Heterodimeric amino acid transporters: molecular biology and pathological and pharmacological relevance.

In the last decade, a lot of amino acid transporters were identified by molecular cloning and assigned to the classically characterized amino acid transport systems. Among them, ones which belong to the heterodimeric amino acid transporter family are unique because of their broad substrate selectivity and their pathological implications as well as their structural features. The heterodimeric amino acid transporter family is a subfamily of SLC7 solute transporter family which includes 14-transmembrane cationic amino acid transporters as well as 12-transmembrane heterodimeric amino acid transporters. The members of heterodimeric amino acid transporter family are linked via a disulfide bond to single membrane spanning type II membrane glycoproteins such as 4F2hc (4F2 heavy chain) and rBAT (related to b(0,+)-amino acid transporter). Six members are associated with 4F2hc and one is linked to rBAT. The neutral amino acid transporter of this family seems to rely on the hydrophobic interactions for their substrate recognition which can explain their broad substrate selectivity. Because of this characteristic, they can permeate amino-acid-related drugs and contribute to the pharmacokinetics of these drugs. A neutral amino acid transporter LAT1 (L-type amino acid transporter 1) has actually been shown to be present at the blood-brain-barrier. Because the members of the heterodimeric amino acid transporter family exhibit variety of substrate selectivity, it is proposed that this family members have been diverged from the prototype neutral amino acid transporter such as LAT1 by acquiring the mechanisms for the recognition of electric charges on the substrate amino acid side chains. The dysfunction or hyperfunction of the members of the heterodimeric amino acid transporter family are involved in some diseases and pathologic conditions. The genetic defects of the renal and intestinal transporters BAT1/b(0,+) AT (b(0,+)-type amino acid transporter 1/b(0,+)-type amino acid transporter) and y+ LAT1 (y+ L-type amino acid transporter 1) result in the amino aciduria with sever clinical symptoms such as cystinuria and lysinuric protein intolerance, respectively. LAT1 is proposed to be involved in the progression of malignant tumor. xCT (x- C-type transporter) functions to protect cells against oxidative stress, while its over-function may be damaging neurons leading to the exacerbation of brain damage after, brain ischemia. Therefore, these transporters would be candidates for therapeutic targets based on new strategies. Through the interaction with the associating proteins, the transporters of this family would be endowed with more possibility to be regulated via intracellular and extracellular signalling pathways, which is critical to tune the transporter functions to meet the metabolic requirements of cells.