Potassium channel Kir4.1 regulates oligodendrocyte differentiation via intracellular pH regulation

Abstract In humans, loss‐of‐function mutations of Kcnj10 in SeSAME/EAST syndrome, which encodes the inwardly rectifying K + channel 4.1 (K ir 4.1), causes progressive neurological decline. Despite its rich expression in oligodendrocyte (OL) lineage cells and an emerging link with demyelinating disease, the function of K ir 4.1 in OLs is unclear. Here we show a novel role of K ir 4.1 in OL development. K ir 4.1 expression is markedly greater in OLs than in OL precursor cells (OPCs), and the down‐regulation of K ir 4.1 impairs OL maturation by affecting OPC differentiation. Interestingly, K ir 4.1 regulates the intracellular pH of OPCs and OLs via the Na + /H + exchanger, which underlies impeded OPC differentiation by K ir 4.1 inhibition. Furthermore, K ir 4.1 regulates GSK3β and SOX10, two molecules critical to OPC development. Collectively, our work opens a new avenue to understanding the functions of K ir 4.1 and intracellular pH in OLs.