4F2hc/y+LAT2 is a major arginine transporter in human erythroid cells

Arginine, the precursor of nitric oxide and polyamines, may influence the expression of genes involved in erythroid differentiation. It has been claimed that arginine transport in K562 erythroleukemia cells mainly occurs through CAT1 transporter (system y+) and is needed for erythroid differentiation of these cells and of normal erythroid precursors (Shima Y et al, Blood. 2006;107:1352-1356). Our results demonstrate that (a) K562 cells markedly express the mRNA for another arginine transporter, y+LAT2 (system y+L); (b) the 50% inhibition of arginine influx by leucine is partially Na+-dependent, an hallmark of system y+L; (c) similarly, leucine inhibits arginine transport in Xenopus oocytes expressing 4F2hc/y+LAT2 but not in oocytes expressing CAT1; (d) silencing of SLC7A6, the gene for y+LAT2, lowers SLC7A6 mRNA, y+LAT2 protein and arginine transport in K562 cells; (e) upon SLC7A6 silencing, intracellular Arg is doubled. In addition, (f) the expression of the y+LAT2 gene (SLC7A6) increases following K562 erythroid differentiation, and (g) CAT1 and 4F2hc/y+LAT2 are also expressed in human erythroid precursor cells isolated from peripheral blood. We thus conclude that 4F2hc/y+LAT2 transporter (system y+L) is expressed in human erythroid cells, mediates predominantly Arg efflux and contributes significantly to the regulation of intracellular Arg concentration.