Transient upregulation of the glial glutamate transporter GLAST in response to fibroblast growth factor, insulin-like growth factor and epidermal growth factor in cultured astrocytes

Abstract

Although expression of the glial glutamate transporter GLAST is tightly regulated during development and under pathophysiological conditions, little is known about endogenous modulators of GLAST expression. Because growth factors are generally believed to regulate glial functions, we addressed their possible contribution to GLAST regulation in cultured rat astrocytes. Of the six growth factors tested (basic fibroblast growth factor (bFGF), insulin-like growth factor-1 (IGF-1), epidermal growth factor (EGF), insulin, platelet-derived growth factor, and hepatocyte growth factor), bFGF, IGF-1 and EGF enhanced [3H]glutamate transport activity in a concentration-dependent manner. These effects were accompanied by an increase in the Vmax value for transport activity and in GLAST protein and mRNA levels, which suggests that GLAST expression is transcriptionally regulated by the growth factors. Interestingly, the effects reached a peak after 36 hours of exposure to growth factors, and rapidly returned to baseline by 48 hours. A combination of IGF-1 with either bFGF or EGF showed an additive effect on the glutamate uptake activity, but a combination of bFGF and EGF did not. Pharmacological blockade of protein kinase C inhibited the effects of IGF-1 and EGF, but not bFGF. By contrast, genistein, an inhibitor of tyrosine kinases, blocked the effects of bFGF and EGF without affecting the effect of IGF-1. These results suggest that the growth factors activate different signaling pathways for GLAST upregulation. The present study may indicate a novel regulatory system of glial glutamate transporters.

Acute up‐regulation of glutamate uptake mediated by mGluR5a in reactive astrocytes

“…In addition, increased brain levels of several growth factors are observed in pathological circumstances involving gliosis, in which activated astrocytes are suggested to enhance local neuroprotection (Liberto et al 2004). Accordingly, increased expression of glial glutamate transporters was reported in astrocytes showing an activated phenotype (Zelenaia et al 2000;Suzuki et al 2002;Aronica et al 2003;Figiel et al 2003). As well as growth factors, transmitters can also influence the expression of glutamate transporters in astrocytes (Figiel and Engele 2000).…”

“…Accordingly, increased expression of glial glutamate transporters was reported in astrocytes showing an activated phenotype (Zelenaia et al . 2000; Suzuki et al . 2002; Aronica et al .…”

Citrullinated isomer of myelin basic protein can induce inflammatory responses in astrocytes

“…Phagocytosis of myelin debris by astrocytes early after damage leads to NF-κB signaling and chemokine secretion ( Claycomb et al, 2013 , Ponath et al, 2017 ). The receptor of FGF, one of the targets of MBP, as well as the LRP-1, another possible binding partner of MBP, can regulate glutamate homeostasis in astrocytes via the ERK/NF-kB pathway ( Swanson et al, 1997 , Suzuki et al, 2001 , Ghosh et al, 2011 ). Furthermore, plasma membrane pattern recognition receptors (PRRs) expressed in astrocytes play an essential role in the activation of NF-κB and mitogen-activated protein kinase inflammatory pathways ( Heneka et al, 2014 ).…”

Aryl Hydrocarbon Receptor Involvement in the Sodium-Dependent Glutamate/Aspartate Transporter Regulation in Cerebellar Bergmann Glia Cells

“…The activity of GLAST/EAAT1 is regulated by a rapid process dependent on the amount of active membrane transporters and their affinity and in the long term through transcriptional control. It has been documented that the glast promoter activity is modulated positively by IGF-1 (Insulin-like growth factor-1), FGF (Fibroblast growth factor), EGF (Epidermal growth factor), TGF alpha, estrogen, HDACs inhibitors and negatively by TNF alpha, YY-1 and environmental toxins as manganese. ,,− Despite the key role of GLAST/EAAT1 in several neurological disorders, the molecular mechanisms involved in its transcriptional regulation are not completely understood. In this context, we decided to evaluate the effects of AhR, an environmental sensor receptor expressed in the Gallus central nervous system, since within the chglast promoter, cis elements capable of binding AhR are present (Figure ).…”