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Contributions of system A subtypes to α-methylaminoisobutyric acid uptake by placental microvillous membranes of human and rat

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Abstract

System A consists of three subtypes, sodium-coupled neutral amino acid transporter 1 (SNAT1), SNAT2, and SNAT4, which are all expressed in the placenta. The aim of this study was to evaluate the contributions of each of the three subtypes to total system A-mediated uptake in placental MVM of human and rat, using betaine and l-arginine as subtype-selective inhibitors of SNAT2 and SNAT4, respectively. Appropriate concentrations of betaine and l-arginine for subtype-selective inhibition in SNAT-overexpressing cells were identified. It was found that 10 mM betaine specifically and almost completely inhibited human and rat SNAT2-mediated [14C]α-methylaminoisobutyric acid ([14C]MeAIB) uptake, while 5 mM l-arginine specifically and completely inhibited [3H]glycine uptake via human SNAT4, as well as [14C]MeAIB uptake via rat SNAT4. In both human and rat placental MVM vesicles, sodium-dependent uptake of [14C]MeAIB was almost completely inhibited by 20 mM unlabeled MeAIB. l-Arginine (5 mM) partly inhibited the uptake in humans, but hardly affected that in rats. Betaine (10 mM) partly inhibited the uptake in rats, but hardly affected it in humans. These results suggest that SNAT1 is most likely the major contributor to system A-mediated MeAIB uptake by human and rat MVM vesicles and that the remaining uptake is mainly mediated by SNAT4 in humans and SNAT2 in rats. Thus, inhibition studies using betaine and l-arginine are useful to characterize the molecular mechanisms of system A-mediated transport.

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Authors and Affiliations

  1. Faculty of Pharmacy, Keio University, 1-5-30 Shibakoen, Minato-ku, Tokyo, 105-8512, Japan

    Yu Takahashi, Tomohiro Nishimura, Masatoshi Tomi & Emi Nakashima

  2. Department of Obstetrics and Gynecology, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan

    Tetsuo Maruyama

Authors
  1. Yu Takahashi
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  2. Tomohiro Nishimura
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  3. Tetsuo Maruyama
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  4. Masatoshi Tomi
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  5. Emi Nakashima
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Correspondence to Masatoshi Tomi.

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Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Uncomplicated term human placental tissues were obtained with the approval of the Institutional Ethics Committee of Keio University Faculty of Pharmacy (120301-3) and Keio University School of Medicine (20110250). All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

Funding

This study was supported in part by JSPS KAKENHI Grant Numbers 15K15007, 15K08595, 26282028, and 25560063. It was also funded in part by the Ministry of Education, Culture, Sports, Science, and Technology-Supported Program for Strategic Research at Private Universities, the Food Safety Commission of Japan (Cabinet Office) (#1107), Keio Gijuku Academic Development Funds, Takeda Science Foundation, Suzuken Memorial Foundation, The Uehara Memorial Foundation, and the Nakatomi Foundation.

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Informed consent was obtained from all individual participants included in the study.

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Handling Editor: E. I. Closs.

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Takahashi, Y., Nishimura, T., Maruyama, T. et al. Contributions of system A subtypes to α-methylaminoisobutyric acid uptake by placental microvillous membranes of human and rat. Amino Acids 49, 795–803 (2017). https://doi.org/10.1007/s00726-017-2384-7

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  • DOI: https://doi.org/10.1007/s00726-017-2384-7

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