GPR68 Is a Neuroprotective Proton Receptor in Brain Ischemia.
GPR68 Is a Neuroprotective Proton Receptor in Brain Ischemia.
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DOI：
10.1161/strokeaha.120.031479
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发表时间：
2020-12
期刊：
影响因子：
8.3
通讯作者：
Zha XM
中科院分区：
文献类型：
--
作者：
Wang T;Zhou G;He M;Xu Y;Rusyniak WG;Xu Y;Ji Y;Simon RP;Xiong ZG;Zha XM
文本中提供了补充数字内容。脑酸中毒在中风和其他神经系统疾病中很常见。酸中毒可能会产生矛盾的伤害和保护作用。本研究的目的是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，在体外检查了酸中毒诱导的信号传导，并使用体外和体内小鼠模型研究了神经元损伤。 GPR68 是一种质子敏感的 GPCR，存在于小鼠和人类大脑中，并在酸中毒和缺血条件下引发神经保护作用。 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 依赖性方式加剧 pH 6 诱导的神经元损伤。与其神经保护功能一致，GPR68 过度表达可减轻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传导的认识，包括神经保护性代谢维度，并提供 GPR68 作为减轻缺血和多种其他神经系统疾病中的神经元损伤的新治疗靶点。
Supplemental Digital Content is available in the text. 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.