Molecular and physiological evidence for multifunctionality of carnitine/organic cation transporter OCTN2.
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 [(14)C]TEA. Pharmacokinetic analysis of [(14)C]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.
Ohashi
R
R
Faculty of Pharmaceutical Sciences, Faculty of Medicine, Kanazawa University, Kanazawa, Japan.
Tamai
I
I
Nezu Ji
J
J
Nikaido
H
H
Hashimoto
N
N
Oku
A
A
Sai
Y
Y
Shimane
M
M
Tsuji
A
A
D000818:Animals; D001692:Biological Transport; D002250:Carbon Radioisotopes; D002331:Carnitine / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008809:Mice, Inbred C3H; D027701:Organic Cation Transport Proteins; D000074058:Solute Carrier Family 22 Member 5; D019789:Tetraethylammonium / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics; D014018:Tissue Distribution; D014316:Tritium
D002250:Carbon Radioisotopes; D002352:Carrier Proteins; D008565:Membrane Proteins; D027701:Organic Cation Transport Proteins; C492020:SLC22A5 protein, human; D000074058:Solute Carrier Family 22 Member 5; D014316:Tritium; D019789:Tetraethylammonium; D002331:Carnitine