Expression and functional role of mGluR3 and mGluR5 in human astrocytes and glioma cells: opposite regulation of glutamate transporter proteins.
We examined the regulation of glutamate transporter protein expression after stimulation with selective metabotropic glutamate receptor (mGluR) agonists in cultured human glial cells. mGluR3 and mGluR5 are expressed in human astrocytes and in human glioma cells in vivo as well as in vitro, as shown by either RT-PCR or western blot analysis. The selective group I agonist (S)-3,5-dihydroxyphenylglycine produced a significant down-regulation of both GLAST and GLT-1 protein expression in astrocytes cultured in the presence of growth factors. This condition mimics the morphology of reactive glial cells in vivo including an increased expression of mGluR5 protein (observed in pathological conditions). In contrast, (2S,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)glycine, a selective agonist of group II metabotropic glutamate receptors, positively modulates the expression of GLAST and GLT-1 proteins. A similar opposite effect of (S)-3,5-dihydroxyphenylglycine and (2S,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)glycine was observed for the expression of EAAT3 protein in U373 glioblastoma cell line. Selective group I and II antagonists prevented these effects. Pharmacological inhibition of mitogen-activated protein kinase and phosphatidylinositol-3-K pathways reduces the induction of GLT-1 observed in response to the group II metabotropic glutamate receptor agonist (2S,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)glycine. Thus, mGluR3 and mGluR5 can critically and differentially modulate the expression of glutamate transporters and may represent interesting pharmacological targets to regulate the extracellular levels of glutamate in pathological conditions.
Aronica
Eleonora
E
Department of (Neuro)Pathology, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. e.aronica@amc.uva.nl
Gorter
Jan A
JA
Ijlst-Keizers
Helen
H
Rozemuller
Annemieke J
AJ
Yankaya
Bulent
B
Leenstra
Sieger
S
Troost
Dirk
D
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D027322:Amino Acid Transport System X-AG / Q000235:genetics* / Q000378:metabolism; D001253:Astrocytes / Q000166:cytology / Q000502:physiology*; D027341:Excitatory Amino Acid Transporter 1; D027342:Excitatory Amino Acid Transporter 2 / Q000235:genetics* / Q000378:metabolism; D050580:Excitatory Amino Acid Transporter 3; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D005909:Glioblastoma; D050491:Glutamate Plasma Membrane Transport Proteins; D006133:Growth Substances / Q000494:pharmacology; D006801:Humans; D016130:Immunophenotyping; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000235:genetics* / Q000378:metabolism; D027981:Symporters / Q000235:genetics* / Q000378:metabolism; D014407:Tumor Cells, Cultured
D027322:Amino Acid Transport System X-AG; D027341:Excitatory Amino Acid Transporter 1; D027342:Excitatory Amino Acid Transporter 2; D050580:Excitatory Amino Acid Transporter 3; C578935:GRM5 protein, human; D050491:Glutamate Plasma Membrane Transport Proteins; D006133:Growth Substances; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; C493400:SLC1A1 protein, human; C493394:SLC1A3 protein, human; D027981:Symporters; C102718:metabotropic glutamate receptor 3