PT  - JOURNAL ARTICLE
AU  - Mantuano, Elisabetta
AU  - Lam, Michael S.
AU  - Shibayama, Masataka
AU  - Campana, W. Marie
AU  - Gonias, Steven L.
TI  - The NMDA receptor functions independently and as an LRP1 co-receptor to promote Schwann cell survival and migration
AID  - 10.1242/jcs.173765
DP  - 2015 Sep 15
TA  - Journal of Cell Science
PG  - 3478--3488
VI  - 128
IP  - 18
4099  - http://jcs.biologists.org/content/128/18/3478.short
4100  - http://jcs.biologists.org/content/128/18/3478.full
SO  - J. Cell Sci.2015 Sep 15; 128
AB  - 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.