Endoplasmic reticulum D-myo-inositol 1,4,5-trisphosphate-sensitive stores regulate nuclear factor-kappaB binding activity in a calcium-independent manner

The Journal of Biological Chemistry
G W GlaznerM P Mattson

Abstract

The transcription factor nuclear factor-kappaB (NF-kappaB) plays critical roles in neuronal survival and plasticity and in activation of immune responses. The activation of NF-kappaB has been closely associated with changes in intracellular calcium levels, but the relationship between the two remains unclear. Here we report that inhibition of endoplasmic reticulum (ER) d-myo-inositol 1,4,5-trisphosphate (IP(3))-gated calcium release caused decreased basal NF-kappaB DNA-binding activity in cultured rat cortical neurons. Activation of NF-kappaB in response to tumor necrosis factor-alpha and glutamate was completely abolished when IP(3) receptors were blocked, and NF-kappaB activation in response to depletion of ER calcium by thapsigargin treatment was also decreased by IP(3) receptor blockade. We further investigated the relationship between IP(3) receptor activation and NF-kappaB activity using a cell-free system. Microsomes enriched in the ER were isolated from adult rat cerebral cortex, resuspended, and treated with agents that induce or inhibit ER calcium release. They were then recentrifuged, and the supernatant was added to cytoplasmic extract isolated from the same source tissue. We found that microsomes released an NF-kap...Continue Reading

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