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WIREs Membr Transp Signal

OCTs , OATs , and OCTNs : structure and function of the polyspecific organic ion transporters of the SLC22 family

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The SLC22 protein family includes more than 30 different proteins that operate as transporters for organic cations (OCTs), organic cations and zwitterions (OCTNs) or organic anions (OATs). These transporters play a pivotal role in the secretion of organic ions in kidney and liver. Furthermore, they contribute to the homeostasis of organic ions in several other tissues such as brain, placenta, intestine, and lung. Substrates include not only endogenous compounds such as monoamine neurotransmitters, choline, carnitine, α‐ketoglutarate, urate, or steroid hormones, but also a broad spectrum of therapeutic drugs. Therefore, they control the bioavailability of many drugs and are responsible for several side effects or drug–drug interactions. SLC22 proteins are polyspecific transporters as they are able to transport structurally different compounds. All SLC22 proteins share a common membrane topology with 12 α‐helical transmembrane domains. Mutational analyses and homology modeling of the steric structure of the proteins led to the conclusion that they possess a large cleft that is accessible from the aqueous phase. Located within this cleft is an inner cavity containing different interaction sites for different substrates. During the transport cycle the transporter undergoes conformational changes including an outward‐open conformation, a transient occluded state and an inward‐open conformation. WIREs Membr Transp Signal 2014, 3:1–13. doi: 10.1002/wmts.100

Conflict of interest: The author has declared no conflicts of interest for this article.

SLC22 transporters in a human renal proximal tubule cell. Abbreviations: DC, dicarboxylate; OA+, organic anion; OC, organic cation; ZI, zwitterion. The difference in line thickness in case of the OCTs indicates that uptake of organic cations is the favored direction of transport.
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Sterical model of rOCT1 (side view) derived from the tertiary structure of LacY. A large cleft that is accessible from the aqueous phase is flanked by eight transmembrane α‐helices. This cleft contains an inner cavity with interaction sites for substrate binding. Binding of a corticosterone molecule to the inner cavity is also shown. Mutation of the designated amino acids induces changes in affinity or selectivity for substrates, indicating their involvement in substrate binding. Left: inward‐open conformation; right: outward‐open conformation.
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Membrane topology of SLC22 transporters by the example of rOCT1. C‐ and N‐terminus are located intracellularly. Between transmembrane domains (TMDs) 1 and 2 a large extracellular loop exists, containing conserved cysteins that are involved in membrane trafficking. The intracellular loop between TMDs 6 and 7 contains several regulatory phosphorylation sites.
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