br Regulation of Glu transporters The

Regulation of Glu transporters The pivotal role of Glu transporters in the fine tuning and turnover of this excitatory amino adenosine deaminase inhibitor calls for a detailed characterization of its regulation. Several general mechanisms that modify Glu uptake activity have been described. These include transcription of the genes encoding the transporters, the maturation and stabilization of its encoding mRNA (Bessho et al., 1993, Testa et al., 1995), the posttranslational modifications of the transporter protein (Traynelis et al., 2010), its trafficking to and from the plasma membrane (Robinson, 2006, Robinson, 2002), and its diffusion within the plasma membrane (Benediktsson et al., 2012, Murphy-Royal et al., 2015, Shin et al., 2009). Whereas DNA transcription and protein expression events require long time periods (hours) to reflect effects on the activity of the transporter, posttranslational modifications may occur shortly (minutes). It is likely that a combination of all of these regulation mechanisms is essential for an efficient Glu uptake activity, both in neurons and glial cells.
Conclusion Until recently, astrocytes were recognized solely for their maintenance role in the regulation of brain homeostasis. Nowadays, this idea has changed, it is clear that these cells play a crucial role in the regulation of neuronal activity and signal transmission. In particular, glial Glu transporters are responsible for the vast majority of the removal of this neurotransmitter from the synaptic cleft, highlighting the importance of these cells in brain physiology. Currently, the number of diseases related to the imbalance of the glutamatergic system, is increasing. Therefore, the interest and importance on the regulation of Glu transporters gene expression and function has also increased. Glu transporters are tightly regulated at different levels including gene expression, transporter protein targeting and trafficking (Fig. 1). Posttranslational modifications of the transporter protein are also involved the regulatory mechanisms. It is clear that the establishment of the biochemical transactions involved in the regulation of Glu transporters is fundamental for the development of new therapeutic strategies for a significant number of neurological diseases associated to glutamatergic neurotransmission.
Conflicts of interest
Acknowledgments The work in the laboratory is supported by Conacyt-Mexico (255087) and Soluciones para un México Verde S.A. de C.V. grants to A.O.
Introduction Glutamate is the most important excitatory neurotransmitter in the brain, and its level is very low under normal conditions [1,2]. The maintenance of low glutamate levels in the brain mainly depends on its constant transport by excitatory amino acid transporters (EAATs), which are the primary subclass of glutamate transporters. In addition to uptake by the presynaptic membrane or astrocytes that are wrapped around the synapse [3], the EAATs on abluminal endothelial membranes, mainly including GLAST and GLT-1, constantly transport glutamate in the cerebral extracellular fluid into endothelial cells and then into the blood through facilitated transport [4,5], thus playing an irreplaceable role in maintaining the homeostasis of brain glutamate levels. In addition to the increased release and decreased re-uptake of glutamate by nerve cells after acute brain injury, such as traumatic brain injury (TBI) and stroke [6,7], dysfunction of endothelial EAATs or even reverse transport may be another important factor contributing to the rapid increase in glutamate levels in the brain [8]. However, few studies have focused on the causes and regulatory mechanisms underlying the changes in the function of endothelial EAATs, and specific mechanisms have rarely been reported. After brain injury, adenosine levels rapidly increase in the brain [9,10]. As shown in our previous studies, the increased adenosine concentration acts on adenosine A2A receptors (A2ARs), increasing post-traumatic glutamate levels in the brain and exacerbating the severity of injuries [11,12]. According to the results of in vitro tests, A2AR activation decreases the expression of glial EAATs [13] and inhibits the uptake of glutamate [14]. However, researchers have not clearly determined whether A2AR play an important role in regulating brain endothelial EAATs.