Campana Wendy M, Mantuano Elisabetta, Azmoon Pardis, Henry Kenneth, Banki Michael A, Kim John H, Pizzo Donald P, Gonias Steven L
Department of Anesthesiology School of Medicine, University of California, San Diego, La Jolla, California, USA;
Department of Pathology, School of Medicine, University of California, San Diego, La Jolla, California, USA.
FASEB J. 2017 Apr;31(4):1744-1755. doi: 10.1096/fj.201601121R. Epub 2017 Jan 10.
In the peripheral nervous system, Schwann cells (SCs) demonstrate surveillance activity, detecting injury and undergoing -differentiation to support repair. SC receptors that detect peripheral nervous system injury remain incompletely understood. We used RT-PCR to profile ionotropic glutamate receptor expression in cultured SCs. We identified subunits required for assembly of -methyl-d-aspartic acid (NMDA) receptors (NMDA-Rs), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, and kainate receptors. Treatment of SCs with 40-100 µM glutamate or with 0.5-1.0 µM NMDA robustly activated Akt and ERK1/2. The response was transient and bimodal; glutamate concentrations that exceeded 250 µM failed to activate cell signaling. Phosphoprotein profiling identified diverse phosphorylated proteins in glutamate-treated SCs in addition to ERK1/2 and Akt, including p70 S6-kinase, glycogen synthase kinase-3, ribosomal S6 kinase, c-Jun, and cAMP response element binding protein. Activation of SC signaling by glutamate was blocked by EGTA and dizocilpine and by silencing expression of the NMDA-R NR1 subunit. Phosphoinositide 3-kinase/PI3K functioned as an essential upstream activator of Akt and ERK1/2 in glutamate-treated SCs. When glutamate or NMDA was injected directly into crush-injured rat sciatic nerves, ERK1/2 phosphorylation was observed in myelinated and nonmyelinating SCs. Glutamate promoted SC migration by a pathway that required PI3K and ERK1/2. These results identified ionotropic glutamate receptors and NMDA-Rs, specifically, as potentially important cell signaling receptors in SCs.-Campana, W. M., Mantuano, E., Azmoon, P., Henry, K., Banki, M. A., Kim, J. H., Pizzo, D. P., Gonias, S. L. Ionotropic glutamate receptors activate cell signaling in response to glutamate in Schwann cells.
在周围神经系统中，施万细胞（SCs）具有监测活性，能检测损伤并进行分化以支持修复。然而，对于检测周围神经系统损伤的施万细胞受体，人们仍了解不足。我们运用逆转录聚合酶链反应（RT-PCR）来分析培养的施万细胞中离子型谷氨酸受体的表达情况。我们鉴定出了组装N-甲基-D-天冬氨酸（NMDA）受体（NMDA-Rs）、α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体和海人藻酸受体所需的亚基。用40 - 100 μM谷氨酸或0.5 - 1.0 μM NMDA处理施万细胞，能强烈激活Akt和细胞外信号调节激酶1/2（ERK1/2）。这种反应是短暂且双峰的；超过250 μM的谷氨酸浓度无法激活细胞信号传导。磷酸化蛋白分析表明，除了ERK1/2和Akt外，谷氨酸处理的施万细胞中还有多种磷酸化蛋白，包括p70 S6激酶、糖原合酶激酶-3、核糖体S6激酶、c-Jun和cAMP反应元件结合蛋白。谷氨酸对施万细胞信号传导的激活被乙二醇双四乙酸（EGTA）、地卓西平以及沉默NMDA-R NR1亚基的表达所阻断。磷脂酰肌醇3-激酶（PI3K）在谷氨酸处理的施万细胞中作为Akt和ERK1/2的重要上游激活剂发挥作用。当将谷氨酸或NMDA直接注射到挤压损伤的大鼠坐骨神经中时，在有髓和无髓施万细胞中均观察到ERK1/2的磷酸化。谷氨酸通过一条需要PI3K和ERK1/2的途径促进施万细胞迁移。这些结果明确了离子型谷氨酸受体和NMDA-Rs具体作为施万细胞中潜在重要的细胞信号受体。 - 坎帕纳，W.M.，曼图亚诺，E.，阿兹穆恩，P.，亨利，K.，班基，M.A.，金，J.H.，皮佐，D.P.，戈尼亚斯，S.L. 离子型谷氨酸受体在施万细胞中响应谷氨酸激活细胞信号传导。
