Kir2.1 channel in an oxidative stress-related model of aging neuroglia

Epilepsy is a chronic disease of the brain and its prevalence increases with age. Metabolic changes, including the production of ROS, may contribute to epilepsy development. Glia plays a crucial role in epilepsy by controlling neuronal hyperexcitability. One of the key roles of glial cells is the spatial buffering of extracellular K+ ions that are released by excited neurons and transported through glial inwardly rectifying potassium (Kir) channels from extracellular regions of high K+ to those of low K+ to inhibit epileptogenesis. Among experimental oxidative stress (OS)-related aging models, exposure to D-galactose (D-gal) is considered the most similar to natural aging. In this study, we investigated the effect of D-gal-induced aging on Kir channel function in glioblastoma U87-MG cells. Screening of all Kir isoforms revealed that the predominant transcript corresponds to Kir2.1 with minor contribution of Kir4.1. D-galactose had no obvious cytotoxicity, but activated OS pathways, namely significantly enhanced lipoperoxidation levels and reduced the abundance of SH groups. Interestingly, D-gal exposure was associated with a decrease of inwardly rectifying K+ currents sensitive to ML-133, a specific inhibitor of Kir2.1. Our data reveal a novel Kir2.1 channel modulation that is likely to occur in OS. We suggest that inhibition of Kir2.1 in glia cells may alter extracellular K+ buffering and contribute to OS-related neuronal hyperexcitability and epileptogenesis during aging.