ID S22A3_MOUSE Reviewed; 551 AA. AC Q9WTW5; Q9R209; DT 19-OCT-2002, integrated into UniProtKB/Swiss-Prot. DT 01-NOV-1999, sequence version 1. DT 27-MAR-2024, entry version 168. DE RecName: Full=Solute carrier family 22 member 3 {ECO:0000303|PubMed:9933568}; DE AltName: Full=Organic cation transporter 3 {ECO:0000303|PubMed:10966924}; DE Short=OCT3 {ECO:0000303|PubMed:10966924}; GN Name=Slc22a3 {ECO:0000312|MGI:MGI:1333817}; GN Synonyms=Oct3 {ECO:0000303|PubMed:10966924}; OS Mus musculus (Mouse). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; OC Murinae; Mus; Mus. OX NCBI_TaxID=10090; RN [1] {ECO:0000305} RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA], TISSUE SPECIFICITY, AND RP DEVELOPMENTAL STAGE. RC STRAIN=CD-1; TISSUE=Placenta; RX PubMed=9933568; DOI=10.1006/geno.1998.5639; RA Verhaagh S., Schweifer N., Barlow D.P., Zwart R.; RT "Cloning of the mouse and human solute carrier 22a3 (Slc22a3/SLC22A3) RT identifies a conserved cluster of three organic cation transporters on RT mouse chromosome 17 and human 6q26-q27."; RL Genomics 55:209-218(1999). RN [2] {ECO:0000305} RP NUCLEOTIDE SEQUENCE, FUNCTION, BIOPHYSICOCHEMICAL PROPERTIES, AND TISSUE RP SPECIFICITY. RC TISSUE=Kidney; RX PubMed=10966924; DOI=10.1152/ajprenal.2000.279.3.f449; RA Wu X., Huang W., Ganapathy M.E., Wang H., Kekuda R., Conway S.J., RA Leibach F.H., Ganapathy V.; RT "Structure, function, and regional distribution of the organic cation RT transporter OCT3 in the kidney."; RL Am. J. Physiol. 279:F449-F458(2000). RN [3] RP FUNCTION, CATALYTIC ACTIVITY, DISRUPTION PHENOTYPE, TISSUE SPECIFICITY, AND RP MISCELLANEOUS. RX PubMed=18513366; DOI=10.1111/j.1471-4159.2008.05506.x; RA Vialou V., Balasse L., Callebert J., Launay J.M., Giros B., Gautron S.; RT "Altered aminergic neurotransmission in the brain of organic cation RT transporter 3-deficient mice."; RL J. Neurochem. 106:1471-1482(2008). RN [4] RP FUNCTION, DISRUPTION PHENOTYPE, TISSUE SPECIFICITY, AND MISCELLANEOUS. RX PubMed=19416912; DOI=10.1073/pnas.0900358106; RA Cui M., Aras R., Christian W.V., Rappold P.M., Hatwar M., Panza J., RA Jackson-Lewis V., Javitch J.A., Ballatori N., Przedborski S., Tieu K.; RT "The organic cation transporter-3 is a pivotal modulator of RT neurodegeneration in the nigrostriatal dopaminergic pathway."; RL Proc. Natl. Acad. Sci. U.S.A. 106:8043-8048(2009). RN [5] RP FUNCTION, SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY. RX PubMed=27659446; DOI=10.1007/s00429-016-1315-9; RA Gasser P.J., Hurley M.M., Chan J., Pickel V.M.; RT "Organic cation transporter 3 (OCT3) is localized to intracellular and RT surface membranes in select glial and neuronal cells within the basolateral RT amygdaloid complex of both rats and mice."; RL Brain Struct. Funct. 222:1913-1928(2017). CC -!- FUNCTION: Electrogenic voltage-dependent transporter that mediates the CC transport of a variety of organic cations such as endogenous bioactive CC amines, cationic drugs and xenobiotics (PubMed:10966924, CC PubMed:18513366). Cation cellular uptake or release is driven by the CC electrochemical potential, i.e. membrane potential and concentration CC gradient (PubMed:10966924). Functions as a Na(+)- and Cl(-)- CC independent, bidirectional uniporter (By similarity). Implicated in CC monoamine neurotransmitters uptake such as dopamine, CC adrenaline/epinephrine, noradrenaline/norepinephrine, homovanillic CC acid, histamine, serotonin and tyramine, thereby supporting a role in CC homeostatic regulation of aminergic neurotransmission in the brain CC (PubMed:18513366, PubMed:19416912). Transports dopaminergic CC neuromodulators cyclo(his-pro) and salsolinol with low efficiency (By CC similarity). May be involved in the uptake and disposition of cationic CC compounds by renal clearance from the blood flow (PubMed:10966924). May CC contribute to regulate the transport of cationic compounds in testis CC across the blood-testis-barrier (By similarity). Mediates the transport CC of polyamine spermidine and putrescine (By similarity). Mediates the CC bidirectional transport of polyamine agmatine (By similarity). Also CC transports guanidine (PubMed:10966924). May also mediate intracellular CC transport of organic cations, thereby playing a role in amine CC metabolism and intracellular signaling (PubMed:27659446). CC {ECO:0000250|UniProtKB:O75751, ECO:0000250|UniProtKB:O88446, CC ECO:0000269|PubMed:10966924, ECO:0000269|PubMed:18513366, CC ECO:0000269|PubMed:19416912, ECO:0000269|PubMed:27659446}. CC -!- CATALYTIC ACTIVITY: CC Reaction=(R)-noradrenaline(out) = (R)-noradrenaline(in); CC Xref=Rhea:RHEA:73871, ChEBI:CHEBI:72587; CC Evidence={ECO:0000269|PubMed:18513366}; CC -!- CATALYTIC ACTIVITY: CC Reaction=(R)-adrenaline(out) = (R)-adrenaline(in); CC Xref=Rhea:RHEA:73875, ChEBI:CHEBI:71406; CC Evidence={ECO:0000250|UniProtKB:O75751}; CC -!- CATALYTIC ACTIVITY: CC Reaction=serotonin(out) = serotonin(in); Xref=Rhea:RHEA:73867, CC ChEBI:CHEBI:350546; Evidence={ECO:0000269|PubMed:18513366}; CC -!- CATALYTIC ACTIVITY: CC Reaction=dopamine(out) = dopamine(in); Xref=Rhea:RHEA:73863, CC ChEBI:CHEBI:59905; Evidence={ECO:0000269|PubMed:18513366}; CC -!- CATALYTIC ACTIVITY: CC Reaction=histamine(out) = histamine(in); Xref=Rhea:RHEA:73879, CC ChEBI:CHEBI:58432; Evidence={ECO:0000250|UniProtKB:O75751}; CC -!- CATALYTIC ACTIVITY: CC Reaction=tyramine(in) = tyramine(out); Xref=Rhea:RHEA:74783, CC ChEBI:CHEBI:327995; Evidence={ECO:0000250|UniProtKB:O75751}; CC -!- CATALYTIC ACTIVITY: CC Reaction=guanidine(out) = guanidine(in); Xref=Rhea:RHEA:73883, CC ChEBI:CHEBI:30087; Evidence={ECO:0000269|PubMed:10966924}; CC -!- CATALYTIC ACTIVITY: CC Reaction=agmatine(out) = agmatine(in); Xref=Rhea:RHEA:72131, CC ChEBI:CHEBI:58145; Evidence={ECO:0000250|UniProtKB:O75751}; CC -!- CATALYTIC ACTIVITY: CC Reaction=spermidine(in) = spermidine(out); Xref=Rhea:RHEA:35039, CC ChEBI:CHEBI:57834; Evidence={ECO:0000250|UniProtKB:O88446}; CC -!- CATALYTIC ACTIVITY: CC Reaction=L-histidyl-L-proline diketopiperazine(in) = L-histidyl-L- CC proline diketopiperazine(out); Xref=Rhea:RHEA:74787, CC ChEBI:CHEBI:90039; Evidence={ECO:0000250|UniProtKB:O75751}; CC -!- CATALYTIC ACTIVITY: CC Reaction=(R)-salsolinol(in) = (R)-salsolinol(out); CC Xref=Rhea:RHEA:74791, ChEBI:CHEBI:194082; CC Evidence={ECO:0000250|UniProtKB:O75751}; CC -!- BIOPHYSICOCHEMICAL PROPERTIES: CC pH dependence: CC Optimum pH is 8.5 for TEA uptake. {ECO:0000269|PubMed:10966924}; CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:27659446}; CC Multi-pass membrane protein {ECO:0000305}. Apical cell membrane CC {ECO:0000250|UniProtKB:O75751}; Multi-pass membrane protein CC {ECO:0000305}. Basolateral cell membrane CC {ECO:0000250|UniProtKB:O75751}; Multi-pass membrane protein CC {ECO:0000305}. Mitochondrion membrane {ECO:0000269|PubMed:27659446}. CC Endomembrane system {ECO:0000269|PubMed:27659446}. Nucleus membrane CC {ECO:0000305|PubMed:27659446}. Nucleus outer membrane CC {ECO:0000250|UniProtKB:O88446}. Note=Located to neuronal and glial CC endomembranes, including mitochondrial and nuclear membranes. CC {ECO:0000269|PubMed:27659446}. CC -!- TISSUE SPECIFICITY: Highly expressed in placenta (PubMed:10966924, CC PubMed:9933568). Highly expressed in kidney cortex (PubMed:10966924). CC In kidney, expressed specifically in the proximal and distal convoluted CC tubules and within Bowman capsule (PubMed:10966924). Expressed in CC brain, particularly in dopaminergic neurons of the substantia nigra CC compacta, non-aminergic neurons of the ventral tegmental area, CC substantia nigra reticulata, locus coeruleus, hippocampus and cortex CC (PubMed:18513366). In brain, also detected in astrocytes in the CC substantia nigra reticulata, several hypothalamic nuclei and CC nigrostriatal region (PubMed:18513366, PubMed:19416912). Expressed in CC neurons and glial cells of amygdala (PubMed:27659446). CC {ECO:0000269|PubMed:10966924, ECO:0000269|PubMed:18513366, CC ECO:0000269|PubMed:19416912, ECO:0000269|PubMed:27659446, CC ECO:0000269|PubMed:9933568}. CC -!- DEVELOPMENTAL STAGE: Levels are high during gestation, but decrease CC greatly towards the end of gestation. {ECO:0000269|PubMed:9933568}. CC -!- DOMAIN: Contains one proline-rich sequence (Pro-Glu-Ser-Pro-Arg) that CC is required for transport activity. {ECO:0000250|UniProtKB:O75751}. CC -!- DISRUPTION PHENOTYPE: Knockout mice show altered monoamine CC neurotransmission in the brain, with decreased intracellular content CC and increased turnover of aminergic transmitters. Knockout mice show CC subtle alterations in behaviors such as increased sensitivity to CC psychostimulants and increased levels of anxiety and stress CC (PubMed:18513366). Also exhibit impaired removal of the excess CC extracellular dopamine induced by methamphetamine and increased CC striatal dopaminergic terminal damage caused by this psychostimulant CC (PubMed:19416912). {ECO:0000269|PubMed:18513366, CC ECO:0000269|PubMed:19416912}. CC -!- MISCELLANEOUS: Mediates the uptake of clinically used drugs including CC neurotoxin 1-methyl-4-phenylpyridinium (MPP(+)) and platinum-based drug CC oxaliplatin (PubMed:10966924, PubMed:18513366, PubMed:19416912). Plays CC a role in the anticancer activity of oxaliplatin and may contribute to CC antitumor specificity (By similarity). {ECO:0000250|UniProtKB:O75751, CC ECO:0000269|PubMed:10966924, ECO:0000269|PubMed:18513366, CC ECO:0000269|PubMed:19416912}. 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 --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AF078750; AAD20978.1; -; mRNA. DR EMBL; AF078748; AAD20238.1; -; Genomic_DNA. DR EMBL; AF082566; AAD53007.1; -; mRNA. DR CCDS; CCDS28391.1; -. DR RefSeq; NP_035525.1; NM_011395.2. DR AlphaFoldDB; Q9WTW5; -. DR SMR; Q9WTW5; -. DR STRING; 10090.ENSMUSP00000024595; -. DR ChEMBL; CHEMBL2073684; -. DR GlyCosmos; Q9WTW5; 5 sites, No reported glycans. DR GlyGen; Q9WTW5; 5 sites. DR iPTMnet; Q9WTW5; -. DR PhosphoSitePlus; Q9WTW5; -. DR SwissPalm; Q9WTW5; -. DR MaxQB; Q9WTW5; -. DR PaxDb; 10090-ENSMUSP00000024595; -. DR ProteomicsDB; 260884; -. DR Antibodypedia; 20034; 244 antibodies from 34 providers. DR DNASU; 20519; -. DR Ensembl; ENSMUST00000024595.4; ENSMUSP00000024595.3; ENSMUSG00000023828.4. DR GeneID; 20519; -. DR KEGG; mmu:20519; -. DR UCSC; uc008aku.1; mouse. DR AGR; MGI:1333817; -. DR CTD; 6581; -. DR MGI; MGI:1333817; Slc22a3. DR VEuPathDB; HostDB:ENSMUSG00000023828; -. DR eggNOG; KOG0255; Eukaryota. DR GeneTree; ENSGT00940000160810; -. DR HOGENOM; CLU_001265_33_5_1; -. DR InParanoid; Q9WTW5; -. DR OMA; NYWCRIP; -. DR OrthoDB; 1474205at2759; -. DR PhylomeDB; Q9WTW5; -. DR TreeFam; TF315847; -. DR Reactome; R-MMU-2161517; Abacavir transmembrane transport. DR Reactome; R-MMU-549127; Organic cation transport. DR BioGRID-ORCS; 20519; 3 hits in 76 CRISPR screens. DR ChiTaRS; Slc22a3; mouse. DR PRO; PR:Q9WTW5; -. DR Proteomes; UP000000589; Chromosome 17. DR RNAct; Q9WTW5; Protein. DR Bgee; ENSMUSG00000023828; Expressed in placenta labyrinth and 95 other cell types or tissues. DR ExpressionAtlas; Q9WTW5; baseline and differential. DR GO; GO:0016324; C:apical plasma membrane; IDA:UniProtKB. DR GO; GO:0016323; C:basolateral plasma membrane; ISS:UniProtKB. DR GO; GO:0012505; C:endomembrane system; IDA:UniProtKB. DR GO; GO:0031966; C:mitochondrial membrane; IDA:UniProtKB. DR GO; GO:0043025; C:neuronal cell body; IDA:ARUK-UCL. DR GO; GO:0005640; C:nuclear outer membrane; IEA:UniProtKB-SubCell. DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB. DR GO; GO:0098793; C:presynapse; IEA:GOC. DR GO; GO:0005330; F:dopamine:sodium symporter activity; ISO:MGI. DR GO; GO:0008504; F:monoamine transmembrane transporter activity; IMP:UniProtKB. DR GO; GO:0005326; F:neurotransmitter transmembrane transporter activity; IMP:UniProtKB. DR GO; GO:0008514; F:organic anion transmembrane transporter activity; ISO:MGI. DR GO; GO:0015101; F:organic cation transmembrane transporter activity; IDA:MGI. DR GO; GO:0015651; F:quaternary ammonium group transmembrane transporter activity; IDA:MGI. DR GO; GO:0015606; F:spermidine transmembrane transporter activity; ISS:UniProtKB. DR GO; GO:0019534; F:toxin transmembrane transporter activity; ISO:MGI. DR GO; GO:0022857; F:transmembrane transporter activity; IDA:MGI. DR GO; GO:0015872; P:dopamine transport; IMP:UniProtKB. DR GO; GO:0090494; P:dopamine uptake; ISO:MGI. DR GO; GO:0048241; P:epinephrine transport; ISO:MGI. DR GO; GO:0051625; P:epinephrine uptake; ISO:MGI. DR GO; GO:0051649; P:establishment of localization in cell; IMP:MGI. DR GO; GO:0051608; P:histamine transport; IMP:ARUK-UCL. DR GO; GO:0051615; P:histamine uptake; IMP:MGI. DR GO; GO:0015844; P:monoamine transport; IMP:MGI. DR GO; GO:0015718; P:monocarboxylic acid transport; IMP:ARUK-UCL. DR GO; GO:0006836; P:neurotransmitter transport; IMP:ARUK-UCL. DR GO; GO:0015874; P:norepinephrine transport; IMP:UniProtKB. DR GO; GO:0051620; P:norepinephrine uptake; ISO:MGI. DR GO; GO:0015711; P:organic anion transport; ISO:MGI. DR GO; GO:0015695; P:organic cation transport; IDA:MGI. DR GO; GO:0015850; P:organic hydroxy compound transport; IMP:ARUK-UCL. DR GO; GO:0015697; P:quaternary ammonium group transport; IDA:MGI. DR GO; GO:0032098; P:regulation of appetite; IMP:MGI. DR GO; GO:0006837; P:serotonin transport; IMP:UniProtKB. DR GO; GO:0051610; P:serotonin uptake; ISO:MGI. DR GO; GO:0015848; P:spermidine transport; ISS:UniProtKB. DR GO; GO:1901998; P:toxin transport; ISO:MGI. DR GO; GO:0042908; P:xenobiotic transport; ISO:MGI. DR CDD; cd17379; MFS_SLC22A1_2_3; 1. DR Gene3D; 1.20.1250.20; MFS general substrate transporter like domains; 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 NCBIfam; TIGR00898; 2A0119; 1. DR PANTHER; PTHR24064; SOLUTE CARRIER FAMILY 22 MEMBER; 1. DR PANTHER; PTHR24064:SF52; SOLUTE CARRIER FAMILY 22 MEMBER 3; 1. DR Pfam; PF00083; Sugar_tr; 1. DR SUPFAM; SSF103473; MFS general substrate transporter; 1. DR PROSITE; PS50850; MFS; 1. DR PROSITE; PS00216; SUGAR_TRANSPORT_1; 1. DR Genevisible; Q9WTW5; MM. PE 1: Evidence at protein level; KW Cell membrane; Glycoprotein; Ion transport; Membrane; Mitochondrion; KW Nucleus; Reference proteome; Transmembrane; Transmembrane helix; Transport. FT CHAIN 1..551 FT /note="Solute carrier family 22 member 3" FT /id="PRO_0000220504" FT TRANSMEM 21..41 FT /note="Helical" FT /evidence="ECO:0000255" FT TRANSMEM 177..197 FT /note="Helical" FT /evidence="ECO:0000255" FT TRANSMEM 236..256 FT /note="Helical" FT /evidence="ECO:0000255" FT TRANSMEM 264..284 FT /note="Helical" FT /evidence="ECO:0000255" FT TRANSMEM 376..396 FT /note="Helical" FT /evidence="ECO:0000255" FT TRANSMEM 464..484 FT /note="Helical" FT /evidence="ECO:0000255" FT TRANSMEM 493..513 FT /note="Helical" FT /evidence="ECO:0000255" FT MOTIF 284..288 FT /note="Proline-rich sequence" FT /evidence="ECO:0000250|UniProtKB:O75751" FT CARBOHYD 72 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 99 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 114 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 199 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 317 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" SQ SEQUENCE 551 AA; 61053 MW; C4D66AAC2EFCFBDB CRC64; MPTFDQALRK AGEFGRFQRR VFLLLCLTGV TFAFLFVGVV FLGSQPDYYW CRGPRATALA ERCAWSPEEE WNLTTPELHV PAERRGQGHC HRYLLEATNT SSELSCDPLT AFPNRSAPLV SCSGDWRYVE THSTIVSQFD LVCSNAWMLD LTQAILNLGF LAGAFTLGYA ADRYGRLIIY LISCFGVGIT GVVVAFAPNF SVFVIFRFLQ GVFGKGAWMT CFVIVTEIVG SKQRRIVGIV IQMFFTLGII ILPGIAYFTP SWQGIQLAIS LPSFLFLLYY WVVPESPRWL ITRKQGEKAL QILRRVAKCN GKHLSSNYSE ITVTDEEVSN PSCLDLVRTP QMRKCTLILM FAWFTSAVVY QGLVMRLGLI GGNLYIDFFI SGLVELPGAL LILLTIERLG RRLPFAASNI VAGVSCLVTA FLPEGIPWLR TTVATLGRLG ITMAFEIVYL VNSELYPTTL RNFGVSLCSG LCDFGGIIAP FLLFRLAAIW LELPLIIFGI LASVCGGLVM LLPETKGIAL PETVEDVEKL GSSQLHQCGR KKKTQVSTSD V //