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

Anupriya Mehra (1) , Sylvaine Guérit (1) , Richard Macrez (1) , Fabien Gosselet (2) , Emmanuel Sevin (2) , Héloïse Lebas (1) , Eric Maubert (1) , Helga de Vries (3) , Isabelle Bardou (1) , Denis Vivien (1) , Fabian Docagne (1)

1 PhIND - Physiopathologie et imagerie des troubles neurologiques
2 LBHE - Laboratoire de la Barrière Hémato-Encéphalique
3 Department of Molecular Cell Biology and Immunology (Academic Medical Center, Amsterdam)

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.

Mots clés: NMDA; blood–brain barrier; endothelial cells; neuroinflammation; permeability; signal transduction

Domaines: Sciences du Vivant [q-bio]

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⟩