Increased adenine nucleotide translocator 1 in reactive astrocytes facilitates glutamate transport.
A hallmark of central nervous system (CNS) pathology is reactive astrocyte production of the chronic glial scar that is inhibitory to neuronal regeneration. The reactive astrocyte response is complex; these cells also produce neurotrophic factors and are responsible for removal of extracellular glutamate, the excitatory neurotransmitter that rises to neurotoxic levels in injury and disease. To identify genes expressed by reactive astrocytes, we employed an in vivo model of the glial scar and differential display PCR and found an increase in the level of Ant1, a mitochondrial ATP/ADP exchanger that facilitates the flux of ATP out of the mitochondria. Ant1 expression in reactive astrocytes is regulated by transforming growth factor-beta1, a pluripotent CNS injury-induced cytokine. The significance of increased Ant1 is evident from the observation that glutamate uptake is significantly decreased in astrocytes from Ant1 null mutant mice while a specific Ant inhibitor reduces glutamate uptake in wild-type astrocytes. Thus, the astrocytic response to CNS injury includes an apparent increase in energy mobilization capacity by Ant1 that contributes to neuroprotective, energy-dependent glutamate uptake.
Buck
Charles R
CR
Oridis Biomed, Elisabethstrasse 84, A-8010, Graz, Austria. buck@oridis-biomed.com
Jurynec
Michael J
MJ
Gupta
Deepak K
DK
Law
Alick K T
AK
Bilger
Johannes
J
Wallace
Douglas C
DC
McKeon
Robert J
RJ
D033741:Adenine Nucleotide Translocator 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D001278:Atractyloside / Q000031:analogs & derivatives* / Q000494:pharmacology; D001692:Biological Transport / Q000502:physiology; D001930:Brain Injuries / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D003101:Collodion; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D017930:Genes, Reporter; D005911:Gliosis / Q000473:pathology; D018698:Glutamic Acid / Q000378:metabolism* / Q000493:pharmacokinetics; D020007:Implants, Experimental; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D016133:Polymerase Chain Reaction / Q000379:methods; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D016212:Transforming Growth Factor beta / Q000494:pharmacology / Q000502:physiology; D053773:Transforming Growth Factor beta1
D033741:Adenine Nucleotide Translocator 1; D012333:RNA, Messenger; C508961:Tgfb1 protein, mouse; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D001278:Atractyloside; D018698:Glutamic Acid; D003101:Collodion; C003853:carboxyatractyloside