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

ABSTRACT: Glutamate is traditionally viewed as the first messenger to activate NMDAR (N-methyl-D-aspartate receptor)-dependent cell death pathways in stroke^1,2, but unsuccessful clinical trials with NMDAR antagonists implicate the engagement of other mechanisms^3-7. 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-bindin

SUBMITTER: Lai K 

PROVIDER: S-EPMC11269185 | biostudies-literature | 2024 Jul

REPOSITORIES: biostudies-literature