Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Lai, K; Pritišanac, I; Liu, ZQ; Liu, HW; Gong, LN; Li, MX; Lu, JF; Qi, X; Xu, TL; Forman-Kay, J; Shi, HB; Wang, LY; Yin, SK.
Glutamate acts on acid-sensing ion channels to worsen ischaemic brain injury.
Nature. 2024; 631(8022): 826-834.
Doi: 10.1038/s41586-024-07684-7
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- Pritisanac Iva
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- 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.
- Find related publications in this database (using NLM MeSH Indexing)
- Animals - administration & dosage
- Female - administration & dosage
- Humans - administration & dosage
- Male - administration & dosage
- Mice - administration & dosage
- 2-Amino-5-phosphonovalerate - adverse effects, metabolism, pharmacology
- Acid Sensing Ion Channels - chemistry, deficiency, drug effects, genetics, metabolism
- Allosteric Regulation - drug effects
- Binding Sites - genetics
- Brain Ischemia - chemically induced, drug therapy, metabolism, pathology
- Disease Models, Animal - administration & dosage
- Drug Evaluation, Preclinical - administration & dosage
- Glutamic Acid - analogs & derivatives, metabolism, pharmacology, toxicity
- Mice, Knockout - administration & dosage
- Mutagenesis, Site-Directed - administration & dosage
- Protons - administration & dosage
- Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors, chemistry, metabolism