Renal and brain phenotype revealed by gene targeting of L‐type amino acid transporter 2

L‐type amino acid transporter 2 (Lat2, Slc7a8 ) is a 12‐transmembrane transporter that mediate transport of neutral amino acids and thyroid hormones. LAT2 is expressed along the basolateral membrane of kidney proximal tubulus in humans and mice. In the brain, Lat2 is expressed in neurons, microglia, and astrocytes. In murine cortical neurons Lat2 is coexpressed with Mct8, a thyroid hormone transporter mutated in Allan‐Herndon‐Dudley syndrome. We have hypothesized that Lat2 compensates for lack of Mct8 in the mouse model of the disease. To investigate the physiological role of Lat2, we have analyzed transgenic Lat2 ‐ deficient mice. Analysis of urinary amino acid excretion revealed increased loss of several amino acids in Lat2 −/− mice indicative of the in vivo substrate spectrum of Lat2. Interestingly, excretion of leucine and isoleucine, paradigmatic L‐type amino acid transporter substrates, remained unaltered. As in Mct8 ‐deficient mice, urinary thyroid hormone excretion was increased in Lat2 −/− mice. Astrocytes coexpress Mct8 and Lat2 as thyroid hormone transporters. We performed uptake assays in primary mouse astrocytes. Gene targeting significantly reduced thyroid hormone uptake in Lat2 −/− astrocytes and to the same extent as co‐application of the Lat inhibitor BCH. A role for Lat2 in brain function is suggested by the significantly reduced motor performance on the rotarod apparatus.