Publications

• Deorphaning a solute carrier 22 family member, SLC22A15, through functional genomic studies.

  Yee S.W., Buitrago D., Stecula A., Ngo H.X., Chien H.C., Zou L., Koleske M.L., Giacomini K.M.

  The human solute carrier 22A (SLC22A) family consists of 23 members, representing one of the largest families in the human SLC superfamily. Despite their pharmacological and physiological importance in the absorption and disposition of a range of solutes, eight SLC22A family members remain classif ... >> More

  The human solute carrier 22A (SLC22A) family consists of 23 members, representing one of the largest families in the human SLC superfamily. Despite their pharmacological and physiological importance in the absorption and disposition of a range of solutes, eight SLC22A family members remain classified as orphans. In this study, we used a multifaceted approach to identify ligands of orphan SLC22A15. Ligands of SLC22A15 were proposed based on phylogenetic analysis and comparative modeling. The putative ligands were then confirmed by metabolomic screening and uptake assays in SLC22A15 transfected HEK293 cells. Metabolomic studies and transporter assays revealed that SLC22A15 prefers zwitterionic compounds over cations and anions. We identified eight zwitterions, including ergothioneine, carnitine, carnosine, gabapentin, as well as four cations, including MPP⁺ , thiamine, and cimetidine, as substrates of SLC22A15. Carnosine was a specific substrate of SLC22A15 among the transporters in the SLC22A family. SLC22A15 transport of several substrates was sodium-dependent and exhibited a higher Km for ergothioneine, carnitine, and carnosine compared to previously identified transporters for these ligands. This is the first study to characterize the function of SLC22A15. Our studies demonstrate that SLC22A15 may play an important role in determining the systemic and tissue levels of ergothioneine, carnosine, and other zwitterions. << Less

  FASEB J. 34:15734-15752(2020) [PubMed] [EuropePMC]

  This publication is cited by 11 other entries.

• Functional characterization of ergothioneine transport by rat organic cation/carnitine transporter Octn1 (slc22a4).

  Nakamura T., Yoshida K., Yabuuchi H., Maeda T., Tamai I.

  It has been reported that organic cation/carnitine transporter 1 (OCTN1) is associated with rheumatoid arthritis and Crohn's disease. Additionally, we reported that OCTN1 is expressed in hematopoietic cells, and is associated with proliferation and differentiation of erythroid cells. However, phys ... >> More

  It has been reported that organic cation/carnitine transporter 1 (OCTN1) is associated with rheumatoid arthritis and Crohn's disease. Additionally, we reported that OCTN1 is expressed in hematopoietic cells, and is associated with proliferation and differentiation of erythroid cells. However, physiological role of OCTN1 is still unclear. Ergothioneine, an anti-oxidant, was recently reported to be a good substrate of human OCTN1. However, the transport characteristics of ergothioneine in rat remains to be clarified. The present study, is to further investigate the role of rat Octn1 on transport of ergothioneine in rat Octn1 transfected cells and natively expressing cell line PC12 derived from rat adrenal pheochromocytoma. [(3)H]Ergothioneine uptake by rat Octn1 stably transfected HEK293 cells was saturable, sodium dependent with 1 : 1 stoichiometry of ergothioneine, and pH dependent. Since ergothioneine was reported to presumably play a protective role against oxidative stress-induced apoptosis in PC12 cells, its transport in this cell line was investigated. The expression of rat Octn1 and a saturable and Na(+)-dependent transport of ergothioneine were observed in PC12 cells, suggesting that ergothioneine transport in this cell line may be mediated by rat Octn1. These findings suggested that rat Octn1 may act as a survival factor by taking up ergothioneine to suppress oxidative stress in this cell line. In conclusion, functional characteristics of ergothioneine transport by rat Octn1 is similar to that of human OCTN1 and it is suggested that rat Octn1 is important by transporting anti-oxidant ergothioneine in PC12 cells, though its role in vivo is to be investigated. << Less

  Biol. Pharm. Bull. 31:1580-1584(2008) [PubMed] [EuropePMC]

• Discovery of the ergothioneine transporter.

  Gruendemann D., Harlfinger S., Golz S., Geerts A., Lazar A., Berkels R., Jung N., Rubbert A., Schoemig E.

  Variants of the SLC22A4 gene are associated with susceptibility to rheumatoid arthritis and Crohn's disease. SLC22A4 codes for an integral membrane protein, OCTN1, that has been presumed to carry organic cations like tetraethylammonium across the plasma membrane. Here, we show that the key substra ... >> More

  Variants of the SLC22A4 gene are associated with susceptibility to rheumatoid arthritis and Crohn's disease. SLC22A4 codes for an integral membrane protein, OCTN1, that has been presumed to carry organic cations like tetraethylammonium across the plasma membrane. Here, we show that the key substrate of this transporter is in fact ergothioneine (ET). Human OCTN1 was expressed in 293 cells. A substrate lead, stachydrine (alias proline betaine), was identified by liquid chromatography MS difference shading, a new substrate search strategy. Analysis of transport efficiency of stachydrine-related solutes, affinity, and Na+ dependence indicates that the physiological substrate is ET. Efficiency of transport of ET was as high as 195 microl per min per mg of protein. By contrast, the carnitine transporter OCTN2 from rat did not transport ET at all. Because ET is transported >100 times more efficiently than tetraethylammonium and carnitine, we propose the functional name ETT (ET transporter) instead of OCTN1. ET, all of which is absorbed from food, is an intracellular antioxidant with metal ion affinity. Its particular purpose is unresolved. Cells with expression of ETT accumulate ET to high levels and avidly retain it. By contrast, cells lacking ETT do not accumulate ET, because their plasma membrane is virtually impermeable for this compound. The real-time PCR expression profile of human ETT, with strong expression in CD71+ cells, is consistent with a pivotal function of ET in erythrocytes. Moreover, prominent expression of ETT in monocytes and SLC22A4 polymorphism associations suggest a protective role of ET in chronic inflammatory disorders. << Less

  Proc. Natl. Acad. Sci. U.S.A. 102:5256-5261(2005) [PubMed] [EuropePMC]