TNF-α-mediates neuroprotection against glutamate-induced excitotoxicity via NF-κB-dependent up-regulation of Kca2.2 channels

Previous studies have shown that tumor necrosis factor-alpha (TNF-α) induces neuroprotection against excitotoxic damage in primary cortical neurons via sustained nuclear factor-kappa B (NF-κB) activation. The transcription factor NF-κB can regulate the expression of small conductance calcium-activated potassium (KCa) channels. These channels reduce neuronal excitability and as such may yield neuroprotection against neuronal overstimulation. In the present study we investigated whether TNF-α-mediated neuroprotective signaling is inducing changes in the expression of small conductance KCa channels. Interestingly, the expression of KCa2.2 channel was up-regulated by TNF-α treatment in a time-dependent manner whereas the expression of KCa2.1 and KCa2.3 channels was not altered. The increase in KCa2.2 channel expression after TNF-α treatment was shown to be dependent on TNF-R2 and NF-κB activation. Furthermore, activation of small conductance KCa channels by 6,7-dichloro-1H-indole-2,3-dione 3-oxime or cyclohexyl-[2-(3,5-dimethyl-pyrazol-1-yl)-6-methyl-pyrimidin-4-yl]-amine-induced neuroprotection against a glutamate challenge. Treatment with the small conductance KCa channel blocker apamin or KCa2.2 channel siRNA reverted the neuroprotective effect elicited by TNF-α. We conclude that treatment of primary cortical neurons with TNF-α leads to increased KCa2.2 channel expression which renders neurons more resistant to excitotoxic cell death.