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    • Bergmann glia cells BGCs are the

    2022-08-05

    Bergmann glia Carmustine sale (BGCs) are the most abundant glia cells in the cerebellum, comprising more than 90% of the cerebellar glia. These cells span the entire cerebellar molecular layer and encapsulate neuronal somata, dendrites and axons. BGC are involved in neurotransmitter uptake, K+ homeostasis and pH regulation due to the expression of a battery of receptors and transporters (Lopez-Bayghen et al., 2007). In terms of glutamatergic transmission, BGC are in a very short proximity to the parallel fiber-Purkinje cell synapses, and are involved in the Glu/glutamine shuttle that assures the Glu supply to the presynaptic terminals. In this sense, BGC respond to glutamatergic stimulation, as we have been able to characterize over the years (Barrera et al., 2010). Activity-dependent gene expression regulation stabilizes the synaptic changes that underlie the late phase of long-term potentiation (Pittenger and Kandel, 1998). Transcription and translation are essential for long-term memory (Hu et al., 2006). While most studies have focused in gene expression regulation at the transcriptional level, regulation of protein synthesis has a crucial role in synaptic plasticity (Cammalleri et al., 2003). Translational control offers the possibility of a rapid response to external stimulus without mRNA synthesis and transport. Therefore, immediacy is the most conspicuous advantage of translational over transcriptional control. The mammalian target of rapamycin (mTOR) is a master regulator of protein synthesis (Proud, 2007). It is a multi-domain serine/threonine kinase that phosphorylates a wide array of proteins like phosphatase 2A and Huntingtin. It forms the catalytic core of two different complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). During acute exposure, rapamycin inhibits mTORC1 but not mTORC2. In a rather simplified scenario, mTORC1 mediates the mTOR effects that are rapamycin-sensitive. The canonical pathway that leads to mTOR serine 2448 phosphorylation and thus activation, includes phosphatidylinositol 3-kinase (PI3-K), which produces phosphatidylinositol 3,4,5-triphosphate (PIP3), that anchors phosphoinositide-dependent kinase 1 (PDK1) and protein kinase B (PKB) to the cell membrane (Sabatini, 2006). PKB is activated through a sequential phosphorylation cascade by PDK1 and a PDK2 activity that now it has been shown to correspond to mTORC2 (Bayascas and Alessi, 2005). Phosphorylated PKB activates mTORC1 that acts upon several translation components like eukaryotic initiation factor 4E binding protein-1 (4EBP1) and the 70kDa S6 ribosomal kinase (p70S6K) increasing protein synthesis (Bayascas and Alessi, 2005, Foster and Fingar, 2010). Glu is removed from the synaptic cleft by a family of electrogenic sodium-dependent transporters expressed in neurons and glia cells (Danbolt, 2001). Five subtypes of transporters named excitatory amino acids transporters 1–5 (EAAT-1–5) have been characterized. The glial transporters EAAT-1 (GLAST) and EAAT-2 (GLT-1) account for more than 80% of the Glu uptake activity in the brain (Eulenburg and Gomeza, 2010, Swanson, 2005). Within BGC, EAAT-1/GLAST is the predominant transporter (Maragakis et al., 2004). Evidences suggest that Glu transporters might also participate in the signaling transactions triggered by this amino acid. In fact, Glu regulates the uptake process in a receptor-independent manner (Gonzalez and Ortega, 2000). More recently, it has also been reported that EAAT-1 is coupled to the Na+/K+ ATPase (Gegelashvili et al., 2007, Rose et al., 2009). To provide further evidence for a role of EAAT-1/GLAST in Glu signaling, in the present contribution we challenged the plausible participation of Glu transporters in gene expression regulation. We show here that Glu uptake is linked to an increase in the translation process and that it is also coupled to the transcriptional activation of an AP-1 driven construct. These results are discussed in terms of the physiological significance of an alternative signaling entity to Glu receptors and the identity of the genes regulated. A preliminary description of a d-Asp-dependent mTOR phosphorylation was reported earlier (Zepeda et al., 2009).