The NMDA receptor functions independently and as an LRP1 co-receptor to promote Schwann cell survival and migration

Abstract

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.

Evidence that LDL receptor-related protein 1 acts as an early injury detection receptor and activates c-Jun in Schwann cells

“…Within 5 min, ERK1/2 was activated (Fig. 1a), as anticipated [15]. Robust c-Jun phosphorylation also was observed in the same timeframe.…”

“…Sprague-Dawley rats (200 g) from Harlan Laboratories (San Diego, CA) were housed in pairs with 12-h-light/dark cycles and ad libitum access to food and water. Surgeries were performed as described previously [15]. Briefly, animals were anesthetized with 5 % isoflurane (Fluriso ™ , VetOne, Boise, ID) and anesthesia was maintained at 3 % isoflurane.…”

The activities of LDL Receptor-related Protein-1 (LRP1) compartmentalize into distinct plasma membrane microdomains

“…It is therefore plausible that rafts are essential for LRP1 signaling selectively in neurons and neuron-like cells because, in these cells, rafts facilitate formation of LRP1-NMDA-R complexes (Mantuano et al, 2013). The NMDA-R also has been identified as an essential LRP1 co-receptor in Schwann cells (Mantuano et al, 2015). Whether the NMDA-R functions in LRP1 signaling in other cell types remains to be determined.…”

Physiological Roles of Non-Neuronal NMDA Receptors

“…Although the involvement of SGC NMDARs in DRG sensitization remains to be demonstrated with conditional silencing approaches in vivo, these data highlight the possibility that PNS glial NMDARs are important nociceptive intermediates. Also in the PNS, NMDAR expression has been reported in Schwann cells [62] and enteric glia [63]. The functional significance of NMDARs in enteric glia is not yet understood; however, in Schwann cells NMDARs are required to mediate the migratory and pro-survival effects of LDL receptor-related protein-1 in vitro and in vivo [62].…”

“…Also in the PNS, NMDAR expression has been reported in Schwann cells [62] and enteric glia [63]. The functional significance of NMDARs in enteric glia is not yet understood; however, in Schwann cells NMDARs are required to mediate the migratory and pro-survival effects of LDL receptor-related protein-1 in vitro and in vivo [62]. Much like their central counterparts, Schwann cell NMDARs appear to influence myelin morphology on peripheral axons [64].…”