Mechanisms of glutamate receptor induced proliferation of astrocytes

Abstract

Astrocytes express mainly metabotropic glutamate receptor 3 and metabotropic glutamate receptor 5 receptor subtypes, which show opposing effects on cellular proliferation upon activation. In this study, we investigated the mechanisms by which activation of these receptors modulates astrocyte proliferation. Activation of metabotropic glutamate receptor 5 with (S)-3,5-dihydroxyphenylglycine increased phospholipase D activity in astrocytes as well as astrocyte proliferation. The 3,5-dihydroxyphenylglycine-induced proliferation was inhibited in the presence of the metabotropic glutamate receptor 5 antagonist (2-methyl-6-(phenylethynyl)pyridine), the protein kinase C inhibitor GF109203X, brefeldin A and 1-butanol. Activation of metabotropic glutamate receptor 3 with (2'S,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)glycine-IV (DCG-IV) inhibited astrocyte proliferation without affecting metabotropic glutamate receptor 5-mediated phospholipase D activity. Metabotropic glutamate receptor 3 activation, however, only partially inhibited metabotropic glutamate receptor 5-mediated proliferation. In conclusion, metabotropic glutamate receptor 5 stimulates astrocyte proliferation via a protein kinase C-phospholipase D-phosphatidic acid-dependent pathway, whereas metabotropic glutamate receptor 3-mediated inhibition of astrocyte proliferation does not involve phospholipase D, and is independent of metabotropic glutamate receptor 5-mediated effects.

Essential Role for Epidermal Growth Factor Receptor in Glutamate Receptor Signaling to NF-κB

“…These results demonstrate that glutamate receptorinduced Ca 2ϩ release is dependent on EGFR-dependent signaling. Finally, there is strong evidence that altered calcium homeostasis is an important factor in neuronal death following injury (15), and glutamate has been shown to regulate glial cell proliferation and survival (2,10,27). To determine whether the calcium mobilization induced by glutamate signaling through mGluR5 and EGFR affects U87-MG cell proliferation, we examined cellular metabolic activity, which is directly proportional to the number of living cells in culture.…”

“…mGluR5 is one of the most abundant and best-characterized glutamate receptors in glial cells. The stimulation of mGluR5 has been shown to promote cytosolic Ca 2ϩ release, glutamate transporter 1 (GLT-1)/excitatory amino acid transporter 2 (EAAT2)-mediated glutamate uptake (37), immediate-early gene expression (6), and glial cell proliferation and survival (10). Additionally, mGluR5 expression is rapidly upregulated by treatment with growth factors and in response to injury (36).…”

“…Glutamate-induced Ca 2ϩ elevation is also believed to promote excitotoxic neuronal cell death associated with brain injury and disease (15). Recently, particular attention has been paid to the role of mGluRs in regulating glial cell functions such as proliferation, glutamate uptake, and modulation of neuronal activity (10,35,38). mGluR5 is one of the most abundant and best-characterized glutamate receptors in glial cells.…”

Opposite regulation of metabotropic glutamate receptor 3 and metabotropic glutamate receptor 5 by inflammatory stimuli in cultured microglia and astrocytes

“…Beside members of the family of glutamate transporters/ exchanger and glutamate metabolizing enzymes, glial cells express a variety of mGluRs, which were shown to modulate several activities, including cell proliferation (Ciccarelli et al, 1997;Kanumilli and Roberts, 2006), glutamate uptake Vermeiren et al, 2005b), neurotrophic support (Bruno et al, 1998;Ciccarelli et al, 1999;Viwatpinyo and Chongthammakun, 2009), and inflammatory responses (Byrnes et al, 2009b;Loane et al, 2009). Focusing here on mGluR5 and mGluR3, the two major representatives of group I and II mGluRs, but also the predominant and almost exclusive subtypes of mGluRs expressed in cortical astrocytes Byrnes et al, 2009a;Ciccarelli et al, 1997), we demonstrated that the pro-inflammatory cytokines, TNF␣ and IL-1␤, induced a massive decrease in mGluR5 and an increase in mGluR3 gene expression in cultured astrocytes.…”

“…The roles of glial mGluRs are not yet fully elucidated but likely involve the regulation of glial activities in response to the local excitatory tone (D'Antoni et al, 2008;Verkhratsky and Kirchhoff, 2007), thereby contributing to glia-neuron interactions. In astroglial cultures, mGluR3 and mGluR5 were respectively shown to negatively and positively influence cell proliferation (Ciccarelli et al, 1997;Kanumilli and Roberts, 2006). These receptors also act as sensors of glutamate homeostasis, through the modulation of the expression or activity (Vermeiren et al, 2005b) of glutamate transporters.…”