title: Discovery of the ergothioneine transporter.
abstract: 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.
authors.affiliation: Department of Pharmacology, University of Cologne, Gleueler Strasse 24, 50931 Cologne, Germany. dirk.gruendemann@uni-koeln.de
authors.forename: Dirk
authors.initials: D
authors.lastname: Gründemann
authors.forename: Stephanie
authors.initials: S
authors.lastname: Harlfinger
authors.forename: Stefan
authors.initials: S
authors.lastname: Golz
authors.forename: Andreas
authors.initials: A
authors.lastname: Geerts
authors.forename: Andreas
authors.initials: A
authors.lastname: Lazar
authors.forename: Reinhard
authors.initials: R
authors.lastname: Berkels
authors.forename: Norma
authors.initials: N
authors.lastname: Jung
authors.forename: Andrea
authors.initials: A
authors.lastname: Rubbert
authors.forename: Edgar
authors.initials: E
authors.lastname: Schömig
mesh_terms: D000818:Animals; D001483:Base Sequence; D001693:Biological Transport, Active; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D018076:DNA, Complementary / Q000235:genetics; D004880:Ergothioneine / Q000378:metabolism*; D020869:Gene Expression Profiling; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D007700:Kinetics; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism*; D027701:Organic Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D011392:Proline / Q000031:analogs & derivatives* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D000074058:Solute Carrier Family 22 Member 5; D000070590:Solute Carrier Proteins; D027981:Symporters; D009626:Terminology as Topic; D014018:Tissue Distribution
chemical_list: D002352:Carrier Proteins; D018076:DNA, Complementary; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D027701:Organic Cation Transport Proteins; D012333:RNA, Messenger; D011994:Recombinant Proteins; C109807:SLC22A4 protein, human; C000705567:Slc22a4 protein, rat; C115441:Slc22a5 protein, rat; D000074058:Solute Carrier Family 22 Member 5; D000070590:Solute Carrier Proteins; D027981:Symporters; D011392:Proline; D004880:Ergothioneine; C003342:stachydrine