Review
The SLC22 family with transporters of organic cations, anions and zwitterions

https://doi.org/10.1016/j.mam.2012.10.010Get rights and content

Abstract

The SLC22 family contains 13 functionally characterized human plasma membrane proteins each with 12 predicted α-helical transmembrane domains. The family comprises organic cation transporters (OCTs), organic zwitterion/cation transporters (OCTNs), and organic anion transporters (OATs). The transporters operate as (1) uniporters which mediate facilitated diffusion (OCTs, OCTNs), (2) anion exchangers (OATs), and (3) Na+/zwitterion cotransporters (OCTNs). They participate in small intestinal absorption and hepatic and renal excretion of drugs, xenobiotics and endogenous compounds and perform homeostatic functions in brain and heart. Important endogeneous substrates include monoamine neurotransmitters, l-carnitine, α-ketoglutarate, cAMP, cGMP, prostaglandins, and urate. It has been shown that mutations of the SLC22 genes encoding these transporters cause specific diseases like primary systemic carnitine deficiency and idiopathic renal hypouricemia and are correlated with diseases such as Crohn’s disease and gout. Drug–drug interactions at individual transporters may change pharmacokinetics and toxicities of drugs.

Introduction

This review presents a comprehensive overview of the properties, distribution, physiological functions and biomedical implications of human transporters of the SLC22 family (Table 1, Table 2 and Fig. 1). The SLC22 family belongs to the major facilitator superfamily (MFS) which is assigned 2.A.1 in the “transporter classification system” of Milton Saier (see http://www.tcdb.org/). For details such as characterization of compounds that inhibit the human transporters but have not been identified to be transported, Michaelis Menten (Km) values of substrates, listing of polymorphisms, properties of transporters from animals, differences between species, gender dependence in animals, and detailed descriptions of the physiological functions of SLC22 transporters in liver and brain, earlier reviews are recommended (Burckhardt and Burckhardt, 2003, Ciarimboli and Schlatter, 2005, Funk, 2008, Hosoya and Tachikawa, 2011, Kido et al., 2011, Koepsell et al., 2003, Koepsell et al., 2007, Masereeuw and Russel, 2010, Minuesa et al., 2011, Nies et al., 2010, Rizwan and Burckhardt, 2007, Srimaroeng et al., 2008, Terada and Inui, 2008, Vanwert et al., 2010). Citation is restricted to identification of first transporter subtypes, a few important earlier findings and earlier findings that have not been acknowledged in earlier reviews, and recent findings.

The members of the SLC22 transporter family all have a similar predicted membrane topology consisting of 12 α-helical trans-membrane domains (TMDs), a large extracellular loop between TMDs 1/2 and a large intracellular loop between TMDs 6/7 (see e.g.Fig. 2 upper panel). The large extracellular loop is glycosylated and mediates homo-oligomerization (Brast et al., 2011, Keller et al., 2011) whereas the large intracellular loop is involved in posttranscriptional regulation (Koepsell et al., 2007). Most transporters of the SLC22 family are polyspecific, i.e., they transport multiple structurally different substrates (Table 2) and numerous additional compounds can act as high and/or low affinity inhibitors (Koepsell et al., 2007, Minuesa et al., 2009, Nies et al., 2010). The family contains three subgroups with transporters of closely related primary structures. The transporters within each subgroup often exhibit similarity concerning transport mechanism and substrate selectivity. Individual compounds may be transported and/or inhibit transporters from different subgroups (Ahn et al., 2009, Tachampa et al., 2008). One subgroup comprises the OCT subtypes 1-3, encoded by SLC22A1-3, which translocate organic cations, weak bases and some neutral compounds (Koepsell et al., 2003, Koepsell et al., 2007, Nies et al., 2010). OCT1-3 are facilitative diffusion systems that translocate organic cations in both directions across the plasma membrane. The driving force is supplied by the electrochemical gradient of the transported compounds (Koepsell, 2011). A second subgroup comprises the transporters OCTN1, OCTN2 and OCT6, encoded by the genes SLC22A4, SLC22A5 and SLC22A16, respectively (Koepsell et al., 2007). Human OCTN1 mediates uniport of organic cations including the antoxidant ergothioneine as well as H+/organic cation antiport whereas human OCTN2 and human OCT6 mediate transport of organic cation uniport as well as Na+/carnitine cotransport (Koepsell et al., 2007). A third subgroup comprises the organic anion transporters OAT1-7 and 10 (encoded by SLC22A6, 7, 8, 11, 10, 16, 9 and 13 respectively) and URAT1 (encoded by SLC22A12) (Bahn et al., 2008, Rizwan and Burckhardt, 2007, Vanwert et al., 2010). These transporters are able to translocate anions in either direction; some of them (OAT1, OAT3, OAT4, and URAT1) mediate exchange with divalent organic anions.

Since the identification and characterization of the first transporter of the SLC22 family in 1994 (Gründemann et al., 1994) the other family members were cloned from various species including man, and many of them were characterized functionally. In recent years attempts were made to elucidate the transport mechanisms of selected transporters (Keller et al., 2011, Koepsell, 2011, Rizwan et al., 2007). In addition investigations on the regulation of transporter expression and function were performed (Barros et al., 2009, Ciarimboli and Schlatter, 2005, Grabner et al., 2011, Pochini et al., 2011, Vanwert et al., 2010, Zhang et al., 2008a), and physiological properties of transporters in various organs were investigated (Bacq et al., 2011, Hosoya et al., 2009, Jong et al., 2011, Kaler et al., 2006, Koepsell et al., 2007, Lin et al., 2010). A main focus was put on investigation of the biomedical implications of the transporters. This includes (1) identification of new transported or inhibitory drugs and identification of drug–drug interactions at specific transporters, (2) attempts to identify critical transporters for pharmacokinetics of specific drugs, (3) elucidation of interindividual differences in transporter expression and function including sex differences and effects of polymorphisms, (4) effects of diseases on transporter expression, and (5) identification of diseases and drug treatments in which theses transporters play pivotal roles.

Section snippets

SLC22A1 (OCT1)

In 1994 Slc22a1 was cloned from rat (Gründemann et al., 1994). Later SLC22A1 was cloned from man and many other species (Koepsell et al., 2007). OCT1, the product of SLC22A1, is mainly expressed in liver where it is located in the sinusoidal membrane of the hepatocytes (Nies et al., 2009) (Fig. 1). In rat, mouse, and rabbit, strong expression of OCT1 was also observed in kidney whereas only small amounts of SLC22A1 mRNA were detected in human kidney (Koepsell et al., 2007). Using

SLC22A2 (OCT2)

In 1996 cloning of Slc22a2 encoding OCT2 from rat was reported (Okuda et al., 1996). Later OCT2 was cloned from many other species including human (Koepsell et al., 2003). Human OCT2 is mainly expressed in the kidney where it was localized to the basolateral membrane of renal proximal tubules (Motohashi et al., 2002). Additional expression of human OCT2 was observed in small intestine, lung, placenta, thymus, brain and the inner ear (Ciarimboli et al., 2010, Koepsell et al., 2003). In human

SLC22A3 (OCT3)

The Slc22a3/SLC22A3 gene encoding OCT3 in rat and human were cloned in the same year (Gründemann et al., 1998, Kekuda et al., 1998). The tissue expression of SLC22A3 is broad (Koepsell et al., 2007, Nies et al., 2010), and it is expressed in heart, skeletal muscle, brain, small intestine, liver, lung, kidneys, urinary bladder, mammary gland, cornea (Zhang et al., 2008b), skin, blood vessels, and tumor cells. In human brain OCT3 has been detected in neurons, glial cells and epithelial cells of

SLC22A4 (OCTN1)

In 1997 SLC22A4 was cloned (Tamai et al., 1997). The encoded OCTN1 transporter is expressed in kidney, ileum, colon (Meier et al., 2007), spleen, heart, skeletal muscle, brain, mammary gland (Gilchrist and Alcorn, 2010, Lamhonwah et al., 2011), lung (Horvath et al., 2007), thymus, prostate, airways, testis, bone marrow, skin (Markova et al., 2009), cornea, blood–retina barrier, iris–ciliary body (Garrett et al., 2008, Zhang et al., 2008b), fetal liver, inflammatory joints (Tokuhiro et al., 2003

SLC22A5 (OCTN2)

The Slc22a5/SLC22A5 genes encoding this transporter were also cloned in parallel from rat and man (Sekine et al., 1998b, Tamai et al., 1998, Wu et al., 1998). Expression of human OCTN2 was observed in liver, kidney, ileum, colon (Meier et al., 2007), skeletal muscle, lung (Horvath et al., 2007), mammary gland (Gilchrist and Alcorn, 2010), ovary, heart (Grube et al., 2006), placenta, central nervous system, cornea, blood-retina barrier, and iris-ciliary body (Garrett et al., 2008, Koepsell et

SLC22A16 (OCT6)

Human OCT6 is expressed mainly in testis but SLC22A16 mRNA was also detected in heart, skeletal muscle, kidney, liver, placenta, mammary gland and brain (Enomoto et al., 2002b, Eraly and Nigam, 2002, Kwok et al., 2006, Sato et al., 2007). In human testis OCT6 is located in plasma membranes of Sertoli cells and in the luminal membrane of epithelial cells in the epididymis. In addition, human OCT6 was detected in embryonic liver, in hematopoietic cells, in leukemias, endometrial cancer,

SLC22A6 (OAT1)

In 1997 the first mammalian organic anion transporter of the SLC22 family, Slc22a6 (OAT1), was cloned from rat (Sekine et al., 1997, Sweet et al., 1997). Slc22a6 orthologs from different species including man and three splice variants of human OAT1 were identified (Rizwan and Burckhardt, 2007, Vanwert et al., 2010). Human OAT1 is strongly expressed in kidney, with additional expression in brain, choroid plexus, spinal cord and iris–ciliary body (Alebouyeh et al., 2003, Bleasby et al., 2006,

SLC22A7 (OAT2)

In 1998 the previously cloned but not functional characterized gene product NLT from rat (Simonson et al., 1994) was identified as polyspecific organic anion transporter, and renamed OAT2 (Sekine et al., 1998a). The human ortholog encoded by the SLC22A7 gene is expressed in liver, to a smaller extent in kidney, and in minor quantities in testis, ileum and uterus (Fork et al., 2011, Hilgendorf et al., 2007, Sun et al., 2001). OAT2 is located in the sinusoidal membrane of hepatocytes (Simonson et

SLC22A8 (OAT3)

In 1999 cloning and characterization of Slc22a8 from rat was reported (Kusuhara et al., 1999). In the same year SLC22A8 was cloned from man (Race et al., 1999) but the functional characterizion of OAT3 from human and other species was reported later (Rizwan and Burckhardt, 2007, Srimaroeng et al., 2008, Vanwert et al., 2010). High expression of human OAT3 was observed in kidney whereas low concentrations of OAT3 mRNA were found in spinal cord, choroid plexus (Alebouyeh et al., 2003), eye (Zhang

SLC22A11 (OAT4)

First cloning and functional characterization of human OAT4 (encoded by SLC22A11) was reported in 2000 (Cha et al., 2000). This subtype has been also detected in monkey and dog but not in rodents (Bleasby et al., 2006, Rizwan and Burckhardt, 2007). The strongest expression of human OAT4 expression was observed in kidneys. Minor expression was also detected in placenta, adrenal gland (Asif et al., 2005), small intestine, colon, liver, brain, heart, lung, pituitary gland, prostate, skeletal

SLC22A10 (OAT5)

Expression of the gene product of SLC22A10 (OAT5) was detected in human liver, however, this gene product had not been cloned and characterized (Eraly and Nigam, 2002, Sun et al., 2001, Taylor et al., 2006). Transcription of the SLC22A10 promoter is transactivated by hepatocyte nuclear factor-1α (Klein et al., 2010). Phylogenetic analysis on the SLC22 family in human, mouse and rat revealed that the genomes of rodents do not contain SLC22A10 orthologs (Jacobsson et al., 2007). A further member

SLC22A20 (OAT6)

So far the gene product of SLC22A20, OAT6, has not been cloned from human, however, the mouse ortholog has been cloned and characterized (Kaler et al., 2006, Monte et al., 2004, Schnabolk et al., 2006). Mouse OAT6 is an anion/dicarboxylate exchanger which is strongly expressed in the olfactory mucosa. This subtype of the SLC22 family may play a role in olfaction. Future investigations shall determine the distribution, physiological function and potential biomedical impact of human OAT6.

SLC22A9 (OAT7)

In 2007 SLC22A9 was cloned and the OAT7 product characterized (Shin et al., 2007). Human OAT7 appears to be exclusively expressed in liver where it is located at the sinusoidal membrane of hepatocytes. It mediates uptake of estrone-3-sulfate, dehydroepiandrosterone sulfate, and butyrate and exhibits trans-stimulation of estrone-3-sulfate uptake by butyrate and vice versa (Shin et al., 2007). Compared to the other characterized human OAT subtypes, OAT7 exhibits a more specific substrate

SLC22A13 (OAT10)

The previously cloned gene product of SLC22A13 named ORCTL3 (Nishiwaki et al., 1998) was functionally characterized and renamed OAT10 (Bahn et al., 2008). In human OAT10 is strongly expressed in kidneys, pancreas and skeletal muscle. Small amounts of SLC22A13 mRNA were observed in heart, brain, placenta, prostate, testis, small intestine and colon (Bahn et al., 2008, Nishiwaki et al., 1998). Rat OAT10 was located at the brush-border membrane of renal proximal tubules. The endogenous compounds

SLC22A12 (URAT1)

In 2002 the SLC22A12 gene was cloned and characterized (Enomoto et al., 2002a). On mRNA level, the strongest expression of SLC22A12 was observed in kidneys, however, lower expression of SLC22A12 was also observed in small intestine, colon, liver, heart, skeletal muscle, prostate, adrenal gland and pituitary gland (Bleasby et al., 2006, Nishimura and Naito, 2005). In human kidney URAT1 protein was localized to the apical membrane of proximal tubule cells (Enomoto et al., 2002a). After expression

References (202)

  • G. D’Argenio et al.

    Colon OCTN2 gene expression is up-regulated by peroxisome proliferator-activated receptor gamma in humans and mice and contributes to local and systemic carnitine homeostasis

    J. Biol. Chem.

    (2010)
  • A. Dehghan et al.

    Association of three genetic loci with uric acid concentration and risk of gout: a genome-wide association study

    Lancet

    (2008)
  • K. Eder et al.

    The role of peroxisome proliferator-activated receptor a in transcriptional regulation of novel organic cation transporters

    Eur. J. Pharmacol.

    (2010)
  • A. Enomoto et al.

    Molecular identification of a novel carnitine transporter specific to human testis: Insights into the mechanism of carnitine recognition

    J. Biol. Chem.

    (2002)
  • S.A. Eraly et al.

    Organic anion and cation transporters occur in pairs of similar and similarly expressed genes

    Biochem. Biophys. Res. Commun.

    (2003)
  • S.A. Eraly et al.

    Novel human cDNAs homologous to Drosophila Orct and mammalian carnitine transporters

    Biochem. Biophys. Res. Commun.

    (2002)
  • J. Fan et al.

    Linkage disequilibrium mapping of the chromosome 6q21-22.31 bipolar I disorder susceptibility locus

    Am. J. Med. Genet. B. Neuropsychiatr. Genet.

    (2010)
  • M. Fujiya et al.

    The Bacillus subtilis quorum-sensing molecule CSF contributes to intestinal homeostasis via OCTN2, a host cell membrane transporter

    Cell Host Microbe

    (2007)
  • S. Gong et al.

    Identification of OCT6 as a novel organic cation transporter preferentially expressed in hematopoietic cells and leukemias

    Exp. Hematol.

    (2002)
  • K. Höcherl et al.

    COX-2 inhibition attenuates endotoxin-induced downregulation of organic anion transporters in the rat renal cortex

    Kidney Int.

    (2009)
  • D. Iwata et al.

    Involvement of carnitine/organic cation transporter OCTN2 (SLC22A5) in distribution of its substrate carnitine to the heart

    Drug Metab. Pharmacokinet.

    (2008)
  • J.A. Jacobsson et al.

    Identification of six putative human transporters with structural similarity to the drug transporter SLC22 family

    Genomics

    (2007)
  • E. Januszewicz et al.

    Organic cation/carnitine transporter OCTN3 is present in astrocytes and is up-regulated by peroxisome proliferators-activator receptor agonist

    Int. J. Biochem. Cell Biol.

    (2009)
  • G. Kaler et al.

    Olfactory mucosa-expressed organic anion transporter, Oat6, manifests high affinity interactions with odorant organic anions

    Biochem. Biophys. Res. Commun.

    (2006)
  • R. Kekuda et al.

    Cloning and functional characterization of a potential-sensitive, polyspecific organic cation transporter (OCT3) most abundantly expressed in placenta

    J. Biol. Chem.

    (1998)
  • T. Keller et al.

    The large extracellular loop of organic cation transporter 1 influences substrate affinity and is pivotal for oligomerization

    J. Biol. Chem.

    (2011)
  • H. Kusuhara et al.

    Molecular cloning and characterization of a new multispecific organic anion transporter from rat brain

    J. Biol. Chem.

    (1999)
  • A.-M. Lamhonwah et al.

    Upregulation of mammary gland OCTNs maintains carnitine homeostasis in suckling infants

    Biochem. Biophys. Res. Commun.

    (2011)
  • J.D. Lewis et al.

    Rosiglitazone for active ulcerative colitis: a randomized placebo-controlled trial

    Gastroenterology

    (2008)
  • B. Ling et al.

    Acute administration of cefepime lowers l-carnitine concentrations in early lactation stage rat milk

    J. Nutr.

    (2008)
  • N.G. Markova et al.

    Skin cells and tissue are capable of using l-ergothioneine as an integral component of their antioxidant defense system

    Free Radical Biol. Med.

    (2009)
  • R. Masereeuw et al.

    Therapeutic implications of renal anionic drug transporters

    Pharmacol. Ther.

    (2010)
  • G. Ahlin et al.

    Genotype-dependent effects of inhibitors of the organic cation transporter, OCT1: predictions of metformin interactions

    Pharmacogenomics

    (2010)
  • M. Aoki et al.

    Kidney-specific expression of human organic cation transporter 2 (OCT2/SLC22A2) is regulated by DNA methylation

    Am. J. Physiol. Renal Physiol.

    (2008)
  • A.C. Aperia

    Intrarenal dopamine: a key signal in the interactive regulation of sodium metabolism

    Annu. Rev. Physiol.

    (2000)
  • A.R. Asif et al.

    Presence of organic anion transporters 3 (OAT3) and 4 (OAT4) in human adrenocortical cells

    Pflugers Arch. – Eur. J. Physiol.

    (2005)
  • A. Bacq et al.

    Organic cation transporter 2 controls brain norepinephrine and serotonin clearance and antidepressant response

    Mol. Psychiatry

    (2011)
  • N.L. Baganz et al.

    Organic cation transporter 3: Keeping the brake on extracellular serotonin in serotonin-transporter-deficient mice

    Proc. Natl. Acad. Sci. U.S.A.

    (2008)
  • K. Bleasby et al.

    Expression profiles of 50 xenobiotic transporter genes in humans and pre-clinical species: a resource for investigations into drug disposition

    Xenobiotica

    (2006)
  • S. Brast et al.

    The cysteines of the extracellular loop are crucial for trafficking of human organic cation transporter 2 to the plasma membrane and are involved in oligomerization

    FASEB J.

    (2011)
  • J. Bray et al.

    Influence of pharmacogenetics on response and toxicity in breast cancer patients treated with doxorubicin and cyclophosphamide

    Br. J. Cancer

    (2010)
  • B.C. Burckhardt et al.

    Transport of organic anions across the basolateral membrane of proximal tubule cells

    Rev. Physiol. Biochem. Pharmacol.

    (2003)
  • J. Chen et al.

    Adaptive responses of renal organic anion transporter 3 (OAT3) during cholestasis

    Am. J. Physiol. Renal Physiol.

    (2008)
  • L. Chen et al.

    Role of organic cation transporter 3 (SLC22A3) and its missense variants in the pharmacologic action of metformin

    Pharmacogenet. Genomics

    (2010)
  • M.-K. Choi et al.

    Inhibitory effects of ketoconazole and rifampin on OAT1 and OATP1B1 transport activities: considerations on drug–drug interactions

    Biopharm. Drug Dispos.

    (2011)
  • G. Ciarimboli et al.

    New clues for nephrotoxicity induced by ifosfamide: preferential renal uptake via the human organic cation transporter 2

    Mol. Pharm.

    (2011)
  • G. Ciarimboli et al.

    Regulation of organic cation transport

    Pflugers Arch. Eur. J. Physiol.

    (2005)
  • L.M. Cotton et al.

    Organic cation/carnitine transporter, OCTN2, transcriptional activity is regulated by osmotic stress in epididymal cells

    Mol. Reprod. Dev.

    (2010)
  • C.D. Cropp et al.

    Organic anion transporter 2 (SLC22A7) is a facilitative transporter of cGMP

    Mol. Pharmacol.

    (2008)
  • M. Cui et al.

    The organic cation transporter-3 is a pivotal modulator of neurodegeneration in the nigrostriatal dopaminergic pathway

    Proc. Natl. Acad. Sci. U.S.A.

    (2009)
  • Cited by (0)

    Publication in part sponsored by the Swiss National Science Foundation through the National Center of Competence in Research (NCCR) TransCure, University of Bern, Switzerland; Director Matthias A. Hediger; Web: http://www.transcure.ch.

    View full text