Two Pathways Are Better than One

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Science  15 Aug 2008:
Vol. 321, Issue 5891, pp. 893
DOI: 10.1126/science.321.5891.893c

Glutamate mediates functions such as synaptic plasticity, proliferation, and survival via metabotropic receptors (mGluRs) on neurons and glial cells. Sitcheran et al. demonstrate that glutamate promotes the binding of the p65 and p50 subunits of the transcription factor NF-κB to DNA. Glutamate activation of NF-κB was comparable to that produced by epidermal growth factor (EGF) binding to its receptor EGFR, which is found on astrocytes. Glutamate also induced the phosphorylation and activation of inhibitor of κB kinase α and β (IKKα and IKKβ) and of p65. In canonical NF-κB signaling, IKKβ phosphorylates IκBα, which leads to its degradation and the release of active NF-κB subunits, but glutamate did not increase phosphorylation or degradation of IκBα, although it did dissociate IκBα and p65. Knockdown of EGFR blocked mGluR5-stimulated phosphorylation of p65; conversely, mGluR5 stimulation led to the phosphorylation of tyrosine residues in EGFR and to its association with mGluR5. A Ca2+ chelator blocked mGluR5-mediated NF-κB activation, and an inhibitor of EGFR activity reduced mGluR5-stimulated Ca2+ signaling. Together, these data suggest that EGFR signaling is critical for the activation of NF-κB by glutamate. — JFF

Mol. Cell. Biol. 28, 5061 (2008).

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