Abstract
We identified a novel prostaglandin (PG)-specific organic anion transporter (OAT) in the OAT group of the SLC22 family. The transporter designated OAT-PG from mouse kidney exhibited Na(+)-independent and saturable transport of PGE(2) when expressed in a proximal tubule cell line (S(2)). Unusual for OAT members, OAT-PG showed narrow substrate selectivity and high affinity for a specific subset of PGs, including PGE(2), PGF(2alpha), and PGD(2). Similar to PGE(2) receptor and PGT, a structurally distinct PG transporter, OAT-PG requires for its substrates an alpha-carboxyl group, with a double bond between C13 and C14 as well as a (S)-hydroxyl group at C15. Unlike the PGE(2) receptor, however, the hydroxyl group at C11 in a cyclopentane ring is not essential for OAT-PG substrates. Addition of a hydroxyl group at C19 or C20 impairs the interaction with OAT-PG, whereas an ethyl group at C20 enhances the interaction, suggesting the importance of hydrophobicity around the omega-tail tip forming a "hydrophobic core" accompanied by a negative charge, which is essential for substrates of OAT members. OAT-PG-mediated transport is concentrative in nature, although OAT-PG mediates both facilitative and exchange transport. OAT-PG is kidney-specific and localized on the basolateral membrane of proximal tubules where a PG-inactivating enzyme, 15-hydroxyprostaglandin dehydrogenase, is expressed. Because of the fact that 15-keto-PGE(2), the metabolite of PGE(2) produced by 15-hydroxyprostaglandin dehydrogenase, is not a substrate of OAT-PG, the transport-metabolism coupling would make unidirectional PGE(2) transport more efficient. By removing extracellular PGE(2), OAT-PG is proposed to be involved in the local PGE(2) clearance and metabolism for the inactivation of PG signals in the kidney cortex.
Highlights
We identified a novel prostaglandin (PG)-specific organic anion transporter (OAT) in the OAT group of the SLC22 family
Addition of a hydroxyl group at C19 or C20 impairs the interaction with OAT-PG, whereas an ethyl group at C20 enhances the interaction, suggesting the importance of hydrophobicity around the -tail tip forming a “hydrophobic core” accompanied by a negative charge, which is essential for substrates of OAT members
We identified a novel member of the SLC22 family designated OAT-PG in mouse kidney that transports PGs and is localized on the basolateral membrane of proximal tubules
Summary
To limit or terminate PG actions on the target receptors, some mechanisms must exist for the clearance of PGs in the proximity of the sites of action in the kidney In line with this notion, the aforementioned PG transporter PGT that is expressed mainly in interstitial cells in renal medulla has been. We propose, based on the substrate selectivity and localization, that a newly identified OAT member of the SLC22 family, OAT-PG, is the transporter for the PG clearance in renal cortex. We identified a novel member of the SLC22 family designated OAT-PG (organic anion transporter for prostaglandins) in mouse kidney that transports PGs and is localized on the basolateral membrane of proximal tubules
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