The NMDA receptor functions independently and as an LRP1 co-receptor to promote Schwann cell survival and migration.
NMDA receptors (NMDA-Rs) are ionotropic glutamate receptors, which associate with LDL-receptor-related protein-1 (LRP1) to trigger cell signaling in response to protein ligands in neurons. Here, we demonstrate for the first time that the NMDA-R is expressed by rat Schwann cells and functions independently and with LRP1 to regulate Schwann cell physiology. The NR1 (encoded by GRIN1) and NR2b (encoded by GRIN2B) NMDA-R subunits were expressed by cultured Schwann cells and upregulated in sciatic nerves following crush injury. The ability of LRP1 ligands to activate ERK1/2 (also known as MAPK3 and MAPK1, respectively) and promote Schwann cell migration required the NMDA-R. NR1 gene silencing compromised Schwann cell survival. Injection of the LRP1 ligands tissue-type plasminogen activator (tPA, also known as PLAT) or MMP9-PEX into crush-injured sciatic nerves activated ERK1/2 in Schwann cells in vivo, and the response was blocked by systemic treatment with the NMDA-R inhibitor MK801. tPA was unique among the LRP1 ligands examined because tPA activated cell signaling and promoted Schwann cell migration by interacting with the NMDA-R independently of LRP1, albeit with delayed kinetics. These results define the NMDA-R as a Schwann cell signaling receptor for protein ligands and a major regulator of Schwann cell physiology, which may be particularly important in peripheral nervous system (PNS) injury.
Department of Pathology, University of California San Diego, La Jolla, CA 92093, USA Department of Experimental Medicine, Sapienza University of Rome, Rome 00161, Italy.
Elisabetta
E
Mantuano
Department of Pathology, University of California San Diego, La Jolla, CA 92093, USA.
Michael S
MS
Lam
Department of Anesthesiology, University of California San Diego, La Jolla, CA 92093, USA.
Masataka
M
Shibayama
Department of Anesthesiology, University of California San Diego, La Jolla, CA 92093, USA The Program in Neuroscience, University of California San Diego, La Jolla, CA 92093, USA.
W Marie
WM
Campana
Department of Pathology, University of California San Diego, La Jolla, CA 92093, USA sgonias@ucsd.edu.
Steven L
SL
Gonias
D000818:Animals; D002478:Cells, Cultured; D016291:Dizocilpine Maleate / Q000494:pharmacology; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D059348:Peripheral Nerve Injuries / Q000378:metabolism; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D012583:Schwann Cells / Q000502:physiology*; D012584:Sciatic Nerve; D015398:Signal Transduction; D010959:Tissue Plasminogen Activator / Q000378:metabolism
D026503:Low Density Lipoprotein Receptor-Related Protein-1; D016194:Receptors, N-Methyl-D-Aspartate; D016291:Dizocilpine Maleate; D010959:Tissue Plasminogen Activator; D020780:Matrix Metalloproteinase 9; C572337:Mmp9 protein, rat
LRP1; MMP9; NMDA receptor; Peripheral nerve; Schwann cell; Tissue-type plasminogen activator; α2-macroglobulin