PMID- 22952988
OWN - NLM
STAT- MEDLINE
DCOM- 20130207
LR  - 20211021
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 7
IP  - 8
DP  - 2012
TI  - Potentiation of NMDA receptor-dependent cell responses by extracellular high 
      mobility group box 1 protein.
PG  - e44518
LID - 10.1371/journal.pone.0044518 [doi]
LID - e44518
AB  - 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.
FAU - Pedrazzi, Marco
AU  - Pedrazzi M
AD  - Department of Experimental Medicine (DIMES) University of Genova, Genova, Italy.
FAU - Averna, Monica
AU  - Averna M
FAU - Sparatore, Bianca
AU  - Sparatore B
FAU - Patrone, Mauro
AU  - Patrone M
FAU - Salamino, Franca
AU  - Salamino F
FAU - Marcoli, Manuela
AU  - Marcoli M
FAU - Maura, Guido
AU  - Maura G
FAU - Cervetto, Chiara
AU  - Cervetto C
FAU - Frattaroli, Daniela
AU  - Frattaroli D
FAU - Pontremoli, Sandro
AU  - Pontremoli S
FAU - Melloni, Edon
AU  - Melloni E
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120831
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Acetamides)
RN  - 0 (HMGB1 Protein)
RN  - 0 (Receptors, N-Methyl-D-Aspartate)
RN  - 10028-17-8 (Tritium)
RN  - 30KYC7MIAI (Aspartic Acid)
RN  - 31C4KY9ESH (Nitric Oxide)
RN  - 6384-92-5 (N-Methylaspartate)
RN  - EC 1.14.13.39 (Nitric Oxide Synthase Type I)
RN  - LA133J59VU (hexamethylene bisacetamide)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Acetamides/pharmacology
MH  - Animals
MH  - Aspartic Acid/metabolism
MH  - Calcium/metabolism
MH  - Cell Death/drug effects
MH  - Cell Differentiation/drug effects
MH  - Cell Line, Tumor
MH  - Cell Movement/drug effects
MH  - Enzyme Activation/drug effects
MH  - Extracellular Space/drug effects/*metabolism
MH  - HMGB1 Protein/*pharmacology
MH  - Humans
MH  - Male
MH  - Mice
MH  - N-Methylaspartate/pharmacology
MH  - Neurites/drug effects/metabolism
MH  - Nitric Oxide/biosynthesis
MH  - Nitric Oxide Synthase Type I/metabolism
MH  - Presynaptic Terminals/drug effects/metabolism
MH  - Protein Binding/drug effects
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Receptors, N-Methyl-D-Aspartate/*metabolism
MH  - Synaptosomes/drug effects/metabolism
MH  - Tritium
PMC - PMC3432114
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2012/09/07 06:00
MHDA- 2013/02/08 06:00
PMCR- 2012/08/31
CRDT- 2012/09/07 06:00
PHST- 2012/06/18 00:00 [received]
PHST- 2012/08/08 00:00 [accepted]
PHST- 2012/09/07 06:00 [entrez]
PHST- 2012/09/07 06:00 [pubmed]
PHST- 2013/02/08 06:00 [medline]
PHST- 2012/08/31 00:00 [pmc-release]
AID - PONE-D-12-17499 [pii]
AID - 10.1371/journal.pone.0044518 [doi]
PST - ppublish
SO  - PLoS One. 2012;7(8):e44518. doi: 10.1371/journal.pone.0044518. Epub 2012 Aug 31.