Superoxide enters neurons via LRRC8A-containing volume-regulated anion channels

Superoxide (O2-) is both an intercellular signaling molecule and a cause of neuronal oxidative stress. Superoxide entry into neurons is thought to be indirect, requiring its dismutation to nonpolar hydrogen peroxide. Here we show instead that superoxide enters neurons directly, via LRRC8A-containing volume-sensitive organic anion channels. In primary cultures, neuronal oxidative stress induced either by NMDA receptor stimulation or exposure to authentic superoxide was blocked by the anion channel blockers DIDS and DCPIB and by LRRC8A gene disruption. In mouse cortex, neuronal oxidative stress induced by either NMDA injection or transient ischemia was likewise blocked by both DCPIB and LRRC8A gene disruption. These findings identify a role for LRRC8A-containing volume-sensitive organic anion channels in neuronal oxidative signaling, stress, and glutamate excitotoxicity.