Wang, TaoZhou, GuokunHe, MindiXu, YuanyuanRusyniak, W.G.Xu, YanJi, YonghuaSimon, Roger P.Xiong, Zhi-GangZha, Xiang-ming2022-01-102022-01-102020-12Wang, T., Zhou, G., He, M., Xu, Y., Rusyniak, W. G., Xu, Y., Ji, Y., Simon, R. P., Xiong, Z.-G., & Zha, X. (2020). GPR68 Is a Neuroprotective Proton Receptor in Brain Ischemia. Stroke, 51(12), 3690–3700. https://doi.org/10.1161/STROKEAHA.120.0314790039-2499, 1524-4628https://hdl.handle.net/1805/27327Brain acidosis is prevalent in stroke and other neurological diseases. Acidosis can have paradoxical injurious and protective effects. The purpose of this study is to determine whether a proton receptor exists in neurons to counteract acidosis-induced injury. Methods: We analyzed the expression of proton-sensitive GPCRs (G protein-coupled receptors) in the brain, examined acidosis-induced signaling in vitro, and studied neuronal injury using in vitro and in vivo mouse models. Results: GPR68, a proton-sensitive GPCR, was present in both mouse and human brain, and elicited neuroprotection in acidotic and ischemic conditions. GPR68 exhibited wide expression in brain neurons and mediated acidosis-induced PKC (protein kinase C) activation. PKC inhibition exacerbated pH 6-induced neuronal injury in a GPR68-dependent manner. Consistent with its neuroprotective function, GPR68 overexpression alleviated middle cerebral artery occlusion–induced brain injury. Conclusions: These data expand our knowledge on neuronal acid signaling to include a neuroprotective metabotropic dimension and offer GPR68 as a novel therapeutic target to alleviate neuronal injuries in ischemia and multiple other neurological diseases.en-USAttribution-NonCommercial-NoDerivatives 4.0 Internationalacidosisbrain ischemiamiceneuronsprotonArticle