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Functional characterization and relevance of carnitine transporter OCTN2 to secondary carnitine deficiency.

肉碱转运蛋白 OCTN2 的功能特征及其与继发性肉碱缺乏症的相关性。

基本信息

批准号：
11672212
负责人：
TAMAI Ikumi
金额：
$ 2.5万
依托单位：
KANAZAWA UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2000
项目状态：
已结题

项目摘要

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.

在本研究中，鉴定了来自人和小鼠的新型 Na^+ 依赖性肉碱/有机阳离子转运蛋白家族 OCTN 并进行了功能表征。我们分别从人类和小鼠中分离出 OCTN 家族的两个和三个成员。 OCTN 强烈存在于各种组织中，包括肾、心脏、骨骼肌和胎盘，以及几种人源性癌细胞系中。通过肾脏的免疫组织化学分析，小鼠 OCTN 通常位于肾小管上皮细胞的管腔膜中。大多数人类和小鼠 OCTN 通过运输肉碱和有机阳离子四乙铵 (TEA) 表现出多功能性。此外，钠离子对于人类和小鼠 OCTN1 和 2 的肉毒碱转运至关重要。在系统性肉毒碱缺乏 (SCD) 表型小鼠模型、幼年内脏脂肪变性 (jvs) 小鼠中，发现 OCTN2 基因突变。此外，在人类SCD患者中发现了多种突变，证明OCTN2是生理上重要的肉碱转运蛋白。有趣的是，TEA 的运输不依赖于钠。此外，OCTNs还转运各种阳离子药物，如奎尼丁、维拉帕米和放线菌素D。此外，由于人OCTN2的一种突变失去了肉碱转运活性，但保留了TEA转运活性，表明OCTN2对肉碱和有机阳离子具有不同的功能位点。因此，OCTNs被认为是多功能转运蛋白，分别通过钠离子依赖和独立的方式转运肉碱和有机阳离子，并且对于有机阳离子药物和肉碱的处置具有重要意义。此外，由于通过 OCTN2 的肉碱转运会抑制多种化合物，包括有机阳离子、有机阴离子（例如丙戊酸）和中性化合物（例如皮质醇），因此预计药物诱导的继发性肉碱缺乏可能是由于 OCTN2 上的相互作用引起的。