Ported so far, and their expressions in humans) (Figure 3). 5 cell type. In the

Ported so far, and their expressions in humans) (Figure 3). 5 cell type. In the brain, GLAST (also referred to as EAAT1) and GLT-1 (also called cell type. Within the brain, distributed in astrocytes, whereas EAAC1 differ according to the EAAT2) are mainly GLAST (also known as EAAT1) and GLTis exclusively expressed in neurons. EAAT4 and EAAT5 are distributed in cerebellar Purkinje cells and neurons in the retina, respectively [48]. All of those transporters canInt. J. Mol. Sci. 2021, 22,6 oftake up extracellular Glu in to the cells, but in contrast to GLAST and GLT-1, EAAC1 also can transport Cys using the similar efficiency as Glu [49]. Depending on the experimental benefits applying a mutation model of EAAC1, it has been thought of that the mechanisms of Glu and Cys CYP26 Inhibitor medchemexpress uptake by EAAC1 are independent of each other [50]. There had been no considerable alterations in extracellular Glu concentrations in an EAAC1-knockdown animal model [51]. GLAST and GLT-1 act as Glu transporters in glial cells in vivo and are involved inside the regulation of Glu concentration in synaptic clefts, whereas EAAC1 is not involved within the regulation of extracellular Glu levels in synaptic clefts, but rather within the regulation of GSH CDK2 Activator medchemexpress production by means of extracellular Cys uptake. Moreover, EAAC1-deficient mice exhibit decreased brain GSH levels, vulnerability to oxidative pressure inside the hippocampus, and agerelated learning dysfunction [52]. EAAC1-deficient mice also showed age-dependent loss of dopaminergic neurons in the substantia nigra pars compacta accompanied by increased Int. J. Mol. Sci. 2021, 22, x FOR PEER Overview 7 of 16 oxidative pressure [53]. EAAC1 is accountable for around 700 of Cys uptake in neurons [54], and may transport 10- to 20-fold greater amounts of Cys than can GLAST or GLT-1 [49]. Depending on these final results, the physiological roles of EAAC1 inside the central EAAC1 method (CNS) the activity of AMPK. Therefore, it can be very probable that expression of nervous is regulated bywould be involved within the neuroprotective roles mediated by GSH EAAC1 is [55]. productionsubject to pre- and post-translational regulations in neurons.Figure 3. Regulation of excitatory amino acid carrier 1 (EAAC1) expression. Glutathione (GSH) is Figure three. Regulation of excitatory amino acid carrier 1 (EAAC1) expression. Glutathione (GSH) can be a tripeptide synthesized from glutamate (Glu), cysteine (Cys), and glycine (Gly). Neuronal GSH a tripeptide synthesized from glutamate (Glu), cysteine (Cys), and glycine (Gly). Neuronal GSH synthesis relies on intracellular Cys but not Glu or Gly level. Cys uptake (red font) is subjected to synthesis relies on intracellular Cys but not Glu or Gly level. Cys uptake (red font) is subjected to the regulation both gene expression and and post-translational modifications of EAAC1 beneath the regulation of of each gene expression post-translational modifications of EAAC1 beneath facilitative (arrow) and and suppressive (black circles) controls. EAAC1 expressions are are promoted facilitative (arrow) suppressive (black circles) controls. EAAC1 genegene expressionspromoted by nuclear element erythroid 2-related element two (Nrf2), regulatory factor X1 (RFX1), and all-trans-retinoic by nuclear element erythroid 2-related element 2 (Nrf2), regulatoryfactor X1 (RFX1), and all-trans-retinoic acid (ATRA). Protein kinase C (PKC) and phosphoinositide 3-kinase (PI3K) activations boost acid (ATRA). Protein kinase C (PKC) and phosphoinositide 3-kinase (PI3K) activations raise the the EAAC1 expression on the.