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Role of a novel prostaglandin transporter OAT-PG in sodium transport regulation mechanism

新型前列腺素转运蛋白OAT-PG在钠转运调节机制中的作用

基本信息

批准号：
18590900
负责人：
ANZAI Naohiko
金额：
$ 1.73万
依托单位：
Kyorin University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18590900/
关键词：
Prostaglandin Kidney Cyclooxigenase Anions Transporter COX-2 PDZ PDZ proteins

项目摘要

In the kidney, prostaglandins (PGs), especially prostaglandin E_2(PGE_2), have important roles in renal hemodynamics, renin release, tubular sodium and water reabsorption. Because PGs are charged organic anions at physiological pH, they poorly penetrate biological membranes. Accordingly, PG transport is a carrie瀕ediated process. So far only prostaglandin transporter (PGT) from OATP (SLC0/SLC21) family is known as a transporter specific to PGs. Recently, we isolated a cDNA encoding a novel prostaglandin-specific transporter from mouse kidney. Because this transporter belongs to organic anion transporter (OAT) family (SLC22) structurally distinct from PGT, we named this prostaglandin-specific organic anion transporter (OAT-PG). OAT-PG specifically mediated a transport of PGs such as PGE_2 and PGF_<2a>. It was speculated that OAT-PG plays an important role in renal handling of PGE_2 and contributes to physiological functions involving in PGE_2 metabolism. Particularly, through the interac … More tion with COX-2 and EP4 receptor, PGE_2 may function as a signaling molecule that regulates the sodium transport at the distal segments of nephron.This study was performed to examine the possibility that OAT-PG constitute the renal apical prostaglandin signaling mechanism. First, we investigate the driving force of OAT-PG-mediated PGs transport because in in vitro PG transport via OAT-PG seems bidirectional By using trans-stimulatory experiments, we identified that inorganic sulfate ion may be a counter ion for OATPG-mediated PGs transport. Next, to confirm that the components of renal apical PG signaling such as OATPG, COX-2and EP4 are tethered by some kind of scaffolding protein (s), we perfomed the yeast two-hybrid screening of kidney cDNA library using OATPG C-terminal sequence as bait. From this screening, we succeeded to identify that multivalent PDZ-domain protein CIPP (Channel-Interacting PDZ protein) is the binding partner of OAT-PG. These results will contribute to the clarification of renal apical PG signaling mechanism surrounding OAT-PG. Less

在肾脏中，前列腺素(PGs)尤其是前列腺素E_2(PGE_2)在肾血流动力学、肾素释放、肾小管钠和水重吸收等方面发挥着重要作用。由于PG在生理pH下是带电的有机阴离子，它们很难穿透生物膜。因此，PG运输是一个由Carrie瀕编辑的过程。到目前为止，只有OATP(SLC0/SLC21)家族的前列腺素转运体(PGT)被认为是PGs的专一性转运体。最近，我们从小鼠肾脏中克隆了一种新的前列腺素转运蛋白的编码基因。由于该转运体属于有机阴离子转运体(OAT)家族(SLC22)，在结构上不同于PGT，因此我们将其命名为前列腺素特异性有机阴离子转运体(OAT-PG)。OAT-PG特异性地介导了PGE_2和PGF_2a&gt；等PGs的转运。推测OAT-PG在PGE_2的肾脏处理中起重要作用，并参与参与PGE_2代谢的生理功能。特别是通过Interac…在COX-2和EP4受体的作用下，PGE_2可能是调节肾远端钠转运的信号分子。本研究旨在探讨OAT-PG构成肾尖前列腺素信号转导机制的可能性。首先，我们研究了OAT-PG介导的PGs转运的驱动力，因为在体外通过OAT-PG的PG转运似乎是双向的。通过反式刺激实验，我们发现无机硫酸盐离子可能是OATPG介导的PGs转运的反离子。接下来，为了证实肾尖PG信号的组成成分OATPG、COX-2和EP4是否被某种支架蛋白(S)所束缚，我们以OATPG的C端序列为诱饵，进行了肾脏cDNA库的酵母双杂交筛选。通过这次筛选，我们成功地鉴定了多价PDZ结构域蛋白CIPP(Channel-Interaction PDZ Protein)是OAT-PG的结合伙伴。这些结果有助于阐明围绕OAT-PG的肾尖PG信号转导机制。较少