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Vol. 59, Issue 2, 358-366, February 2001

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

Rikiya Ohashi, Ikumi Tamai, Jun-ichi Nezu, Hiroko Nikaido, Noriyoshi Hashimoto, Asuka Oku, Yoshimichi Sai, Miyuki Shimane, and Akira Tsuji

Faculty of Pharmaceutical Sciences (R.O., I.T., Y.S., A.T.) and Institute for Experimental Animals, Faculty of Medicine (H.N., N.H.), Kanazawa University, Kanazawa, Japan; Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, Kawaguchi, Japan (I.T., Y.S., A.T.); and Chugai Research Institute for Molecular Medicine Inc., Ibaraki, Japan (J.N., A.O., M.S.)

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 using jvs mice. The embryonic fibroblasts from jvs mice exhibited significantly decreased transport of [14C]TEA. Pharmacokinetic analysis of [14C]TEA disposition demonstrated that jvs mice 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.

Copyright © 2001 by The American Society for Pharmacology and Experimental Therapeutics


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