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Here we show that glutamate and its structural analogues, including NMDAR antagonist <jats:sc>l<\/jats:sc>-AP5 (also known as APV), robustly potentiate currents mediated by acid-sensing ion channels (ASICs) associated with acidosis-induced neurotoxicity in stroke<jats:sup>4<\/jats:sup>. 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 <jats:italic>Asic1a<\/jats:italic> knockout or knockout of other cation channels<jats:sup>4\u20137<\/jats:sup>. 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.<\/jats:p>","DOI":"10.1038\/s41586-024-07684-7","type":"journal-article","created":{"date-parts":[[2024,7,10]],"date-time":"2024-07-10T16:01:55Z","timestamp":1720627315000},"page":"826-834","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":75,"title":["Glutamate acts on acid-sensing ion channels to worsen ischaemic brain injury"],"prefix":"10.1038","volume":"631","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3705-1795","authenticated-orcid":false,"given":"Ke","family":"Lai","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iva","family":"Priti\u0161anac","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen-Qi","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Han-Wei","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li-Na","family":"Gong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming-Xian","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian-Fei","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Qi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1438-0038","authenticated-orcid":false,"given":"Tian-Le","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8265-972X","authenticated-orcid":false,"given":"Julie","family":"Forman-Kay","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2920-0183","authenticated-orcid":false,"given":"Hai-Bo","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5399-944X","authenticated-orcid":false,"given":"Lu-Yang","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3689-8599","authenticated-orcid":false,"given":"Shan-Kai","family":"Yin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,7,10]]},"reference":[{"key":"7684_CR1","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1016\/S0166-2236(99)01401-0","volume":"22","author":"U Dirnagl","year":"1999","unstructured":"Dirnagl, U., Iadecola, C. & Moskowitz, M. 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