S22A2_RAT
ID S22A2_RAT Reviewed; 555 AA.
AC Q9R0W2; P70485; P97558;
DT 26-FEB-2008, integrated into UniProtKB/Swiss-Prot.
DT 01-MAY-2000, sequence version 1.
DT 03-AUG-2022, entry version 134.
DE RecName: Full=Solute carrier family 22 member 2;
DE AltName: Full=Organic cation transporter 2;
DE Short=rOCT2;
GN Name=Slc22a2; Synonyms=Oct2;
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, AND TISSUE SPECIFICITY.
RC STRAIN=Sprague-Dawley; TISSUE=Kidney;
RX PubMed=8702418; DOI=10.1006/bbrc.1996.1056;
RA Okuda M., Saito H., Urakami Y., Takano M., Inui K.;
RT "cDNA cloning and functional expression of a novel rat kidney organic
RT cation transporter, OCT2.";
RL Biochem. Biophys. Res. Commun. 224:500-507(1996).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Kidney cortex;
RX PubMed=9260930; DOI=10.1089/dna.1997.16.871;
RA Gorboulev V., Ulzheimer J.C., Akhoundova A., Ulzheimer-Teuber I.,
RA Karbach U., Quester S., Baumann C., Lang F., Busch A.E., Koepsell H.;
RT "Cloning and characterization of two human polyspecific organic cation
RT transporters.";
RL DNA Cell Biol. 16:871-881(1997).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Kidney;
RX PubMed=10385678; DOI=10.1124/mol.56.1.1;
RA Gruendemann D., Liebich G., Kiefer N., Koster S., Schoemig E.;
RT "Selective substrates for non-neuronal monoamine transporters.";
RL Mol. Pharmacol. 56:1-10(1999).
RN [4]
RP BIOPHYSICAL PROPERTIES.
RX PubMed=9812985; DOI=10.1074/jbc.273.47.30915;
RA Grundemann D., Koster S., Kiefer N., Breidert T., Engelhardt M.,
RA Spitzenberger F., Obermuller N., Schomig E.;
RT "Transport of monoamine transmitters by the organic cation transporter type
RT 2, OCT2.";
RL J. Biol. Chem. 273:30915-30920(1998).
RN [5]
RP INDUCTION, AND TISSUE SPECIFICITY.
RX PubMed=10812069; DOI=10.1016/s0014-5793(00)01525-8;
RA Urakami Y., Okuda M., Saito H., Inui K.;
RT "Hormonal regulation of organic cation transporter OCT2 expression in rat
RT kidney.";
RL FEBS Lett. 473:173-176(2000).
RN [6]
RP TISSUE SPECIFICITY.
RX PubMed=11083459; DOI=10.1007/s004180000186;
RA Sugawara-Yokoo M., Urakami Y., Koyama H., Fujikura K., Masuda S., Saito H.,
RA Naruse T., Inui K., Takata K.;
RT "Differential localization of organic cation transporters rOCT1 and rOCT2
RT in the basolateral membrane of rat kidney proximal tubules.";
RL Histochem. Cell Biol. 114:175-180(2000).
RN [7]
RP FUNCTION.
RX PubMed=16242669; DOI=10.1016/j.bcp.2005.09.020;
RA Yonezawa A., Masuda S., Nishihara K., Yano I., Katsura T., Inui K.;
RT "Association between tubular toxicity of cisplatin and expression of
RT organic cation transporter rOCT2 (Slc22a2) in the rat.";
RL Biochem. Pharmacol. 70:1823-1831(2005).
RN [8]
RP FUNCTION, TISSUE SPECIFICITY, AND BIOPHYSICOCHEMICAL PROPERTIES.
RX PubMed=16272756; DOI=10.2133/dmpk.20.379;
RA Kimura N., Masuda S., Tanihara Y., Ueo H., Okuda M., Katsura T., Inui K.;
RT "Metformin is a superior substrate for renal organic cation transporter
RT OCT2 rather than hepatic OCT1.";
RL Drug Metab. Pharmacokinet. 20:379-386(2005).
RN [9]
RP FUNCTION, AND BIOPHYSICOCHEMICAL PROPERTIES.
RX PubMed=16006492; DOI=10.1124/jpet.105.088104;
RA Tahara H., Kusuhara H., Endou H., Koepsell H., Imaoka T., Fuse E.,
RA Sugiyama Y.;
RT "A species difference in the transport activities of H2 receptor
RT antagonists by rat and human renal organic anion and cation transporters.";
RL J. Pharmacol. Exp. Ther. 315:337-345(2005).
RN [10]
RP MUTAGENESIS OF CYS-451.
RX PubMed=17567940; DOI=10.1152/ajprenal.00106.2007;
RA Sturm A., Gorboulev V., Gorbunov D., Keller T., Volk C., Schmitt B.M.,
RA Schlachtbauer P., Ciarimboli G., Koepsell H.;
RT "Identification of cysteines in rat organic cation transporters rOCT1
RT (C322, C451) and rOCT2 (C451) critical for transport activity and substrate
RT affinity.";
RL Am. J. Physiol. 293:F767-F779(2007).
RN [11]
RP FUNCTION.
RX PubMed=17582384; DOI=10.1016/j.bcp.2007.03.004;
RA Yokoo S., Yonezawa A., Masuda S., Fukatsu A., Katsura T., Inui K.;
RT "Differential contribution of organic cation transporters, OCT2 and MATE1,
RT in platinum agent-induced nephrotoxicity.";
RL Biochem. Pharmacol. 74:477-487(2007).
RN [12]
RP FUNCTION, AND INDUCTION BY ISCHEMIA.
RX PubMed=18180268; DOI=10.1124/dmd.107.019869;
RA Matsuzaki T., Morisaki T., Sugimoto W., Yokoo K., Sato D., Nonoguchi H.,
RA Tomita K., Terada T., Inui K., Hamada A., Saito H.;
RT "Altered pharmacokinetics of cationic drugs caused by down-regulation of
RT renal rat organic cation transporter 2 (slc22a2) and rat multidrug and
RT toxin extrusion 1 (slc47a1) in ischemia/reperfusion-induced acute kidney
RT injury.";
RL Drug Metab. Dispos. 36:649-654(2008).
CC -!- FUNCTION: Mediates tubular uptake of organic compounds from
CC circulation. Mediates the influx of agmatine, serotonin, choline,
CC ranitidine, histamine, creatinine, amantadine, memantine, acriflavine,
CC 4-[4-(dimethylamino)-styryl]-N-methylpyridinium ASP and amiloride (By
CC similarity). Mediates the influx of adrenaline, noradrenaline
CC (norepinephrine), dopamine, cimetidine, famotidine, metformin, N-1-
CC methylnicotinamide (NMN), 1-methyl-4-phenylpyridinium (MPP),
CC tetraethylammonium (TEA), oxaliplatin and cisplatin. Cisplatin may
CC develop a nephrotoxic action. Transport of creatinine is inhibited by
CC fluoroquinolones such as DX-619 and LVFX. This transporter is a major
CC determinant of the anticancer activity of oxaliplatin and may
CC contribute to antitumor specificity. {ECO:0000250,
CC ECO:0000269|PubMed:16006492, ECO:0000269|PubMed:16242669,
CC ECO:0000269|PubMed:16272756, ECO:0000269|PubMed:17582384,
CC ECO:0000269|PubMed:18180268, ECO:0000269|PubMed:8702418}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=68.8 uM for cimetidine (at pH 7.4 and 37 degrees Celsius)
CC {ECO:0000269|PubMed:16006492, ECO:0000269|PubMed:16272756};
CC KM=60.6 uM for famotidine {ECO:0000269|PubMed:16006492,
CC ECO:0000269|PubMed:16272756};
CC KM=0.63 mM for metformin {ECO:0000269|PubMed:16006492,
CC ECO:0000269|PubMed:16272756};
CC KM=4.4 mM for noradrenaline {ECO:0000269|PubMed:16006492,
CC ECO:0000269|PubMed:16272756};
CC KM=1.3 mM for histamine {ECO:0000269|PubMed:16006492,
CC ECO:0000269|PubMed:16272756};
CC KM=1.9 mM for dopamine {ECO:0000269|PubMed:16006492,
CC ECO:0000269|PubMed:16272756};
CC KM=3.6 mM for serotonin {ECO:0000269|PubMed:16006492,
CC ECO:0000269|PubMed:16272756};
CC Vmax=1490 pmol/min/mg enzyme for cimetidine uptake
CC {ECO:0000269|PubMed:16006492, ECO:0000269|PubMed:16272756};
CC Vmax=117 pmol/min/mg enzyme for famotidine uptake
CC {ECO:0000269|PubMed:16006492, ECO:0000269|PubMed:16272756};
CC Vmax=1.446 nmol/min/mg enzyme for metformin uptake
CC {ECO:0000269|PubMed:16006492, ECO:0000269|PubMed:16272756};
CC -!- SUBCELLULAR LOCATION: Membrane {ECO:0000305}; Multi-pass membrane
CC protein {ECO:0000305}.
CC -!- TISSUE SPECIFICITY: Expressed in the kidney; in the proximal tubule of
CC the outer medulla. Expression is greater in the kidney of male than of
CC female. {ECO:0000269|PubMed:10812069, ECO:0000269|PubMed:11083459,
CC ECO:0000269|PubMed:16272756, ECO:0000269|PubMed:8702418}.
CC -!- INDUCTION: Down-regulated in ischemia/reperfusion (I/R) kidneys. Up-
CC regulated by testosterone and moderately down-regulated by estradiol.
CC {ECO:0000269|PubMed:10812069, ECO:0000269|PubMed:18180268}.
CC -!- SIMILARITY: Belongs to the major facilitator (TC 2.A.1) superfamily.
CC Organic cation transporter (TC 2.A.1.19) family. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=BAA11754.1; Type=Frameshift; Evidence={ECO:0000305};
CC Sequence=CAA66979.1; Type=Frameshift; Evidence={ECO:0000305};
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DR EMBL; D83044; BAA11754.1; ALT_FRAME; mRNA.
DR EMBL; X98334; CAA66979.1; ALT_FRAME; mRNA.
DR EMBL; Y13154; CAB52215.1; -; mRNA.
DR PIR; JC4884; JC4884.
DR RefSeq; NP_113772.1; NM_031584.2.
DR AlphaFoldDB; Q9R0W2; -.
DR SMR; Q9R0W2; -.
DR STRING; 10116.ENSRNOP00000023116; -.
DR BindingDB; Q9R0W2; -.
DR ChEMBL; CHEMBL1770032; -.
DR TCDB; 2.A.1.19.19; the major facilitator superfamily (mfs).
DR GlyGen; Q9R0W2; 1 site.
DR iPTMnet; Q9R0W2; -.
DR PhosphoSitePlus; Q9R0W2; -.
DR PaxDb; Q9R0W2; -.
DR PRIDE; Q9R0W2; -.
DR GeneID; 29503; -.
DR KEGG; rno:29503; -.
DR CTD; 6582; -.
DR RGD; 61936; Slc22a2.
DR eggNOG; KOG0255; Eukaryota.
DR InParanoid; Q9R0W2; -.
DR OrthoDB; 326501at2759; -.
DR PhylomeDB; Q9R0W2; -.
DR TreeFam; TF315847; -.
DR Reactome; R-RNO-112311; Neurotransmitter clearance.
DR Reactome; R-RNO-181430; Norepinephrine Neurotransmitter Release Cycle.
DR Reactome; R-RNO-2161517; Abacavir transmembrane transport.
DR Reactome; R-RNO-442660; Na+/Cl- dependent neurotransmitter transporters.
DR Reactome; R-RNO-549127; Organic cation transport.
DR PRO; PR:Q9R0W2; -.
DR Proteomes; UP000002494; Unplaced.
DR GO; GO:0016324; C:apical plasma membrane; IDA:ARUK-UCL.
DR GO; GO:0016323; C:basolateral plasma membrane; IDA:RGD.
DR GO; GO:0005887; C:integral component of plasma membrane; IDA:RGD.
DR GO; GO:0005886; C:plasma membrane; ISO:RGD.
DR GO; GO:0098793; C:presynapse; IEA:GOC.
DR GO; GO:0005275; F:amine transmembrane transporter activity; ISO:RGD.
DR GO; GO:0015220; F:choline transmembrane transporter activity; IDA:RGD.
DR GO; GO:0015562; F:efflux transmembrane transporter activity; ISO:RGD.
DR GO; GO:0015179; F:L-amino acid transmembrane transporter activity; ISO:RGD.
DR GO; GO:0061459; F:L-arginine transmembrane transporter activity; ISO:RGD.
DR GO; GO:0008504; F:monoamine transmembrane transporter activity; ISO:RGD.
DR GO; GO:0005326; F:neurotransmitter transmembrane transporter activity; ISO:RGD.
DR GO; GO:0015101; F:organic cation transmembrane transporter activity; IDA:ARUK-UCL.
DR GO; GO:0015214; F:pyrimidine nucleoside transmembrane transporter activity; ISO:RGD.
DR GO; GO:0015651; F:quaternary ammonium group transmembrane transporter activity; IDA:RGD.
DR GO; GO:0005496; F:steroid binding; IDA:RGD.
DR GO; GO:0019534; F:toxin transmembrane transporter activity; IDA:ARUK-UCL.
DR GO; GO:0042910; F:xenobiotic transmembrane transporter activity; IMP:ARUK-UCL.
DR GO; GO:0006919; P:activation of cysteine-type endopeptidase activity involved in apoptotic process; IMP:ARUK-UCL.
DR GO; GO:0015837; P:amine transport; ISO:RGD.
DR GO; GO:0089718; P:amino acid import across plasma membrane; ISO:RGD.
DR GO; GO:0006812; P:cation transport; ISO:RGD.
DR GO; GO:0015871; P:choline transport; ISO:RGD.
DR GO; GO:0090494; P:dopamine uptake; ISO:RGD.
DR GO; GO:0140115; P:export across plasma membrane; ISO:RGD.
DR GO; GO:0051608; P:histamine transport; IDA:RGD.
DR GO; GO:0051615; P:histamine uptake; ISO:RGD.
DR GO; GO:1902475; P:L-alpha-amino acid transmembrane transport; ISO:RGD.
DR GO; GO:0097638; P:L-arginine import across plasma membrane; ISO:RGD.
DR GO; GO:0006836; P:neurotransmitter transport; ISO:RGD.
DR GO; GO:0051620; P:norepinephrine uptake; ISO:RGD.
DR GO; GO:0015695; P:organic cation transport; IDA:ARUK-UCL.
DR GO; GO:0010628; P:positive regulation of gene expression; IMP:ARUK-UCL.
DR GO; GO:0015697; P:quaternary ammonium group transport; IDA:RGD.
DR GO; GO:0051610; P:serotonin uptake; ISO:RGD.
DR GO; GO:1901998; P:toxin transport; IDA:ARUK-UCL.
DR GO; GO:0042908; P:xenobiotic transport; IDA:ARUK-UCL.
DR GO; GO:1990962; P:xenobiotic transport across blood-brain barrier; NAS:ARUK-UCL.
DR Gene3D; 1.20.1250.20; -; 1.
DR InterPro; IPR020846; MFS_dom.
DR InterPro; IPR005828; MFS_sugar_transport-like.
DR InterPro; IPR036259; MFS_trans_sf.
DR InterPro; IPR004749; Orgcat_transp/SVOP.
DR InterPro; IPR005829; Sugar_transporter_CS.
DR Pfam; PF00083; Sugar_tr; 1.
DR SUPFAM; SSF103473; SSF103473; 1.
DR TIGRFAMs; TIGR00898; 2A0119; 1.
DR PROSITE; PS50850; MFS; 1.
DR PROSITE; PS00216; SUGAR_TRANSPORT_1; 2.
PE 1: Evidence at protein level;
KW Glycoprotein; Ion transport; Membrane; Reference proteome; Transmembrane;
KW Transmembrane helix; Transport.
FT CHAIN 1..555
FT /note="Solute carrier family 22 member 2"
FT /id="PRO_0000320962"
FT TOPO_DOM 1..21
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 22..42
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 43..150
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 151..171
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 172..177
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 178..198
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 199..210
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 211..231
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 232..238
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 239..259
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 260..263
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 264..284
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 285..348
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 349..369
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 370..375
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 376..396
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 397..404
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 405..425
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 426..432
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 433..453
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 454..464
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 465..485
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 486..494
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 495..515
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 516..555
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT SITE 451
FT /note="Involved in recognition of organic cations and
FT participates in structural changes that occur during
FT translocation of organic cations"
FT CARBOHYD 71
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT MUTAGEN 451
FT /note="C->M: Transport activity strongly reduced."
FT /evidence="ECO:0000269|PubMed:17567940"
FT CONFLICT 332
FT /note="N -> K (in Ref. 1; BAA11754)"
FT /evidence="ECO:0000305"
FT CONFLICT 335
FT /note="F -> I (in Ref. 1; BAA11754)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 555 AA; 62343 MW; 29521969AE1AC206 CRC64;
MSTVDDILEH IGEFHLFQKQ TFFLLALLSG AFTPIYVGIV FLGFTPDHHC WSPGAAKLSQ
RCGWSQAEEL NYTVPGLGPS DEASFLSQCM RYEVDWNQST LDCVDPLSSL AADRNQLPLG
PCEHGWVYNT PGSSIVTEFN LVCAHSWMLD LFQSVVNVGF FIGAMMIGYL ADRFGRKFCL
LVTILINAIS GALMAISPNY AWMLVFRFLQ GLVSKAGWLI GYILITEFVG LGYRRMVGIC
YQIAFTVGLL ILAGVAYVIP NWRWLQFAVT LPNFCFLLYF WCIPESPRWL ISQNKIVKAM
KIIKHIAKKN GKSVPVSLQN LTPDEDAGKK LNPSFLDLVR TPQIRKHTLI LMYNWFTSSV
LYQGLIMHMG LAGDNIYLDF FYSALVEFPA AFIIILTIDR VGRRYPWAVS NMVAGAACLA
SVFIPDDLQW LKITIACLGR MGITMAYEMV CLVNAELYPT YIRNLGVLVC SSMCDIGGII
TPFLVYRLTD IWMEFPLVVF AVVGLVAGAL VLLLPETKGK ALPETIEDAE NMQRPRKKKE
KRIYLQVKQA DRPLS
