TY - JOUR
T1 - Expression and functional role of mGluR3 and mGluR5 in human astrocytes and glioma cells
T2 - Opposite regulation of glutamate transporter proteins
AU - Aronica, Eleonora
AU - Gorter, Jan A.
AU - Ijlst-Keizers, Helen
AU - Rozemuller, Annemieke J.
AU - Yankaya, Bulent
AU - Leenstra, Sieger
AU - Troost, Dirk
PY - 2003/5/1
Y1 - 2003/5/1
N2 - 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.
AB - 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.
KW - Cultures
KW - Glioma
KW - Glutamate transporters
KW - Human astrocytes
KW - Metabotropic glutamate receptors
KW - Western blot
UR - http://www.scopus.com/inward/record.url?scp=0038810014&partnerID=8YFLogxK
U2 - https://doi.org/10.1046/j.1460-9568.2003.02657.x
DO - https://doi.org/10.1046/j.1460-9568.2003.02657.x
M3 - Article
C2 - 12786977
SN - 0953-816X
VL - 17
SP - 2106
EP - 2118
JO - European Journal of Neuroscience
JF - European Journal of Neuroscience
IS - 10
ER -