Nonionotropic Action of Endothelial NMDA Receptors on Blood–Brain Barrier Permeability via Rho/ROCK-Mediated Phosphorylation of Myosin - Archive ouverte HAL Access content directly
Journal Articles Journal of Neuroscience Year : 2020

Nonionotropic Action of Endothelial NMDA Receptors on Blood–Brain Barrier Permeability via Rho/ROCK-Mediated Phosphorylation of Myosin

(1) , (1) , (1) , (2) , (2) , (1) , (1) , (3) , (1) , (1) , (1)
1
2
3

Abstract

Increase in blood-brain barrier (BBB) permeability is a crucial step in neuroinflammatory processes. We previously showed that N Methyl D Aspartate Receptor (NMDARs), expressed on cerebral endothelial cells forming the BBB, regulate immune cell infiltration across this barrier in the mouse. Here, we describe the mechanism responsible for the action of NMDARs on BBB permeabilization. We report that mouse CNS endothelial NMDARs display the regulatory GluN3A subunit. This composition confers to NMDARs' unconventional properties: these receptors do not induce Ca2+ influx but rather show nonionotropic properties. In inflammatory conditions, costimulation of human brain endothelial cells by NMDA agonists (NMDA or glycine) and the serine protease tissue plasminogen activator, previously shown to potentiate NMDAR activity, induces metabotropic signaling via the Rho/ROCK pathway. This pathway leads to an increase in permeability via phosphorylation of myosin light chain and subsequent shrinkage of human brain endothelial cells. Together, these data draw a link between NMDARs and the cytoskeleton in brain endothelial cells that regulates BBB permeability in inflammatory conditions.SIGNIFICANCE STATEMENT The authors describe how NMDARs expressed on endothelial cells regulate blood-brain barrier function via myosin light chain phosphorylation and increase in permeability. They report that these non-neuronal NMDARs display distinct structural, functional, and pharmacological features than their neuronal counterparts.
Fichier principal
Vignette du fichier
Mehra et al., 2020.pdf (3.69 Mo) Télécharger le fichier
Origin : Publisher files allowed on an open archive

Dates and versions

hal-02535778 , version 1 (12-01-2022)

Licence

Attribution - NonCommercial - ShareAlike - CC BY 4.0

Identifiers

Cite

Anupriya Mehra, Sylvaine Guérit, Richard Macrez, Fabien Gosselet, Emmanuel Sevin, et al.. Nonionotropic Action of Endothelial NMDA Receptors on Blood–Brain Barrier Permeability via Rho/ROCK-Mediated Phosphorylation of Myosin. Journal of Neuroscience, 2020, 40 (8), pp.1778-1787. ⟨10.1523/JNEUROSCI.0969-19.2019⟩. ⟨hal-02535778⟩
33 View
21 Download

Altmetric

Share

Gmail Facebook Twitter LinkedIn More