Oxidative stress targets Kir2.1 channel in a model of aging neuroglia

Abstract

Oxidative stress (OS) has a main role in the pathogenesis of central nervous system disorders. In this regard, epilepsy is a highly prevalent serious brain disease and its prevalence increases with age. Strikingly, about 50% of all epilepsy cases diagnosed in elderly patients (>65 years) are idiopathic. Metabolic changes, including the production of reactive oxygen species (ROS), are regarded to as possible mechanism involved in epileptogenesis. The neuronal 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 OS‐related aging models, long‐term (24 hours) exposure to D‐Galactose (D‐Gal, 100 mM) is considered the most similar to natural aging. In the present study, we investigated the effect of D‐Gal‐induced aging on Kir channel activity in glioblastoma U87‐MG cells. Screening of all fifteen Kir isoforms revealed that the predominant transcript corresponds to Kir2.1, with minor contribution of Kir4.1. D‐Galactose had no obvious cytotoxicity, but strongly promoted OS, namely increased lipoperoxidation levels and decreased the membrane protein sulfhydryl group abundance. Interestingly, D‐Gal exposure was associated with a decrease of inwardly rectifying K+ currents sensitive to ML‐133, a specific inhibitor of Kir2.1 channels. Our findings reveal a novel Kir2.1 channel modulation that is likely to occur in OS. We suggest that inhibition of Kir2.1 channels in glia cells may alter extracellular K+ buffering and contribute to OS‐related neuronal hyperexcitability and epileptogenesis during aging.