Molecular and Physiological Evidence for Multifunctionality of Carnitine/Organic Cation Transporter OCTN2

  1. Rikiya Ohashi1,
  2. Ikumi Tamai1,3,
  3. Jun-ichi Nezu4,
  4. Hiroko Nikaido2,
  5. Noriyoshi Hashimoto2,
  6. Asuka Oku4,
  7. Yoshimichi Sai1,3,
  8. Miyuki Shimane4 and
  9. Akira Tsuji1,3
  1. 1Faculty of Pharmaceutical Sciences (R.O., I.T., Y.S., A.T.) and2Institute for Experimental Animals, Faculty of Medicine (H.N., N.H.), Kanazawa University, Kanazawa, Japan; 3Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, Kawaguchi, Japan (I.T., Y.S., A.T.); and 4Chugai Research Institute for Molecular Medicine Inc., Ibaraki, Japan (J.N., A.O., M.S.)

    Abstract

    OCTN2 is an Na+-dependent transporter for carnitine, which is essential for fatty acid metabolism, and its functional defect leads to fatal systemic carnitine deficiency (SCD). It also transports the organic cation tetraethylammonium (TEA) in an Na+-independent manner. Here, we studied the multifunctionality of OCTN2, by examining the transport characteristics in cells transfected with mouse OCTN2 and in juvenile visceral steatosis (jvs) mice that exhibit a SCD phenotype owing to mutation of the OCTN2 gene. The physiological significance of OCTN2 as an organic cation transporter was confirmed by usingjvs mice. The embryonic fibroblasts fromjvs mice exhibited significantly decreased transport of [14C]TEA. Pharmacokinetic analysis of [14C]TEA disposition demonstrated that jvsmice showed decreased tissue distribution and renal secretory clearance. In transport experiments using OCTN2-expressing cells, TEA and carnitine showed mutual trans-stimulation effects in their transport, implying a carnitine/TEA exchange mechanism. In addition, Na+ affected the affinity of carnitine for OCTN2, whereas Na+ is unlikely to be involved in TEA transport. This is the first molecular and physiological demonstration of the operation of an organic cation transporter in renal apical membrane. The results are consistent with the physiological coupling of carnitine reabsorption with the secretion of organic cations.

    Footnotes

    • Send reprint requests to: Prof. Akira Tsuji, Ph.D., Department of Pharmacobio-Dynamics, Faculty of Pharmaceutical Sciences, Kanazawa University, 13–1 Takara-machi, Kanazawa 920-0934, Japan. E-mail: tsuji{at}kenroku.kanazawa-u.ac.jp

    • This study was partly supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, Sports and Culture, Japan.

    • Abbreviations:
      TEA
      tetraethylammonium
      jvs
      juvenile visceral steatosis
      SCD
      systemic carnitine deficiency
      MPP
      1-methyl-4-phenylpyridinium
      HEK
      human embryonic kidney
      NMG
      N-methylglucamine
      GFR
      glomerular filtration rate
      AUC
      area under plasma concentration-time curve
      CLr
      renal clearance
      CLs
      renal secretory clearance
      Kp
      tissue-to-plasma concentration ratio
      • Received July 7, 2000.
      • Accepted November 11, 2000.
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    1. Molecular Pharmacology February 1, 2001 vol. 59 no. 2 358-366
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