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TNF‐α‐mediates neuroprotection against glutamate‐induced excitotoxicity via NF‐κB‐dependent up‐regulation of K Ca 2.2 channels
Author(s) -
Dolga Amalia M.,
Granic Ivica,
Blank Thomas,
Knaus HansGuenther,
Spiess Joachim,
Luiten Paul G. M.,
Eisel Ulrich L. M.,
Nijholt Ingrid M.
Publication year - 2008
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2008.05701.x
Subject(s) - neuroprotection , excitotoxicity , apamin , glutamate receptor , potassium channel , chemistry , microbiology and biotechnology , neuroscience , pharmacology , biology , biophysics , biochemistry , receptor
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 (K Ca ) 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 K Ca channels. Interestingly, the expression of K Ca 2.2 channel was up‐regulated by TNF‐α treatment in a time‐dependent manner whereas the expression of K Ca 2.1 and K Ca 2.3 channels was not altered. The increase in K Ca 2.2 channel expression after TNF‐α treatment was shown to be dependent on TNF‐R2 and NF‐κB activation. Furthermore, activation of small conductance K Ca 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 K Ca channel blocker apamin or K Ca 2.2 channel siRNA reverted the neuroprotective effect elicited by TNF‐α. We conclude that treatment of primary cortical neurons with TNF‐α leads to increased K Ca 2.2 channel expression which renders neurons more resistant to excitotoxic cell death.