Essential role for epidermal growth factor receptor in glutamate receptor signaling to NF-κB
Essential role for epidermal growth factor receptor in glutamate receptor signaling to NF-κB
复制标题
DOI：
10.1128/mcb.00578-08
复制
发表时间：
2008-08-01
影响因子：
5.3
通讯作者：
Baldwin, Albert S.
中科院分区：
文献类型：
--
作者：
Sitcheran, Raquel;Comb, William C.;Baldwin, Albert S.
谷氨酸是中枢神经系统（CNS）的重要神经递质，也是细胞存活和增殖的重要调节因子。谷氨酸与代谢型谷氨酸受体的结合诱导导致基因特异性转录的信号转导级联。调节细胞增殖和存活的转录因子NF-κ B被谷氨酸激活;然而，导致这种激活的谷氨酸受体诱导的信号通路尚未明确定义。在这里，我们研究了谷氨酸诱导的激活NF-κ B B在神经胶质细胞的中枢神经系统，包括原代星形胶质细胞。我们发现，谷氨酸诱导磷酸化，核积累，DNA结合，和神经胶质细胞p65的转录激活功能。谷氨酸诱导的NF-κ B活化需要钙依赖性I κ B激酶α（IKK α）和IKK β活化，并在I κ B α磷酸化或降解不存在的情况下诱导p65-I κ B α解离。此外，谷氨酸诱导的IKK优先靶向p65的磷酸化，而不是I κ B α。最后，我们发现谷氨酸激活NF-κ B的能力需要与表皮生长因子受体交叉偶联信号。我们的研究结果提供了一个谷氨酸诱导的调节途径，不同于所描述的精氨酸诱导的NF-κ B激活，并具有重要的意义，与正常的神经胶质细胞的生理和发病机制。
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 NF-kappa B, which regulates cell proliferation and survival, is activated by glutamate; however, the glutamate receptor-induced signaling pathways that lead to this activation are not clearly defined. Here we investigate the glutamate-induced activation of NF-kappa B 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 NF-kappa B requires calcium-dependent I kappa B kinase alpha (IKK alpha) and IKK beta activation and induces p65-I kappa B alpha dissociation in the absence Of I kappa B alpha phosphorylation or degradation. Moreover, glutamate-induced IKK preferentially targets the phosphorylation of p65 but not I kappa B alpha. Finally, we show that the ability of glutamate to activate NF-kappa B 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 NF-kappa B activation and have important implications with regard to both normal glial cell physiology and pathogenesis.