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

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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