SLC7A11

2365726570ENSG00000151012ENSMUSG00000027737Q9UPY5Q9WTR6NM_014331NM_011990NP_055146NP_036120Cystine/glutamate transporter is an antiporter that in humans is encoded by the SLC7A11 gene. Cystine/glutamate transporter is an antiporter that in humans is encoded by the SLC7A11 gene. The SLC7A11 gene codes for a sodium-independent cystine-glutamate antiporter that is chloride dependent, known as system Xc- or xCT. It regulates synaptic activity by stimulating extrasynaptic receptors and performs nonvesicular glutamate release. This gene is highly expressed by astrocytes and couples the uptake of one molecule of cystine with the release of one molecule of glutamate. The dimer cystine gets taken up by glial cells and the monomer of cystine, cysteine, is taken up by neurons. The expression of Xc- was detected throughout the brain with higher expression found in the basolateral amygdala and the prefrontal cortex. The inhibition of system Xc- has been found to alter a number of behaviors, which suggests that it plays a key role in excitatory signaling. SLC7A11 is a member of a heterodimeric Na+-independent anionic amino acid transport system highly specific for cystine and glutamate. This antiporter imports cystine and exports glutamate, which are both amino acids. An antiporter functions with a one-to-one counter-transport, which is when one substance is transported across the membrane at the same time another substance is transported across the membrane in the opposite direction. The antiporter is a heterodimeric amino acid transporter. The structure of this protein includes two chains: a specific light chain, xCT, and a heavy chain, 4F2, which are linked by a disulfide bridge. The xCT chain has 12 transmembrane domains consisting of 501 amino acids, and the 4F2 chain appears to be highly conserved among transporters. The human xCT has an 89% similarity of amino acids to a mouse xCT. The complementary DNA, cDNA, has a total of 9648 base pairs. The SLC7A11 gene has been found not only in the brain, but has also been found to be expressed in the spinal cord, pancreas, and in glioma cells. There are many mechanisms that exist to regulate the expression of system Xc-, although it is not the sole determinate of extracellular glutamate or intracellular glutathione. An example is amino acid deprivation, which triggers up regulation of the transporter. A key regulator is extracellular glutamate; when it becomes excessive, it goes from an excitatory transmitter to an excitotoxin. The inhibition of uptake of extracellular glutamate leads to oxidative glutamate toxicity or ferroptosis. This regulation may be done through Excitatory Amino Acid Transporters (EAATs), which decrease extracellular glutamate and increase intracellular glutamate in astrocytes. When looking at its structure, xCT seems to be the main determinant for the system's activity. Glutamate and cystine can be transported in both directions, but, generally, more cystine is imported and more glutamate is exported. Extracellular glutamate acts as a competitive inhibitor for cystine uptake via system Xc-. There is a copious amount of glutamate in mammalian cells. Glutamate is necessary for excitatory signaling between neurons. The release must be highly organized, due to the large amounts of glutamate at the synaptic cleft, and the fact that it is released at high speeds. This mechanism of release at the synaptic cleft is partially controlled through the active transport of glutamate out of astrocytes by system Xc-. This release also has a physiological role in the regulation of glutamate metabotropic receptors and control of other neurotransmitters. Cystine is a dimer consisting of two cysteine molecules and the formation of a disulfide bond. This amino acid is a rate limiting substrate used in the SLC7A11 cystine/glutamate transporter and is usually imported into the cell. Cysteine-158 is specifically used in the formation of the disulfide bridge for the protein structure of system Xc-. There are neurotoxins, such as BMAA, that can prevent the intake of cystine, which can lead to decreased extracellular glutamate levels and an increase in oxidative stress. System Xc- can be inhibited by many small molecules. Excess amounts of the endogenous substrate glutamate inhibits the function of system Xc-. Synthetic small molecules such as erastin, sulfasalazine, and sorafenib can inhibit system Xc- function and induce ferroptosis. Many central nervous system (CNS) disorders are due to a dysfunction in glutamate signaling. Glutamate is transported via EAATs and system Xc-. If either of these transporters are impaired, it could result in a disruption in glutamate homeostasis and lead to a variety of CNS disorders It has been found that cocaine produces a decrease in Cystine-Glutamate exchange via system Xc-, leading to a decrease in basal, extra synaptic glutamate levels in the nucleus accumbens core (NAcc) region of the brains of cocaine-withdrawn rats. It has also been observed in withdrawn rats that a decrease in Group 2 mGluR inhibition of vesicular release, most likely due to the decrease in extrasynaptic glutamate levels, leads to an increase in cocaine-evoked glutamate signaling in their NAcc. An infusion of cysteine in the NAcc of withdrawn rats leads to an increase in extrasynaptic glutamate, near the levels of the control rats, and prevents an increase in synaptic glutamate signaling after a cocaine injection. These findings suggest there is a decrease in system Xc- activity in cocaine-withdrawn rats. It has also been found that cocaine increases glutamate signaling in the synaptic cleft, further supporting this conclusion.