Establishment of Stable Cell Lines With High Expression of Heterodimers of Human 4F2hc and Human Amino Acid Transporter LAT1 or LAT2 and Delineation of Their Differential Interaction With <I>α</I>-Alkyl Moieties

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  • Khunweeraphong Narakorn
    Division of Bio-system Pharmacology, Department of Pharmacology, Graduate School of Medicine, Osaka University, Japan Department of Pharmacology and Toxicology, Kyorin University School of Medicine, Japan
  • Nagamori Shushi
    Division of Bio-system Pharmacology, Department of Pharmacology, Graduate School of Medicine, Osaka University, Japan
  • Wiriyasermkul Pattama
    Division of Bio-system Pharmacology, Department of Pharmacology, Graduate School of Medicine, Osaka University, Japan
  • Nishinaka Yumiko
    Division of Bio-system Pharmacology, Department of Pharmacology, Graduate School of Medicine, Osaka University, Japan
  • Wongthai Printip
    Division of Bio-system Pharmacology, Department of Pharmacology, Graduate School of Medicine, Osaka University, Japan
  • Ohgaki Ryuichi
    Division of Bio-system Pharmacology, Department of Pharmacology, Graduate School of Medicine, Osaka University, Japan
  • Tanaka Hidekazu
    Division of Bio-system Pharmacology, Department of Pharmacology, Graduate School of Medicine, Osaka University, Japan
  • Tominaga Hideyuki
    Department of Molecular Imaging, Gunma University Graduate School of Medicine, Japan
  • Sakurai Hiroyuki
    Department of Pharmacology and Toxicology, Kyorin University School of Medicine, Japan
  • Kanai Yoshikatsu
    Division of Bio-system Pharmacology, Department of Pharmacology, Graduate School of Medicine, Osaka University, Japan

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Other Title
  • Establishment of Stable Cell Lines With High Expression of Heterodimers of Human 4F2hc and Human Amino Acid Transporter LAT1 or LAT2 and Delineation of Their Differential Interaction With α-Alkyl Moieties
  • Establishment of Stable Cell Lines With High Expression of Heterodimers of Human 4F2hc and Human Amino Acid Transporter LAT1 or LAT2 and Delineation of Their Differential Interaction With ^|^alpha;-Alkyl Moieties

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Abstract

System L is a major transport system for cellular uptake of neutral amino acids. Among system L transporters, L-type amino acid transporter 1 (LAT1) is responsible for the nutrient uptake in cancer cells, whereas L-type amino acid transporter 2 (LAT2) is a transporter for non-cancer cells. In this study, we have established HEK293 cell lines stably expressing high levels of human LAT1 and LAT2 forming heterodimers with native human 4F2hc of the cells. We have found that L-[14C]alanine is an appropriate substrate to examine the function of LAT2, whereas L-[14C]leucine is used for LAT1. By using L-[14C]alanine on LAT2, we have for the first time directly evaluated the function of human LAT2 expressed in mammalian cells and obtained its reliable kinetics. Using α-alkyl amino acids including α-methyl-alanine and α-ethyl-L-alanine, we have demonstrated that α-alkyl groups interfere with the interaction with LAT2. These cell lines with higher practical advantages would be useful for screening and analyzing compounds to develop LAT1-specific drugs that can be used for cancer diagnosis and therapeutics. The strategy that we took to establish the cell lines would also be applicable to the other heterodimeric transporters with important therapeutic implications.

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