Acute up-regulation of glutamate uptake mediated by mGluR5a in reactive astrocytes.
Excitatory transmission in the CNS necessitates the existence of dynamic controls of the glutamate uptake achieved by astrocytes, both in physiological conditions and under pathological circumstances characterized by gliosis. In this context, this study was aimed at evaluating the involvement of group I metabotropic glutamate receptors (mGluR) in the regulation of glutamate transport in a model of rat astrocytes undergoing in vitro activation using a cocktail of growth factors (G5 supplement). The vast majority of the cells were found to take up aspartate, mainly through the glutamate/aspartate transporter (GLAST), and at least 60% expressed functional mGluR5a. When exposed for 15 s to the selective group I mGluR agonist (S)-3,5-dihydroxyphenylglycine, reactive astrocytes showed a significant increase in their capacity to take up aspartate. This effect was confirmed at the single-cell level, since activation of mGluRs significantly increased the initial slope of aspartate-dependent Na+ entry associated with the activity of glutamate transporters. This up-regulation was inhibited by an antagonist of mGluR5 and, more importantly, was sensitive to a specific glutamate transporter 1 (GLT-1) blocker. The acute influence of mGluR5 on aspartate uptake was phospholipase C- and protein kinase C-dependent, and was mimicked by phorbol esters. We conclude that mGluR5a contributes to a dynamic control of GLT-1 function in activated astrocytes, acting as a glial sensor of the extracellular glutamate concentration in order to acutely regulate the excitatory transmission.
Laboratoire de Pharmacologie Expérimentale, Université catholique de Louvain, Brussels, Belgium.
Céline
C
Vermeiren
Mustapha
M
Najimi
Nicolas
N
Vanhoutte
Sébastien
S
Tilleux
Isabelle
I
de Hemptinne
Jean-Marie
JM
Maloteaux
Emmanuel
E
Hermans
D027322:Amino Acid Transport System X-AG / Q000235:genetics / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001224:Aspartic Acid / Q000378:metabolism / Q000494:pharmacology; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D019921:Biotinylation / Q000379:methods; D015153:Blotting, Western / Q000379:methods; D002118:Calcium / Q000378:metabolism; D002217:Carbachol / Q000494:pharmacology; D002478:Cells, Cultured; D018679:Cholinergic Agonists / Q000494:pharmacology; D002867:Chromones / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D027342:Excitatory Amino Acid Transporter 2 / Q000235:genetics / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D007150:Immunohistochemistry / Q000379:methods; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives / Q000494:pharmacology; D010703:Phorbol Esters / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012118:Resorcinols / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D012964:Sodium / Q000378:metabolism; D014316:Tritium / Q000378:metabolism; D010738:Type C Phospholipases / Q000378:metabolism
C117789:7-(hydroxyimino)cyclopropan(b)chromen-1a-carbxoylic acid ethyl ester; D027322:Amino Acid Transport System X-AG; D018679:Cholinergic Agonists; D002867:Chromones; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D027342:Excitatory Amino Acid Transporter 2; C578937:Grm5 protein, rat; D010703:Phorbol Esters; D012333:RNA, Messenger; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D012118:Resorcinols; D014316:Tritium; D001224:Aspartic Acid; D018698:Glutamic Acid; D008734:Methoxyhydroxyphenylglycol; C079215:3,5-dihydroxyphenylglycine; D002217:Carbachol; D012964:Sodium; D011493:Protein Kinase C; D010738:Type C Phospholipases; D002118:Calcium; D005998:Glycine; C010117:3,4-dihydroxyphenylglycol