TNF-alpha-mediates neuroprotection against glutamate-induced excitotoxicity via NF-kappaB-dependent up-regulation of K2.2 channels.
Previous studies have shown that tumor necrosis factor-alpha (TNF-alpha) induces neuroprotection against excitotoxic damage in primary cortical neurons via sustained nuclear factor-kappa B (NF-kappaB) activation. The transcription factor NF-kappaB 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-alpha-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-alpha 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-alpha treatment was shown to be dependent on TNF-R2 and NF-kappaB 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-alpha. We conclude that treatment of primary cortical neurons with TNF-alpha leads to increased K(Ca)2.2 channel expression which renders neurons more resistant to excitotoxic cell death.
Dolga
Amalia M
AM
Department of Molecular Neurobiology, University of Groningen, Haren, The Netherlands. a.m.dolga@rug.nl
Granic
Ivica
I
Blank
Thomas
T
Knaus
Hans-Guenther
HG
Spiess
Joachim
J
Luiten
Paul G M
PG
Eisel
Ulrich L M
UL
Nijholt
Ingrid M
IM
D000818:Animals; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018698:Glutamic Acid / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects; D018696:Neuroprotective Agents / Q000378:metabolism / Q000494:pharmacology; D020258:Neurotoxicity Syndromes / Q000209:etiology* / Q000517:prevention & control*; D009570:Nitriles / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000494:pharmacology; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000172:deficiency; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000172:deficiency; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000235:genetics / Q000378:metabolism*; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism; D013450:Sulfones / Q000494:pharmacology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics / Q000502:physiology*
C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D004791:Enzyme Inhibitors; D016328:NF-kappa B; D018696:Neuroprotective Agents; D009570:Nitriles; D034741:RNA, Small Interfering; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D051640:Small-Conductance Calcium-Activated Potassium Channels; D013450:Sulfones; D014409:Tumor Necrosis Factor-alpha; D018698:Glutamic Acid