Role of endothelins as mediators of injury-induced alterations of glial glutamate turnover.
Astroglia terminate glutamatergic neurotransmission and prevent excitotoxic extracellular glutamate concentration by clearing synaptically released glutamate through the high-affinity, sodium-dependent glutamate transporters GLT-1 and GLAST. Many brain injures are associated with the disturbed expression of glial glutamate transporters and a subsequent increase of extracellular glutamate to neurotoxic levels. We have now followed up initial hints pointing to endothelins, a family of injury-regulated peptides, as mediators of this injury-induced loss of glial glutamate transporter expression. We observed that, in line with such a role, endothelins not only act as potent inhibitors of basal and exogenously (dbcAMP)-induced expression of GLT-1 in cortical astrocytes as shown before, but likewise inhibit expression of GLT-1 or GLAST in astrocytes cultured from the diencephalon, mesencephalon, cerebellum, and spinal cord. We further demonstrate that endothelins equally inhibit GLT-1 expression in cortical slice cultures, a culture system closely resembling the in vivo situation. Although brain injuries are usually associated with an increase in the expression of the glutamate-converting enzyme glutamine synthetase, cultured cortical astrocytes maintained with endothelins showed an almost complete loss of glutamine synthetase. Interestingly, the inhibitory effects of endothelins on the expression of glutamine synthetase, but not of glutamate transporters, was overridden by high extracellular glutamate, indicating that the primarily inhibitory action of endothelins on the various components of glial glutamate turnover dissociates in the injured brain.
Lehmann
Claudia
C
Institute of Anatomy, University of Leipzig, Medical Faculty, Leipzig, Germany.
Eisner
Friederike
F
Engele
Jürgen
J
D027322:Amino Acid Transport System X-AG / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000378:metabolism; D001921:Brain / Q000378:metabolism / Q000473:pathology; D001930:Brain Injuries / Q000378:metabolism* / Q000473:pathology; D003994:Bucladesine / Q000494:pharmacology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D016232:Endothelins / Q000378:metabolism*; D027341:Excitatory Amino Acid Transporter 1 / Q000037:antagonists & inhibitors; D027342:Excitatory Amino Acid Transporter 2 / Q000037:antagonists & inhibitors; D045604:Extracellular Fluid / Q000378:metabolism; D005974:Glutamate-Ammonia Ligase / Q000037:antagonists & inhibitors; D018698:Glutamic Acid / Q000378:metabolism*; D066298:In Vitro Techniques; D009457:Neuroglia / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D013119:Spinal Cord Injuries / Q000378:metabolism* / Q000473:pathology
D027322:Amino Acid Transport System X-AG; D016232:Endothelins; D027341:Excitatory Amino Acid Transporter 1; D027342:Excitatory Amino Acid Transporter 2; C493392:Slc1a3 protein, rat; D018698:Glutamic Acid; D003994:Bucladesine; D005974:Glutamate-Ammonia Ligase