Molecular and physiological evidence for multifunctionality of carnitine/organic cation transporter OCTN2
Molecular and physiological evidence for multifunctionality of carnitine/organic cation transporter OCTN2
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DOI：
10.1124/mol.59.2.358
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发表时间：
2001-02-01
影响因子：
3.6
通讯作者：
Tsuji, A
中科院分区：
文献类型：
--
作者：
Ohashi, R;Tamai, I;Tsuji, A
OCT2是依赖安娜离子转运的肉碱转运体，对脂肪酸代谢至关重要，其功能缺陷导致致死性全身性肉碱缺乏症。它还以安娜不依赖的方式转运有机阳离子四乙基铵(TEA)。在这里，我们通过检测OCTN2基因在转基因细胞和幼年内脏脂肪变性(JVS)小鼠中的转运特性，研究了OCTN2的多功能性。用JVS小鼠证实了OCTN_2作为有机阳离子转运体的生理意义。JVS小鼠胚胎成纤维细胞对[C-14]TEA的转运显著降低。对[C-14]TEA的药代动力学分析表明，JVS小鼠的组织分布和肾脏分泌清除量减少。在使用OCTN2表达细胞的转运实验中，TEA和肉碱在它们的转运过程中显示出相互的反式刺激效应，暗示着肉碱/TEA交换机制。此外，Na+影响肉碱对OCTN 2的亲和力，而Na+不太可能参与茶叶的运输。这是首次对有机阳离子转运体在肾尖膜上的运作进行了分子和生理学证明。这一结果与肉碱重吸收与有机阳离子分泌的生理耦合是一致的。
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 [C-14]TEA. Pharmacokinetic analysis of [C-14]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.