Glutamate cytotoxicity in a neuronal cell line is blocked by membrane depolarization

To understand better the proximate mechanism involved in the excitotoxic response to l-glutamate (Glu), we have exploited the Glu receptor present in the N18-RE-105 neuroblastoma-embryonic retinal hybrid cell line. These cells undergo lysis dependent on extracellular Ca²⁺ when exposed to Glu. We now report that the depolarizing action of Glu is not responsible for its cytotoxic effects. Furthermore, depolarization of these cells with elevated K⁺, ouabain or veratridine does not cause cytotoxicity but rather protects against the cytotoxic effects of Glu. Our results may implicate a role for voltage-sensitive Ca²⁺ channels (VSCCs) in cytotoxicity, and depolarization-induced inactivation of VSCCs (Nature (Lond.), 316 (1985) 440-443.) as a protection against Glu receptor agonists. Our findings demonstrate a clear dissociation between depolarization and the neuronal degeneration caused by Glu.