Essential Role for Epidermal Growth Factor Receptor in Glutamate Receptor Signaling to NF- B

Glutamate is a critical neurotransmitter of the central nervous system (CNS) and also an important regulator of cell survival and proliferation. The binding of glutamate to metabotropic glutamate receptors induces signal transduction cascades that lead to gene-specific transcription. The transcription factor NFB, which regulates cell proliferation and survival, is activated by glutamate; however, the glutamate receptorinduced signaling pathways that lead to this activation are not clearly defined. Here we investigate the glutamate-induced activation of NFB in glial cells of the CNS, including primary astrocytes. We show that glutamate induces phosphorylation, nuclear accumulation, DNA binding, and transcriptional activation function of glial p65. The glutamate-induced activation of NFB requires calcium-dependent I B kinase (IKK ) and IKK activation and induces p65-I B dissociation in the absence of I B phosphorylation or degradation. Moreover, glutamate-induced IKK preferentially targets the phosphorylation of p65 but not I B . Finally, we show that the ability of glutamate to activate NFB requires cross-coupled signaling with the epidermal growth factor receptor. Our results provide insight into a glutamate-induced regulatory pathway distinct from that described for cytokine-induced NFB activation and have important implications with regard to both normal glial cell physiology and pathogenesis.