A novel transporter of SLC22 family specifically transports prostaglandins and co-localizes with 15-hydroxyprostaglandin dehydrogenase in renal proximal tubules.
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.
Shiraya
Katsuko
K
Department of Pharmacology and Toxicology, Kyorin University School of Medicine, Mitaka, Tokyo 181-8611, Japan.
Hirata
Taku
T
Hatano
Ryo
R
Nagamori
Shushi
S
Wiriyasermkul
Pattama
P
Jutabha
Promsuk
P
Matsubara
Mitsunobu
M
Muto
Shigeaki
S
Tanaka
Hidekazu
H
Asano
Shinji
S
Anzai
Naohiko
N
Endou
Hitoshi
H
Yamada
Akira
A
Sakurai
Hiroyuki
H
Kanai
Yoshikatsu
Y
D000595:Amino Acid Sequence; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002460:Cell Line; D015237:Dinoprost / Q000031:analogs & derivatives / Q000494:pharmacology; D015232:Dinoprostone / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D020869:Gene Expression Profiling; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000378:metabolism*; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D007700:Kinetics; D051379:Mice; D008969:Molecular Sequence Data; D027361:Organic Anion Transporters / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011453:Prostaglandins / Q000378:metabolism* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013379:Substrate Specificity / Q000187:drug effects
C551255:OAT-PG protein, mouse; D027361:Organic Anion Transporters; D011453:Prostaglandins; D015237:Dinoprost; D006911:Hydroxyprostaglandin Dehydrogenases; C035859:15-hydroxyprostaglandin dehydrogenase; D015232:Dinoprostone
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