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PI3Kγ contributes to MEK1/2 activation in oxidative glutamate toxicity via PDK1

Jong Seong Ha1, Ki-Sun Kwon, Sung Sup Park

  • 1Aging Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Korea.

Journal of Neurochemistry
|July 18, 2013
PubMed

Insights

Phosphoinositide 3-kinase (PI3K) activation contributes to oxidative glutamate toxicity by increasing hydrogen peroxide generation via ERK1/2 and PDK1. Inhibiting PI3Kγ enhances neuronal survival in glutamate-induced toxicity.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Biochemistry

Background:

  • Oxidative glutamate toxicity is a significant concern in neurological conditions.
  • The precise role of phosphoinositide 3-kinase (PI3K) in this process remains unclear.
  • Understanding PI3K's involvement is crucial for developing therapeutic strategies.

Purpose of the Study:

  • To investigate the role of PI3K in oxidative glutamate toxicity.
  • To identify specific PI3K isoforms involved in glutamate-induced cell death.
  • To elucidate the signaling pathways linking PI3K to hydrogen peroxide generation.

Main Methods:

  • Utilized HT22 mouse hippocampal cells and primary cortical neuronal cultures.
  • Employed PI3K inhibitors (LY294002, wortmannin) and a MEK inhibitor (U0126).
  • Performed small interfering RNA (siRNA) knockdown studies for PI3K isoforms and transfected cells with PI3Kγ and PDK1 constructs.

Main Results:

  • PI3K inhibitors suppressed extracellular hydrogen peroxide (H₂O₂) generation and increased cell survival.
  • PI3Kβ and PI3Kγ isoforms were identified as key contributors to glutamate-induced H₂O₂ generation and cell death.
  • PI3Kγ activation led to ERK1/2 phosphorylation and H₂O₂ generation, a process dependent on PDK1 and MEK signaling.

Conclusions:

  • Activation of PI3Kγ plays a critical role in oxidative glutamate toxicity.
  • The PI3Kγ-PDK1-MEK-ERK1/2 pathway mediates extracellular H₂O₂ generation.
  • Targeting PI3Kγ may offer a neuroprotective strategy against glutamate toxicity.
Keywords:
PDK1PI3Kγoxidative glutamate toxicity

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