title: Ionotropic glutamate receptors activate cell signaling in response to glutamate in Schwann cells.
abstract: In the peripheral nervous system, Schwann cells (SCs) demonstrate surveillance activity, detecting injury and undergoingtrans-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 ofN-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.
authors.affiliation: Department of Anesthesiology School of Medicine, University of California, San Diego, La Jolla, California, USA; wcampana@ucsd.edu.
authors.forename: Wendy M
authors.initials: WM
authors.lastname: Campana
authors.affiliation: Department of Pathology, School of Medicine, University of California, San Diego, La Jolla, California, USA.|Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Mantuano
authors.affiliation: Department of Pathology, School of Medicine, University of California, San Diego, La Jolla, California, USA.
authors.forename: Pardis
authors.initials: P
authors.lastname: Azmoon
authors.affiliation: Department of Anesthesiology School of Medicine, University of California, San Diego, La Jolla, California, USA.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Henry
authors.affiliation: Department of Pathology, School of Medicine, University of California, San Diego, La Jolla, California, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Banki
authors.affiliation: Department of Anesthesiology School of Medicine, University of California, San Diego, La Jolla, California, USA.
authors.forename: John H
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Department of Pathology, School of Medicine, University of California, San Diego, La Jolla, California, USA.
authors.forename: Donald P
authors.initials: DP
authors.lastname: Pizzo
authors.affiliation: Department of Pathology, School of Medicine, University of California, San Diego, La Jolla, California, USA; sgonias@ucsd.edu.
authors.forename: Steven L
authors.initials: SL
authors.lastname: Gonias
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism* / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D058468:Receptors, Ionotropic Glutamate / Q000378:metabolism*; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D012583:Schwann Cells / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D058468:Receptors, Ionotropic Glutamate; D018698:Glutamic Acid; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D019893:Ribosomal Protein S6 Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D038362:Glycogen Synthase Kinase 3
keywords: AMPA receptor; NMDA receptor; kainate receptor; migration; peripheral nerve injury