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Review
. 2008 Jul;38(7-8):889-935.
doi: 10.1080/00498250801927435.

Physiology, structure, and regulation of the cloned organic anion transporters

C Srimaroeng  1 , J L Perry, J B Pritchard
Affiliations
Review

Physiology, structure, and regulation of the cloned organic anion transporters

C Srimaroeng et al. Xenobiotica. 2008 Jul.

Abstract

1. The transport of negatively charged drugs, xenobiotics, and metabolites by epithelial tissues, particularly the kidney, plays critical roles in controlling their distribution, concentration, and retention in the body. Thus, organic anion transporters (OATs) impact both their therapeutic efficacy and potential toxicity. 2. This review summarizes current knowledge of the properties and functional roles of the cloned OATs, the relationships between transporter structure and function, and those factors that determine the efficacy of transport. Such factors include plasma protein binding of substrates, genetic polymorphisms among the transporters, and regulation of transporter expression. 3. Clearly, much progress has been made in the decade since the first OAT was cloned. However, unresolved questions remain. Several of these issues--drug-drug interactions, functional characterization of newly cloned OATs, tissue differences in expression and function, and details of the nature and consequences of transporter regulation at genomic and intracellular sites--are discussed in the concluding Perspectives section.

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Figures

Figure 1
Figure 1
Classical model of basolateral organic anion transport system. Basolateral organic anion uptake is indirectly coupled to the Na+ gradient by a tertiary active transport. (1) Na,K-ATPase derives energy from ATP hydrolysis and pumps Na+ out of the cell. (2) Na+-dicarboxylate co-transporter (NaDC), energetically downhill movement of Na+ into the cell drives dicarboxylate (physiologically αKG) uptake via NaDC, thus, maintaining an outwardly directed αKG gradient. (3) Organic anion transporter (OAT), intracellular αKG is used as a counter-ion by OATs 1 and 3 to drive entry of the organic anions into the cell against the inside negative membrane potential. Cellular metabolism ultimately drives OAT-mediated transport by providing ATP for Na,K-ATPase and the metabolic intermediate, αKG, for OAT-driven exchange.
Figure 2
Figure 2
Localization of cloned organic anion transporters (OATs) in human renal proximal tubule cells. Three isoforms of OATs are found at the basolateral membrane of human renal proximal tubular epithelial cells. OAT1 and OAT3 are responsible for transport organic anions across the basolateral membrane via a tertiary active mechanism (Figure 1). The role of the third transporter, OAT2, remains unclear. Two transporters appear to play important roles for organic anion transport at the luminal membrane. URAT1 is capable of reabsorption of urate in exchange for intracellular organic and/or inorganic anions. Human OAT4 may perform a similar role by exchanging organic anions for OH−, but uncertainties remain.
Figure 3
Figure 3
Critical amino acids for transport of SLC22 members. Three-dimensional arrangement of transmembrane domains. Dotted lines depict extracellular loops and solid lines represent cytoplasmic loops. fOat1 mutants are shown in purple, rOat3 mutants in blue, hOAT3 mutants in orange, hOAT1 mutants in black, and URAT1 mutants in red. 1, N39Q of mOat1; 2, residue also mutated to F, which caused functional decreases; 3, residue also mutated to Y, which caused functional decreases; 4, corresponds to Y353A/W/F and Y354A/W/F mutants in hOAT1, respectively; 5, residue also mutated to S, which caused functional decreases; 6, corresponds to K394A mutated in fOat1; 7, corresponds to F426 in hOAT3; 8, corresponds to R478D mutated in fOat1 and R466K mutated in hOAT1.
Figure 4
Figure 4
Three-dimensional structure of hOAT1, looking into the cytoplasmic open face. The putative binding site is surrounding by yellow aliphatic amino acids, orange polar amino acids, red positively charged amino acids (R466 and K370), and green aromatic amino acids (Y230 and F438).
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