| Research Abstract |
In the present study, novel Na^+-dependent carnitine/organic cation transporter family, OCTNs from human and mouse were identified and functionally characterized. We isolated two and three members of OCTN family from human and mouse, respectively. OCTNs are present in various tissues, including kidney, heart, skeletal muscle and placenta strongly, and in several human-derived cancer cell lines. By immunohistochemical analysis in kidney, mouse OCTNs localized commonly in luminal membrane of tubular epithelial cells. Most of human and mouse OCTNs exhibited multifunctionality by transporting both of carnitine and organic cation, tetraethylammonium (TEA). Furthermore, sodium ions were essential for carnitine transport by human and mouse OCTN1 and 2. In systemic carnitine deficiency (SCD) phenotype mouse model, juvenile visceral steotosis (jvs) mouse, mutation in OCTN2 gene was found. Furthermore, several kinds of mutation in human SCD patients were found, demonstrating that OCTN2 is a physiologically important carnitine transporter. Interestingly, TEA transport was sodium independent. In addition, OCTNs transporterd various cationic drugs such as quinidine, verapamil, and actinomycin D.Furthermore, since one mutation of human OCTN2 lost carnitine transport activity but retained TEA transport activity, it was suggested that OCTN2 have differential functional sites for carnitine and organic cations. So, OCTNs are thought to be multifunctional transporters by transporting carnitine and organic cations by sodium ion dependent and independent manner, respectively, and would be important for disposition of organic cationic drugs as well as carnitine. Furthermore, since carnitine transport via OCTN2 is inhibited various compounds, including organic cations, organic anions such as valproic acid and neutral compound such as cortisole, it is anticipated that drug-induced secondary carnitine deficiency could be caused by interaction on OCTN2.
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