Endoplasmic Reticulum D-myo-Inositol 1,4,5-Trisphosphate-sensitive Stores Regulate Nuclear Factor-κB Binding Activity in a Calcium-independent Manner

Gordon W. Glazner, Simonetta Camandola, Jonathan D. Geiger, Mark P. Mattson

Research output: Contribution to journalArticlepeer-review

Abstract

The transcription factor nuclear factor-κB (NF-κB) plays critical roles in neuronal survival and plasticity and in activation of immune responses. The activation of NF-κB 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 (IP3)-gated calcium release caused decreased basal NF-κB DNA-binding activity in cultured rat cortical neurons. Activation of NF-κB in response to tumor necrosis factor-α and glutamate was completely abolished when IP3 receptors were blocked, and NF-κB activation in response to depletion of ER calcium by thapsigargin treatment was also decreased by IP3 receptor blockade. We further investigated the relationship between IP 3 receptor activation and NF-κB 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-κB-stimulating signal in response to activation of IP3 receptors or inhibition of the ER Ca2+ -ATPase, but not in response to ryanodine. Studies of intact cells and cell-free preparations indicated that the signal released from the ER was not calcium and was heat- and trypsin-sensitive. Our data suggest that activation of IP 3 receptors is required for a major component of both constitutive and inducible NF-κB binding activity in neurons and that decreasing ER intraluminal calcium levels triggers release of a diffusible NF-κB-activating signal from the ER.

Original languageEnglish (US)
Pages (from-to)22461-22467
Number of pages7
JournalJournal of Biological Chemistry
Volume276
Issue number25
DOIs
StatePublished - Jun 22 2001

ASJC Scopus subject areas

  • Biochemistry

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