Faculty of Medicine, Medicum, Division of Physiology, PO Box 63, University of Helsinki, FIN-00014 Helsinki, Finland.
Department of Pathology, Haartmaninkatu 3 (PB 21), University of Helsinki, 00014 Helsinki, Finland.
Biochim Biophys Acta Biomembr. 2019 Jun 1;1861(6):1037-1048. doi: 10.1016/j.bbamem.2019.03.007. Epub 2019 Mar 16.
A stroke causes a hypoxic brain microenvironment that alters neural cell metabolism resulting in cell membrane hyperpolarization and intracellular acidosis. We studied how intracellular pH (pH) is regulated in differentiated mouse neural progenitor cells during hyperpolarizing conditions, induced by prompt reduction of the extracellular K concentration. We found that the radial glia-like population in differentiating embryonic neural progenitor cells, but not neuronal cells, was rapidly acidified under these conditions. However, when extracellular calcium was removed, an instant depolarization and recovery of the pH, back to normal levels, took place. The rapid recovery phase seen in the absence of calcium, was dependent on extracellular bicarbonate and could be inhibited by S0859, a potent Na/HCO3 cotransporter inhibitor. Immunostaining and PCR data, showed that NBCe1 (SLC4A4) and NBCn1 (SLC4A7) were expressed in the cell population and that the pH recovery in the radial glial-like cells after calcium removal was mediated mainly by the electrogenic sodium bicarbonate transporter NBCe1 (SLC4A4). Our results indicate that extracellular calcium might hamper pH regulation and Na/HCO3 cotransporter activity in a brain injury microenvironment. Our findings show that the NBC-type transporters are the main pH regulating systems prevailing in glia-like progenitor cells and that these calcium sensitive transporters are important for neuronal progenitor cell proliferation, survival and neural stem cell differentiation.
中风会导致缺氧的脑微环境，改变神经细胞代谢，导致细胞膜超极化和细胞内酸中毒。我们研究了在快速降低细胞外 K 浓度诱导的超极化条件下，分化的小鼠神经祖细胞中细胞内 pH（pH）是如何调节的。我们发现，在这些条件下，分化中的胚胎神经祖细胞中的放射状胶质样细胞群迅速酸化，但神经元细胞没有。然而，当去除细胞外钙时，会立即发生去极化，pH 恢复到正常水平。在没有钙的情况下观察到的快速恢复阶段依赖于细胞外碳酸氢盐，并且可以被 S0859 抑制，S0859 是一种有效的 Na/HCO3 共转运体抑制剂。免疫染色和 PCR 数据表明，NBCe1（SLC4A4）和 NBCn1（SLC4A7）在细胞群中表达，并且钙去除后放射状胶质样细胞中的 pH 恢复主要由电活性的钠离子碳酸氢盐转运体 NBCe1（SLC4A4）介导。我们的结果表明，细胞外钙可能会干扰脑损伤微环境中的 pH 调节和 Na/HCO3 共转运体活性。我们的研究结果表明，NBC 型转运体是胶质样祖细胞中主要的 pH 调节系统，这些钙敏感转运体对于神经元祖细胞增殖、存活和神经干细胞分化很重要。
