Stimulation of excitatory amino acid release from adult mouse brain glia subcellular particles by high mobility group box 1 protein |
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Authors: | Pedrazzi Marco Raiteri Luca Bonanno Giambattista Patrone Mauro Ledda Sabina Passalacqua Mario Milanese Marco Melloni Edon Raiteri Maurizio Pontremoli Sandro Sparatore Bianca |
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Affiliation: | Department of Experimental Medicine and Center of Excellence for Biomedical Research, University of Genoa, Genoa, Italy. |
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Abstract: | 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. |
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Keywords: | glial glutamate-aspartate transporter gliosomes glutamate release high mobility group box 1 receptor for advanced glycation end products synaptosomes |
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