexpress.cn/ro2959-monohydrochloride.html)

98.19%, CRAC Channel抑制剂

[CRAC Channel](https://www.medchemexpress.cn/Targets/CRAC%20Channel.html); [Interleukin Related](https://www.medchemexpress.cn/Targets/Interleukin%20Related.html)

[Cardiovascular Disease](https://www.medchemexpress.cn/ResearchArea/Cardiovascular%20Disease.html)

- HY-164284

[LK-2](https://www.medchemexpress.cn/lk-2.html)

98.83%, ASIC1a拮抗剂

[Sodium Channel](https://www.medchemexpress.cn/Targets/Sodium%20Channel.html)

[Neurological Disease](https://www.medchemexpress.cn/ResearchArea/Neurological%20Disease.html)

更多资讯平台

![](https://file.medchemexpress.cn/mce-cn-email/2025/on-sale-code-a.png)

公众号

![](https://file.medchemexpress.cn/mce-cn-email/2025/on-sale-code-b.png)

小程序

![](https://file.medchemexpress.cn/mce-cn-email/2025/on-sale-code-c.png)

视频号

![](https://file.medchemexpress.cn/mce-cn-email/2025/on-sale-code-d.png)

小红书

![](https://file.medchemexpress.cn/mce-cn-email/2025/on-sale-code-e.png)

知乎