Document Detail

Potentiation of NMDA receptor-dependent cell responses by extracellular high mobility group box 1 protein.
MedLine Citation:
PMID:  22952988     Owner:  NLM     Status:  MEDLINE    
BACKGROUND: Extracellular high mobility group box 1 (HMGB1) protein can operate in a synergistic fashion with different signal molecules promoting an increase of cell Ca(2+) influx. However, the mechanisms responsible for this effect of HMGB1 are still unknown.
PRINCIPAL FINDINGS: Here we demonstrate that, at concentrations of agonist per se ineffective, HMGB1 potentiates the activation of the ionotropic glutamate N-methyl-D-aspartate receptor (NMDAR) in isolated hippocampal nerve terminals and in a neuroblastoma cell line. This effect was abolished by the NMDA channel blocker MK-801. The HMGB1-facilitated NMDAR opening was followed by activation of the Ca(2+)-dependent enzymes calpain and nitric oxide synthase in neuroblastoma cells, resulting in an increased production of NO, a consequent enhanced cell motility, and onset of morphological differentiation. We have also identified NMDAR as the mediator of HMGB1-stimulated murine erythroleukemia cell differentiation, induced by hexamethylenebisacetamide. The potentiation of NMDAR activation involved a peptide of HMGB1 located in the B box at the amino acids 130-139. This HMGB1 fragment did not overlap with binding sites for other cell surface receptors of HMGB1, such as the advanced glycation end products or the Toll-like receptor 4. Moreover, in a competition assay, the HMGB1((130-139)) peptide displaced the NMDAR/HMGB1 interaction, suggesting that it comprised the molecular and functional site of HMGB1 regulating the NMDA receptor complex.
CONCLUSION: We propose that the multifunctional cytokine-like molecule HMGB1 released by activated, stressed, and damaged or necrotic cells can facilitate NMDAR-mediated cell responses, both in the central nervous system and in peripheral tissues, independently of other known cell surface receptors for HMGB1.
Marco Pedrazzi; Monica Averna; Bianca Sparatore; Mauro Patrone; Franca Salamino; Manuela Marcoli; Guido Maura; Chiara Cervetto; Daniela Frattaroli; Sandro Pontremoli; Edon Melloni
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-08-31
Journal Detail:
Title:  PloS one     Volume:  7     ISSN:  1932-6203     ISO Abbreviation:  PLoS ONE     Publication Date:  2012  
Date Detail:
Created Date:  2012-09-06     Completed Date:  2013-02-07     Revised Date:  2013-07-11    
Medline Journal Info:
Nlm Unique ID:  101285081     Medline TA:  PLoS One     Country:  United States    
Other Details:
Languages:  eng     Pagination:  e44518     Citation Subset:  IM    
Department of Experimental Medicine (DIMES) University of Genova, Genova, Italy.
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MeSH Terms
Acetamides / pharmacology
Aspartic Acid / metabolism
Calcium / metabolism
Cell Death / drug effects
Cell Differentiation / drug effects
Cell Line, Tumor
Cell Movement / drug effects
Enzyme Activation / drug effects
Extracellular Space / drug effects,  metabolism*
HMGB1 Protein / pharmacology*
N-Methylaspartate / pharmacology
Neurites / drug effects,  metabolism
Nitric Oxide / biosynthesis
Nitric Oxide Synthase Type I / metabolism
Presynaptic Terminals / drug effects,  metabolism
Protein Binding / drug effects
Rats, Sprague-Dawley
Receptors, N-Methyl-D-Aspartate / metabolism*
Synaptosomes / drug effects,  metabolism
Reg. No./Substance:
0/Acetamides; 0/HMGB1 Protein; 0/Receptors, N-Methyl-D-Aspartate; 10028-17-8/Tritium; 10102-43-9/Nitric Oxide; 3073-59-4/hexamethylene bisacetamide; 56-84-8/Aspartic Acid; 6384-92-5/N-Methylaspartate; 7440-70-2/Calcium; EC Oxide Synthase Type I

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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