The heterodimeric amino acid transporter 4F2hc/y(+)LAT2 mediates arginine efflux in exchange with glutamine

The cationic amino acid arginine, due to its positive charge, is usually ac cumulated in the cytosol. Nevertheless, arginine has to be released by a nu mber of cell types, e.g. kidney cells, which supply other organs with this amino acid, or the endothelial cells of the blood-brain barrier which relea se arginine into the brain. Arginine release in mammalian cells can be medi ated by two different transporters, y(+)LAT1 and y(+)LAT2. For insertion in to the plasma membrane, these transporters have to be associated with the t ype-II membrane glycoprotein 4F2hc [Torrents, Estevez, Pineda, Fernandez, L loberas, Shi, Zorzano and Palacin (1998) J. Biol. Chem. 273, 32437-32445]. The present study elucidates the function and distribution of y(+)LAT2. In contrast to y(+)LAT1, which is expressed mainly in kidney epithelial cells, lung and leucocytes, y(+)LAT2 has a wider tissue distribution, including b rain, heart, testis, kidney, small intestine and parotis. When co-expressed with 4F2hc in Xenopus laevis oocytes, y(+)LAT2 mediated uptake of arginine , leucine and glutamine. Arginine uptake was inhibited strongly by lysine, glutamate, leucine, glutamine, methionine and histidine. Mutual inhibition was observed when leucine or glutamine was used as substrate. Inhibition of arginine uptake by neutral amino acids depended on the presence of Na+, wh ich is a hallmark of y(+)LAT-type transporters. Although arginine Transport was inhibited strongly by glutamate, this anionic amino acid was only weak ly transported by 4F2hc/y(+)LAT2. Amino acid transport via 4F2hc/y(+)LAT2 f ollowed an antiport mechanism similar to the other members of this new fami ly. Only preloaded arginine could be released in exchange for extracellular amino acids, whereas marginal release of glutamine or leucine was observed under identical conditions. These results indicated that arginine has the highest affinity for the intracellular binding site and that arginine relea se may be the main physiological function of this transporter.