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 c arnitine deficiency (SCD). It also transports the organic cation tetraethyl ammonium (TEA) in an Na+-independent manner. Here, we studied the multifunc tionality of OCTN2, by examining the transport characteristics in cells tra nsfected with mouse OCTN2 and in juvenile visceral steatosis (jvs) mice tha t exhibit a SCD phenotype owing to mutation of the OCTN2 gene. The physiolo gical significance of OCTN2 as an organic cation transporter was confirmed by using jvs mice. The embryonic fibroblasts from jvs mice exhibited signif icantly decreased transport of [C-14]TEA. Pharmacokinetic analysis of [C-14 ]TEA disposition demonstrated that jvs mice showed decreased tissue distrib ution and renal secretory clearance. In transport experiments using OCTN2-e xpressing cells, TEA and carnitine showed mutual trans-stimulation effects in their transport, implying a carnitine/TEA exchange mechanism. In additio n, Na+ affected the affinity of carnitine for OCTN2, whereas Na+ is unlikel y to be involved in TEA transport. This is the first molecular and physiolo gical demonstration of the operation of an organic cation transporter in re nal apical membrane. The results are consistent with the physiological coup ling of carnitine reabsorption with the secretion of organic cations.