Abstract
Normal neuronal functioning is dependent on the blood-brain barrier. This barrier is confined to specialized brain endothelial cells lining the inner vessel wall, and tightly controlling transport of nutrients, efflux of potentially harmful molecules and entry of immune cells into the brain. Loss of blood-brain barrier function is an early and significant event which contributes to inflammation in the brain and subsequent progression of neuronal deficits in a number of brain disorders and has been well-documented for the auto-immune disease multiple sclerosis. Extravasation of cells happens by paracellular transport across the endothelial junctions, transcellularly across the endothelial cells, or both, and requires the active participation of endothelial cells. We and others have shown that this process requires the activity of proteases, including tissue-type plasminogen activator. We here describe a novel role for NMDA receptor, a potential cellular target of tissue-type plasminogen activator, in human brain endothelial cells. Our results show that the NMDA receptor subunit 1 (NR1) is expressed in brain endothelial cells, regulates tissue-type plasminogen activator-induced signal transduction and controls the passage of monocytes through the brain endothelial cell barrier. Together, our results hold significant promise for the treatment of chronic inflammation in the brain.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Blood-Brain Barrier / drug effects
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Blood-Brain Barrier / physiology*
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Brain / cytology*
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Cell Movement / drug effects
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Cell Movement / physiology*
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Cells, Cultured
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Chemokine CCL2 / metabolism
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Disease Models, Animal
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Dizocilpine Maleate / pharmacology
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Encephalomyelitis, Autoimmune, Experimental / etiology
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Encephalomyelitis, Autoimmune, Experimental / immunology
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Encephalomyelitis, Autoimmune, Experimental / pathology
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Endothelial Cells / drug effects
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Endothelial Cells / physiology
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Enzyme Activation / drug effects
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Excitatory Amino Acid Antagonists / pharmacology
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Female
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Humans
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Immunoprecipitation / methods
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Leukocyte Common Antigens / metabolism
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Membrane Proteins / metabolism
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Mice
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Monocytes / drug effects
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Monocytes / physiology*
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Myelin Proteins
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Myelin-Associated Glycoprotein / immunology
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Myelin-Oligodendrocyte Glycoprotein
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Phosphoproteins / metabolism
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Receptors, N-Methyl-D-Aspartate / physiology*
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Signal Transduction / drug effects
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Tissue Plasminogen Activator / pharmacology
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Zonula Occludens-1 Protein
Substances
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CCL2 protein, human
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Chemokine CCL2
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Excitatory Amino Acid Antagonists
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MOG protein, human
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Membrane Proteins
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Mog protein, mouse
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Myelin Proteins
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Myelin-Associated Glycoprotein
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Myelin-Oligodendrocyte Glycoprotein
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NR1 NMDA receptor
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Phosphoproteins
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Receptors, N-Methyl-D-Aspartate
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TJP1 protein, human
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Tjp1 protein, mouse
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Zonula Occludens-1 Protein
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Dizocilpine Maleate
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Leukocyte Common Antigens
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Tissue Plasminogen Activator