Stimulation of excitatory amino acid release from adult mouse brain glia subcellular particles by high mobility group box 1 protein.
The multifunctional protein high mobility group box 1 (HMGB1) is expressed in hippocampus and cerebellum of adult mouse brain. Our aim was to determine whether HMGB1 affects glutamatergic transmission by monitoring neurotransmitter release from glial (gliosomes) and neuronal (synaptosomes) re-sealed subcellular particles isolated from cerebellum and hippocampus. HMGB1 induced release of the glutamate analogue [(3)H]d-aspartate form gliosomes in a concentration-dependent manner, whereas nerve terminals were insensitive to the protein. The HMGB1-evoked release of [(3)H]d-aspartate was independent of modifications of cytosolic Ca(2+) , but it was blocked by dl-threo-beta-benzyloxyaspartate (dl-TBOA), an inhibitor of glutamate transporters. HMGB1 also stimulated the release of endogenous glutamate in a Ca(2+)-independent and dl-TBOA-sensitive manner. These findings suggest the involvement of carrier-mediated release. Moreover, dihydrokainic acid, a selective inhibitor of glutamate transporter 1 (GLT1), does not block the effect of HMGB1, indicating a role for the glial glutamate-aspartate transporter (GLAST) subtype in this response. We also demonstrate that HMGB1/glial particles association is promoted by Ca(2+). Furthermore, although HMGB1 can physically interact with GLAST and the receptor for advanced glycation end products (RAGE), only its binding with RAGE is promoted by Ca(2+). These results suggest that the HMGB1 cytokine could act as a modulator of glutamate homeostasis in adult mammal brain.
Pedrazzi
Marco
M
Department of Experimental Medicine and Center of Excellence for Biomedical Research, University of Genoa, Genoa, Italy.
Raiteri
Luca
L
Bonanno
Giambattista
G
Patrone
Mauro
M
Ledda
Sabina
S
Passalacqua
Mario
M
Milanese
Marco
M
Melloni
Edon
E
Raiteri
Maurizio
M
Pontremoli
Sandro
S
Sparatore
Bianca
B
D000818:Animals; D015153:Blotting, Western; D001923:Brain Chemistry / Q000187:drug effects*; D002118:Calcium / Q000502:physiology; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism; D003902:Detergents / Q000494:pharmacology; D027341:Excitatory Amino Acid Transporter 1 / Q000378:metabolism; D018846:Excitatory Amino Acids / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism; D024243:HMGB1 Protein / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D018613:Microscopy, Confocal; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism*; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism; D013268:Stimulation, Chemical; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism*; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
D003902:Detergents; D027341:Excitatory Amino Acid Transporter 1; D018846:Excitatory Amino Acids; D024243:HMGB1 Protein; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; C493393:Slc1a3 protein, mouse; D018698:Glutamic Acid; D002118:Calcium