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

Anupriya Mehra, Sylvaine Guérit, Richard Macrez, Fabien Gosselet, Emmanuel Sevin, Héloïse Lebas, Eric Maubert, Helga E De Vries, Isabelle Bardou, Denis Vivien, Fabian Docagne

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29 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)1778-1787
Number of pages10
JournalJournal of neuroscience
Issue number8
Publication statusPublished - 19 Feb 2020


  • Animals
  • Blood-Brain Barrier/drug effects
  • Cell Line
  • Cerebral Cortex/drug effects
  • Endothelial Cells/drug effects
  • Excitatory Amino Acid Agonists/pharmacology
  • Male
  • Mice
  • Myosins/metabolism
  • N-Methylaspartate/pharmacology
  • Neurons/drug effects
  • Permeability
  • Phosphorylation/drug effects
  • Receptors, N-Methyl-D-Aspartate/agonists
  • Signal Transduction/drug effects
  • Tissue Plasminogen Activator/pharmacology
  • Tumor Necrosis Factor-alpha/pharmacology
  • rho GTP-Binding Proteins/metabolism
  • rho-Associated Kinases/metabolism

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