Department of Biochemistry, Juntendo University Graduate School of Medicine, Tokyo, 113-8421, Japan.
AMED-PRIME, Japan Agency for Medical Research and Development, Tokyo, 100-0004, Japan.
Nat Commun. 2024 Feb 27;15(1):1530. doi: 10.1038/s41467-024-45579-3.
Homoeostatic regulation of the acid-base balance is essential for cellular functional integrity. However, little is known about the molecular mechanism through which the acid-base balance regulates cellular responses. Here, we report that bicarbonate ions activate a G protein-coupled receptor (GPCR), i.e., GPR30, which leads to G-coupled calcium responses. Gpr30-Venus knock-in mice reveal predominant expression of GPR30 in brain mural cells. Primary culture and fresh isolation of brain mural cells demonstrate bicarbonate-induced, GPR30-dependent calcium responses. GPR30-deficient male mice are protected against ischemia-reperfusion injury by a rapid blood flow recovery. Collectively, we identify a bicarbonate-sensing GPCR in brain mural cells that regulates blood flow and ischemia-reperfusion injury. Our results provide a perspective on the modulation of GPR30 signalling in the development of innovative therapies for ischaemic stroke. Moreover, our findings provide perspectives on acid/base sensing GPCRs, concomitantly modulating cellular responses depending on fluctuating ion concentrations under the acid-base homoeostasis.
酸碱平衡的动态调节对于细胞功能完整性至关重要。然而，目前对于酸碱平衡如何调节细胞反应的分子机制知之甚少。在这里，我们报告说碳酸氢根离子激活了一种 G 蛋白偶联受体（GPCR），即 GPR30，从而引发 G 蛋白偶联的钙反应。Gpr30-Venus 敲入小鼠揭示了 GPR30 在大脑壁细胞中的主要表达。原代培养和新鲜分离的大脑壁细胞显示出碳酸氢盐诱导的、GPR30 依赖性的钙反应。GPR30 缺陷型雄性小鼠通过快速恢复血流对缺血再灌注损伤具有保护作用。总之，我们在大脑壁细胞中鉴定出一种碳酸氢盐感应 GPCR，它调节血流和缺血再灌注损伤。我们的研究结果为调节 GPR30 信号转导以开发用于治疗缺血性中风的创新疗法提供了新视角。此外，我们的研究结果为酸碱感应 GPCR 提供了新视角，同时根据酸碱动态平衡下离子浓度的波动来调节细胞反应。
