Abstract
The SLC22 family comprises organic cation transporters (OCTs), zwitterion/cation transporters (OCTNs), and organic anion transporters (OATs). These transporters contain 12 predicted α-helical transmembrane domains (TMDs) and one large extracellular loop between TMDs 1 and 2. Transporters of the SLC22 family function in different ways: (1) as uniporters that mediate facilitated diffusion in either direction (OCTs), (2) as anion exchangers (OAT1, OAT3 and URAT1), and (3) as Na+/l-carnitine cotransporter (OCTN2). They participate in the absorption and/or excretion of drugs, xenobiotics, and endogenous compounds in intestine, liver and/or kidney, and perform homeostatic functions in brain and heart. The endogenous substrates include monoamine neurotransmitters, choline, l-carnitine, α-ketoglutarate, cAMP, cGMP, prostaglandins, and urate. Defect mutations of transporters of the SLC22 family may cause specific diseases such as "primary systemic carnitine deficiency" or "idiopathic renal hypouricemia" or change drug absorption or excretion.
Similar content being viewed by others
References
Babu E, Takeda M, Narikawa S, Kobayashi Y, Enomoto A, Tojo A, Cha SH, Sekine T, Sakthisekaran D, Endou H (2002) Role of human organic anion transporter 4 in the transport of ochratoxin A. Biochim Biophys Acta 1590:64–75
Brady KP, Dushkin H, Förnzler D, Koike T, Magner F, Her H, Gullans S, Segre GV, Green RM, Beier DR (1999) A novel putative transporter maps to the osteosclerosis (oc) mutation and is not expressed in the oc mutant mouse. Genomics 56:254–261
Budiman T, Bamberg E, Koepsell H, Nagel G (2000) Mechanism of electrogenic cation transport by the cloned organic cation transporter 2 from rat. J Biol Chem 275:29413–29420
Burckhardt BC, Burckhardt G (2003) Transport of organic anions across the basolateral membrane of proximal tubule cells. Rev Physiol Biochem Pharmacol 146:95–158
Busch AE, Karbach U, Miska D, Gorboulev V, Akhoundova A, Volk C, Arndt P, Ulzheimer JC, Sonders MS, Baumann C, Waldegger S, Lang F, Koepsell H (1998) Human neurons express the polyspecific cation transporter hOCT2, which translocates monoamine neurotransmitters, amantadine, and memantine. Mol Pharmacol 54:342–352
Çetinkaya I, Ciarimboli G, Yalçinkaya G, Mehrens T, Velic A, Hirsch JR., Gorboulev V, Koepsell H, Schlatter E (2003) Regulation of human organic cation transporter hOCT2 by PKA, P13K, and calmodulin-dependent kinases. Am J Physiol Renal Physiol 284:F293–F302
Cha SH, Sekine T, Fukushima JI, Kanai Y, Kobayashi Y, Goya T, Endou H (2001) Identification and characterization of human organic anion transporter 3 expressing predominantly in the kidney. Mol Pharmacol 59:1277–1286
Cha SH, Sekine T, Kusuhara H, Yu E, Kim JY, Kim DK, Sugiyama Y, Kanai Y, Endou H (2000) Molecular cloning and characterization of multispecific organic anion transporter 4 expressed in the placenta. J Biol Chem 275:4507–4512
Chen JJ, Li Z, Pan H, Murphy DL, Tamir H, Koepsell H, Gershon MD (2001) Maintenance of serotonin in the intestinal mucosa and ganglia of mice that lack the high-affinity serotonin transporter: abnormal intestinal motility and the expression of cation transporters. J Neurosci 21:6348–6361
Enomoto A, Kimura H, Chairoungdua A, Shigeta Y, Jutabha P, Cha SH, Hosoyamada M, Takeda M, Sekine T, Igarashi T, Matsuo H, Kikuchi Y, Oda T, Ichida K, Hosoya T, Shimokata K, Niwa T, Kanai Y, Endou H (2002) Molecular identification of a renal-urate anion exchanger that regulates blood urate levels. Nature 417:447–452
Enomoto A, Takeda M, Shimoda M, Narikawa S, Kobayashi Y, Kobayashi Y, Yamamoto T, Sekine T, Cha SH, Niwa T, Endou H (2002) Interaction of human organic anion transporters 2 and 4 with organic anion transport inhibitors. J Pharmacol Exp Ther 301:797–802
Enomoto A, Wempe MF, Tsuchida H, Shin HJ, Cha SH, Anzai N, Goto A, Sakamoto A, Niwa T, Kanai Y, Anders MW, Endou H (2002) Molecular identification of a novel carnitine transporter specific to human testis: Insights into the mechanism of carnitine recognition. J Biol Chem 277:36262–36271
Eraly SA, Hamilton BA, Nigam SK (2003) Organic anion and cation transporters occur in pairs of similar and similarly expressed genes. Biochem Biophys Res Commun 300:333–342
Gong S, Lu X, Xu Y, Swiderski CF, Jordan CT, Moscow JA (2002) Identification of OCT6 as a novel organic cation transporter preferentially expressed in hematopoietic cells and leukemias. Exp Hematol 30:1162–1169
Gorboulev V, Ulzheimer JC, Akhoundova A, Ulzheimer-Teuber I, Karbach U, Quester S, Baumann C, Lang F, Busch AE, Koepsell H (1997) Cloning and characterization of two human polyspecific organic cation transporters. DNA Cell Biol 16:871–881
Gorboulev V, Volk C, Arndt P, Akhoundova A, Koepsell H (1999) Selectivity of the polyspecific cation transporter rOCT1 is changed by mutation of aspartate 475 to glutamate. Mol Pharmacol 56:1254–1261
Gründemann D, Gorboulev V, Gambaryan S, Veyhl M, Koepsell H (1994) Drug excretion mediated by a new prototype of polyspecific transporter. Nature 372:549–552
Gründemann D, Schechinger B, Rappold GA, Schömig E (1998) Molecular identification of the corticosterone-sensitive extraneuronal catecholamine transporter. Nat Neurosci 1:349–352
Hosoyamada M, Sekine T, Kanai Y, Endou H (1999) Molecular cloning and functional expression of a multispecific organic anion transporter from human kidney. Am J Physiol Renal Physiol 276:F122–F128
Jonker JW, Wagenaar E, Mol CAAM, Buitelaar M, Koepsell H, Smit JW, Schinkel AH (2001) Reduced hepatic uptake and intestinal excretion of organic cations in mice with a targeted disruption of the organic cation transporter 1 (oct1[Slc22a1]) gene. Mol Cell Biol 21:5471–5477
Karbach U, Kricke J, Meyer-Wentrup F, Gorboulev V, Volk C, Loffing-Cueni D, Kaissling B, Bachmann S, Koepsell H (2000) Localization of organic cation transporters OCT1 and OCT2 in rat kidney. Am J Physiol Renal Physiol 279:F679–F687
Kekuda R, Prasad PD, Wu X, Wang H, Fei Y-J, Leibach FH, Ganapathy V (1998) Cloning and functional characterization of a potential-sensitive, polyspecific organic cation transporter (OCT3) most abundantly expressed in placenta. J Biol Chem 273:15971–15979
Kerb R, Brinkmann U, Chatskaia N, Gorbunov D, Gorboulev V, Mornhinweg E, Keil A, Eichelbaum M, Koepsell H (2002) Identification of genetic variations of the human organic cation transporter hOCT1 and their functional consequences. Pharmacogenetics 12:591–595
Kimura H, Takeda M, Narikawa S, Enomoto A, Ichida K, Endou H (2002) Human organic anion transporters and human organic cation transporters mediate renal transport of prostaglandins. J Pharmacol Exp Ther 301:293–298
Koepsell H (1998) Organic cation transporters in intestine, kidney, liver, and brain. Annu Rev Physiol 60:243–266
Koepsell H, Schmitt BM, Gorboulev V (2003) Organic Cation Transporters. Rev Physiol Biochem Pharmacol DOI 10.1007/s10254-003-0017-x
Kojima R, Sekine T, Kawachi M, Cha SH, Suzuki Y, Endou H (2002) Immunolocalization of multispecific organic anion transporters, OAT1, OAT2, and OAT3, in rat kidney. J Am Soc Nephrol 13:848–857
Kristufek D, Rudorfer W, Pifl C, Huck S (2002) Organic cation transporter mRNA and function in the rat superior cervical ganglion. J Physiol (Lond) 543:117–134
Kusuhara H, Sekine T, Utsunomiya-Tate N, Tsuda M, Kojima R, Cha SH, Sugiyama Y, Kanai Y, Endou H (1999) Molecular cloning and characterization of a new multispecific organic anion transporter from rat brain. J Biol Chem 274:13675–13680
Leabman MK, Huang CC, Kawamoto M, Johns SJ, Stryke D, Ferrin TE, DeYoung J, Taylor T, Clark AG, Herskowitz I, Giacomini KM (2002) Polymorphisms in a human kidney xenobiotic transporter, OCT2, exhibit altered function. Pharmacogenetics 12:395–405
Mehrens T, Lelleck S, Çetinkaya I, Knollmann M, Hohage H, Gorboulev V, Boknik P, Koepsell H, Schlatter E (2000) The affinity of the organic cation transporter rOCT1 is increased by protein kinase C-dependent phosphorylation. J Am Soc Nephrol 11:1216–1224
Motohashi H, Sakurai Y, Saito H, Masuda S, Urakami Y, Goto M, Fukatsu A, Ogawa O, Inui K-I (2002) Gene expression levels and immunolocalization of organic ion transporters in the human kidney. J Am Soc Nephrol 13:866–874
Nezu J-I, Tamai I, Oku A, Ohashi R, Yabuuchi H, Hashimoto N, Nikaido H, Sai Y, Koizumi A, Shoji Y, Takada G, Matsuishi T, Yoshino M, Kato H, Ohura T, Tsujimoto G, Hayakawa J-I, Shimane M, Tsuji A (1999) Primary systemic carnitine deficiency is caused by mutations in a gene encoding sodium ion-dependent carnitine transporter. Nat Genet 21:91–94
Ohashi R, Tamai I, Inano A, Katsura M, Sai Y, Nezu J-I, Tsuji A (2002) Studies on functional sites of organic cation/carnitine transporter OCTN2 (SLC22A5) using a Ser467Cys mutant protein. J Pharmacol Exp Ther 302:1286–1294
Ohashi R, Tamai I, Nezu J-I, Nikaido H, Hashimoto N, Oku A, Sai Y, Shimane M, Tsuji A (2001) Molecular and physiological evidence for multifunctionality of carnitine/organic cation transporter OCTN2. Mol Pharmacol 59:358–366
Ohashi R, Tamai I, Yabuuchi H, Nezu J-I, Oku A, Sai Y, Shimane M, Tsuji A (1999) Na+-dependent carnitine transport by organic cation transporter (OCTN2): its pharmacological and toxicological relevance. J Pharmacol Exp Ther 291:778–784
Ohsiro N, Kobayashi Y, Tokuyama S, Sekine T, Endou H, Yamamoto T (2000) Molecular mechanism of drug transport. Jpn J Pharmacol 82:155P
Okuda M, Saito H, Urakami Y, Takano M, Inui K-I (1996) cDNA cloning and functional expression of a novel rat kidney organic cation transporter, OCT2. Biochem Biophys Res Commun 224:500–507
Reid G, Wolff NA, Dautzenberg FM, Burckhardt G (1998) Cloning of a human renal p-aminohippurate transporter, hROAT1. Kidney Blood Press Res 21:233–237
Schlatter E, Mönnich V, Çetinkaya I, Mehrens T, Ciarimboli G, Hirsch JR, Popp C, Koepsell H (2002) The organic cation transporters rOCT1 and hOCT2 are inhibited by cGMP. J Membr Biol 189:237–244
Schmitt A, Mössner R, Gossmann A, Fischer IG, Gorboulev V, Murphy DL, Koepsell H, Lesch KP (2003) Organic cation transporter capable of transporting serotonin is up-regulated in serotonin transporter-deficient mice. J Neurosci Res 71:701–709
Sekine T, Cha SH, Endou H (2000) The multispecific organic anion transporter (OAT) family. Pflugers Arch 440:337–350
Sekine T, Cha SH, Tsuda M, Apiwattanakul N, Nakajima N, Kanai Y, Endou H (1998) Identification of multispecific organic anion transporter 2 expressed predominantly in the liver. FEBS Lett 429:179–182
Sekine T, Kusuhara H, Utsunomiya-Tate N, Tsuda M, Sugiyama Y, Kanai Y, Endou H (1998) Molecular cloning and characterization of high-affinity carnitine transporter from rat intestine. Biochem Biophys Res Commun 251:586–591
Sekine T, Watanabe N, Hosoyamada M, Kanai Y, Endou H (1997) Expression cloning and characterization of a novel multispecific organic anion transporter. J Biol Chem 272:18526–18529
Seth P, Wu X, Huang W, Leibach FH, Ganapathy V (1999) Mutations in novel organic cation transporter (OCTN2), an organic cation/carnitine transporter, with differential effects on the organic cation transport function and the carnitine transport function. J Biol Chem 274:33388–33392
Simonson GD, Vincent AC, Roberg KJ, Huang Y, Iwanij V (1994) Molecular cloning and characterization of a novel liver-specific transport protein. J Cell Sci 107:1065–1072
Slitt AL, Cherringtion NJ, Hartley DP, Leazer TM, Klaassen CD (2002) Tissue distribution and renal developmental changes in rat organic cation transporter mRNA levels. Drug Metab Dispos 30:212–219
Sun W, Wu RR, van Poelje PD, Erion MD (2001) Isolation of a family of organic anion transporters from human liver and kidney. Biochem Biophys Res Commun 283:417–422
Sweet DH, Chan LMS, Walden R, Yang X-P, Miller DS, Pritchard JB (2003) Organic anion transporter 3 (Slc22a8) is a dicarboxylate exchanger indirectly coupled to the Na+ gradient. Am J Physiol Renal Physiol 284:F763–F769
Sweet DH, Miller DS, Pritchard JB, Fujiwara Y, Beier DR, Nigam SK (2002) Impaired organic anion transport in kidney and choroid plexus of organic anion transporter 3 (Oat3 (Slc22a8)) knockout mice. J Biol Chem 277:26934–26943
Sweet DH, Wolff NA, Pritchard JB (1997) Expression cloning and characterization of ROAT1, the basolateral organic anion transporter in rat kidney. J Biol Chem 272:30088–30095
Tamai I, China K, Sai Y, Kobayashi D, Nezu J-I, Kawahara E, Tsuji A (2001) Na+-coupled transport of l-carnitine via high-affinity carnitine transporter OCTN2 and its subcellular localization in kidney. Biochim Biophys Acta 1512:273–284
Tamai I, Ohashi R, Nezu J-I, Yabuuchi H, Oku A, Shimane M, Sai Y, Tsuji A (1998) Molecular and functional identification of sodium ion-dependent, high affinity human carnitine transporter OCTN2. J Biol Chem 273:20378–20382
Tamai I, Ohashi R, Nezu J-I, Sai Y, Kobayashi D, Oku A, Shimane M, Tsuji A (2000) Molecular and functional characterization of organic cation/carnitine transporter family in mice. J Biol Chem 275:40064–40072
Tamai I, Yabuuchi H, Nezu J-I, Sai Y, Oku A, Shimane M, Tsuji A (1997) Cloning and characterization of a novel human pH-dependent organic cation transporter, OCTN1. FEBS Lett 419:107–111
Wagner CA, Lükewille U, Kaltenbach S, Moschen I, Bröer A, Risler T, Bröer S, Lang F (2000) Functional and pharmacological characterization of the human Na+-carnitine cotransporter hOCTN2. Am J Physiol Renal Physiol 279:F584–F591
Wessler I, Roth E, Deutsch C, Brockerhoff P, Bittinger F, Kirkpatrick CJ, Kilbinger H (2001) Release of non-neuronal acetylcholine from the isolated human placenta is mediated by organic cation transporters. Br J Pharmacol 134:951–956
Wolff NA, Grünwald B, Friedrich B, Lang F, Godehardt S, Burckhardt G (2001) Cationic amino acids involved in dicarboxylate binding of the flounder renal organic anion transporter. J Am Soc Nephrol 12:2012–2018
Wolff NA, Werner A, Burkhardt S, Burckhardt G (1997) Expression cloning and characterization of a renal organic anion transporter from winter flounder. FEBS Lett 417:287–291
Wu X, George RL, Huang W, Wang H, Conway SJ, Leibach FH, Ganapathy V (2000) Structural and functional characteristics and tissue distribution pattern of rat OCTN1, an organic cation transporter, cloned from placenta. Biochim Biophys Acta 1466:315–327
Wu X, Kekuda R, Huang W, Fei Y-J, Leibach FH, Chen J, Conway SJ, Ganapathy V (1998) Identity of the organic cation transporter OCT3 as the extraneuronal monoamine transporter (uptake2) and evidence for the expression of the transporter in the brain. J Biol Chem 273:32776–32786
Wu X, Prasad PD, Leibach FH, Ganapathy V (1998) cDNA sequence, transport function, and genomic organization of human OCTN2, a new member of the organic cation transporter family. Biochem Biophys Res Commun 246:589–595
Yabuuchi H, Tamai I, Nezu J-I, Sakamoto K, Oku A, Shimane M, Sai Y, Tsuji A (1999) Novel membrane transporter OCTN1 mediates multispecific, bidirectional, and pH-dependent transport of organic cations. J Pharmacol Exp Ther 289:768–773
Zhang L, Dresser MJ, Gray AT, Yost SC, Terashita S, Giacomini KM (1997) Cloning and functional expression of a human liver organic cation transporter. Mol Pharmacol 51:913–921
Zwart R, Verhaagh S, Buitelaar M, Popp-Snijders C, Barlow DP (2001) Impaired activity of the extraneuronal monoamine transporter system known as uptake-2 in Orct3/Slc22a3-deficient mice. Mol Cell Biol 21:4188–4196
Author information
Authors and Affiliations
Corresponding authors
Rights and permissions
About this article
Cite this article
Koepsell, H., Endou, H. The SLC22 drug transporter family. Pflugers Arch - Eur J Physiol 447, 666–676 (2004). https://doi.org/10.1007/s00424-003-1089-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00424-003-1089-9