Kainate mediates nuclear factor-kappa B activation in hippocampus via phosphatidylinositol-3 kinase and extracellular signal-regulated protein kinase

Neuroscience. 2005;133(4):969-81. doi: 10.1016/j.neuroscience.2005.03.028.


The transcription factor nuclear factor-kappa B (NF-kappaB) is an inducible regulator of genes that plays a crucial role in the nervous system. Glutamate receptor stimulation is one well-described mechanism for NF-kappaB activation. In the studies presented here we used the glutamate analog, kainate to investigate the signaling mechanisms that couple to NF-kappaB activation in hippocampus. Kainate (250 nM) application to hippocampal slices elicited a time-dependent increase in nuclear NF-kappaB levels in areas CA3 and CA1, but not dentate, compared with controls. Further analysis focused on hippocampal area CA3, revealed increased NF-kappaB DNA binding activity in response to kainate stimulation. Supershift electrophoretic mobility shift assay indicated that the kainate-mediated NF-kappaB complex binding DNA was composed of p65, p50, and c-Rel subunits. Through inhibition studies we found that extracellular signal-regulated protein kinase (ERK) and phosphatidylinositol-3 kinase (PI3K) couple to basal and kainate-mediated NF-kappaB DNA binding activity in area CA3. Kainate elicited decreased total and increased phospho-inhibitor kappa B alpha (IkappaBalpha), suggesting that kainate-mediated activation of NF-kappaB is via the classical IkappaB kinase pathway. Interestingly, inhibition of ERK but not PI3K blocked the kainate-mediated increase in phospho-IkappaBalpha. Thus, our findings support a role for the ERK and PI3K pathways in kainate-mediated NF-kappaB activation in hippocampal area CA3, but these kinases may target the NF-kappaB pathway at different loci.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Blotting, Western / methods
  • Chromones / pharmacology
  • Drug Interactions
  • Electrophoretic Mobility Shift Assay / methods
  • Enzyme Activation / drug effects
  • Enzyme Activation / physiology
  • Enzyme Inhibitors / pharmacology
  • Excitatory Amino Acid Agonists / pharmacology*
  • Flavonoids / pharmacology
  • Hippocampus / drug effects*
  • Immunohistochemistry / methods
  • In Vitro Techniques
  • Kainic Acid / pharmacology*
  • Lamin Type B / metabolism
  • MAP Kinase Kinase Kinases / physiology*
  • Male
  • Morpholines / pharmacology
  • NF-kappa B / metabolism*
  • Phosphatidylinositol 3-Kinases / physiology*
  • Phosphorylation / drug effects
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Time Factors


  • Chromones
  • Enzyme Inhibitors
  • Excitatory Amino Acid Agonists
  • Flavonoids
  • Lamin Type B
  • Morpholines
  • NF-kappa B
  • lamin B1
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Phosphatidylinositol 3-Kinases
  • MAP Kinase Kinase Kinases
  • Kainic Acid
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one