Department of Physiology and Cell Biology (T.W., G.Z., M.H., Yuanyuan Xu, X.-m.Z.), University of South Alabama College of Medicine, Mobile.
Laboratory of Neuropharmacology and Neurotoxicology, Shanghai University, China (G.Z., Y.J.).
Stroke. 2020 Dec;51(12):3690-3700. doi: 10.1161/STROKEAHA.120.031479. Epub 2020 Oct 16.
Brain 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.
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.
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.
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.
脑酸中毒在中风和其他神经疾病中很常见。酸中毒可能具有矛盾的损伤和保护作用。本研究旨在确定神经元中是否存在质子受体来抵消酸中毒引起的损伤。
我们分析了大脑中质子敏感 GPCR（G 蛋白偶联受体）的表达，研究了体外酸中毒诱导的信号转导，并使用体外和体内小鼠模型研究了神经元损伤。
GPR68 是一种质子敏感 GPCR，存在于小鼠和人类大脑中，并在酸中毒和缺血条件下发挥神经保护作用。GPR68 在脑神经元中广泛表达，并介导酸中毒诱导的 PKC（蛋白激酶 C）激活。PKC 抑制以 GPR68 依赖的方式加剧 pH6 诱导的神经元损伤。与其神经保护功能一致，GPR68 的过表达减轻了大脑中动脉闭塞引起的脑损伤。
这些数据扩展了我们对神经元酸信号的认识，包括一种具有保护作用的代谢型维度，并为 GPR68 作为一种新型治疗靶点提供了依据，可减轻缺血和多种其他神经疾病中的神经元损伤。
