Identification of a new urate and high affinity nicotinate transporter, hOAT10 (SLC22A13).
The orphan transporter hORCTL3 (human organic cation transporter like 3; SLC22A13) is highly expressed in kidneys and to a weaker extent in brain, heart, and intestine. hORCTL3-expressing Xenopus laevis oocytes showed uptake of [(3)H]nicotinate, [(3)H]p-aminohippurate, and [(14)C]urate. Hence, hORCTL3 is an organic anion transporter, and we renamed it hOAT10. [(3)H]Nicotinate transport by hOAT10 into X. laevis oocytes and into Caco-2 cells was saturable with Michaelis constants (K(m)) of 22 and 44 microm, respectively, suggesting that hOAT10 may be the molecular equivalent of the postulated high affinity nicotinate transporter in kidneys and intestine. The pH dependence of hOAT10 suggests p-aminohippurate(-)/OH(-), urate(-)/OH(-), and nicotinate(-)/OH(-) exchange as possible transport modes. Urate inhibited [(3)H]nicotinate transport by hOAT10 with an IC(50) value of 759 microm, assuming that hOAT10 represents a low affinity urate transporter. hOAT10-mediated [(14)C]urate uptake was elevated by an exchange with l -lactate, pyrazinoate, and nicotinate. Surprisingly, we have detected urate(-)/glutathione exchange by hOAT10, consistent with an involvement of hOAT10 in the renal glutathione cycle. Uricosurics, diuretics, and cyclosporine A showed substantial interactions with hOAT10, of which cyclosporine A enhanced [(14)C]urate uptake, providing the first molecular evidence for cyclosporine A-induced hyperuricemia.
Bahn
Andrew
A
Zentrum Physiologie und Pathophysiologie, Abteilung Vegetative Physiologie und Pathophysiologie, Humboldtallee 23, 37073 Göttingen, Germany. abahn@physiol.med.uni-goettingen.de
Hagos
Yohannes
Y
Reuter
Stefan
S
Balen
Daniela
D
Brzica
Hrvoje
H
Krick
Wolfgang
W
Burckhardt
Birgitta C
BC
Sabolic
Ivan
I
Burckhardt
Gerhard
G
D000595:Amino Acid Sequence; D000818:Animals; D018938:Caco-2 Cells; D005260:Female; D006801:Humans; D008297:Male; D008954:Models, Biological; D008969:Molecular Sequence Data; D009525:Niacin / Q000737:chemistry / Q000378:metabolism*; D009865:Oocytes / Q000378:metabolism; D027361:Organic Anion Transporters / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution; D014982:Xenopus laevis
D027361:Organic Anion Transporters; C530205:SLC22A13 protein, human; C103862:urate transporter; D009525:Niacin