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  • To maintain low Glu concentrations in

    2022-09-30

    To maintain low Glu concentrations in the synaptic cleft below the affinity of its receptors, this amino Ciclopirox is rapidly removed from the extracellular space by a family of sodium-dependent high-affinity transport systems located mainly in the plasma membrane of perisynaptic astrocytes, and in to a lower extent in neurons (Kanai et al., 1993). Once Glu is taken up, it is either used for metabolic purposes (like protein synthesis or energetic metabolism) or for its recycling as a transmitter (through the Glu/glutamine cycle). It is worth to mention that this biochemical shuttle is critical for Glu turnover (Danbolt, 2001). When the synaptic Glu concentration reaches a concentration in the millimolar range, an over-stimulation of its neuronal receptors triggers an excitotoxicity cascade in postsynaptic neurons (Maragakis and Rothstein, 2004). This cell death cascade is involved in pathological conditions that underlie neurodegenerative diseases (Brassai et al., 2015, Domingues et al., 2010, Gegelashvili and Bjerrum, 2014, Lauriat and McInnes, 2007, McEntee and Crook, 1993, Ribeiro et al., 2017). In order to understand this type of disorders and by these means develop alternatives for their treatment, it is important to characterize the mechanisms that regulate the expression of Glu transporters.
    Characterization and regional localization of Glu transporters Molecular studies led to the description of five subtypes of plasma membrane Glu transporters termed in accordance to their human or rodent origin (Kanai and Hediger, 1992, Pines et al., 1992, Storck et al., 1992). In humans, these transporters are known as excitatory amino acid transporters 1–5 (EAATs 1–5). In contrast, the rodent proteins are known as: Glutamate/Aspartate Transporter (GLAST), Glutamate Transporter 1 (GLT-1), and Excitatory Amino Acid Carrier 1 (EAAC1). EAAT4 and EAAT5 have the same nomenclature in both species (Arriza et al., 1994, Fairman et al., 1995). Besides their ability to transport Glu in a Na+-dependent manner, these transporters are capable of L- and d-aspartate uptake, interestingly, EAAT3/EAAC1 also accepts l-cysteine as a substrate (Danbolt, 2001). Plasma membrane Glu transporters are strictly dependent on the sodium (Na+) gradient across the membrane as the driving force, enabling the reverse function of the transport. The stoichiometry of the transport is 3 Na+ and 1 proton (H+) per transport cycle of 1 molecule of Glu, while 1 potassium (K+) is concurrently released from the cell (Danbolt, 2001, Levy et al., 1998, Zerangue and Kavanaugh, 1996). This stoichiometry allows the transporter to generate up to a million-fold concentration gradient across the membrane (Zerangue and Kavanaugh, 1996). In addition to the fact that Glu transporters are Na+-dependent, they share the characteristic that their expression is developmentally regulated. For example, GLAST is profusely expressed in early stages of development, while GLT-1 levels increase in later stages of development (Furuta et al., 1997); this observation suggests that GLT-1 may be used as an astrocyte maturation marker, while GLAST is indeed a neural progenitor cells (Chen et al., 2017). Although Glu transporters share some characteristics, distinct molecular and pharmacological properties, as well as differential cellular and regional localization have been documented for each subtype (Table 1). For example, EAAT1/GLAST is the major Glu transporter in cerebellar astrocytes (Lehre and Danbolt, 1998, Takatsuru et al., 2007), the inner ear (Furness and Lehre, 1997, Takumi et al., 1997), the circumventricular organs (Berger and Hediger, 2000), and the retina (Derouiche, 1996, Derouiche and Rauen, 1995, Lehre et al., 1997, Pow and Barnett, 1999, Rauen et al., 1998, Rauen et al., 1996). EAAT2/GLT-1 is almost exclusively glial, and it is widespread and abundant in the forebrain and spinal cord (Furuta et al., 1997). It is important to note that this transporter has also been found in neurons (Danbolt et al., 2016). EAAT3/EAAC1 is a neuronal transporter widely expressed in the encephalon and localized mainly to the soma and dendrites (Bjørås et al., 1996, Holmseth et al., 2012, Kanai and Hediger, 1992, Rothstein et al., 1994, Shashidharan et al., 1997). EAAT4 is predominantly found in cerebellar Purkinje cells, where it is targeted to dendrites and spines and it is also expressed in a subset of forebrain neurons (de Vivo et al., 2010, Dehnes et al., 1998, Fairman et al., 1995, Massie et al., 2008). Finally, EAAT5 is preferentially expressed in rod photoreceptors and retina bipolar cells, and it should be noted that in the brain its expression is very low (Arriza et al., 1997, Pow and Barnett, 2000). Differences between the transporters make it evident that there is variation between the mechanisms that regulate their expression in the cells of the nervous system.