ID S22A3_HUMAN Reviewed; 556 AA. AC O75751; Q5SYN6; Q9UP02; DT 19-OCT-2002, integrated into UniProtKB/Swiss-Prot. DT 01-NOV-1998, sequence version 1. DT 27-MAR-2024, entry version 175. DE RecName: Full=Solute carrier family 22 member 3 {ECO:0000303|PubMed:9933568}; DE AltName: Full=Extraneuronal monoamine transporter {ECO:0000303|PubMed:10196521}; DE Short=EMT {ECO:0000303|PubMed:10196521}; DE AltName: Full=Organic cation transporter 3 {ECO:0000303|PubMed:16263091}; DE Short=OCT3 {ECO:0000303|PubMed:16263091}; GN Name=SLC22A3 {ECO:0000312|HGNC:HGNC:10967}; GN Synonyms=EMTH, OCT3 {ECO:0000303|PubMed:16263091}; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, TRANSPORTER ACTIVITY, AND TISSUE RP SPECIFICITY. RC TISSUE=Kidney; RX PubMed=10196521; DOI=10.1038/1557; RA Gruendemann D., Schechinger B., Rappold G.A., Schoemig E.; RT "Molecular identification of the corticosterone-sensitive extraneuronal RT catecholamine transporter."; RL Nat. Neurosci. 1:349-351(1998). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Tongue; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=14574404; DOI=10.1038/nature02055; RA Mungall A.J., Palmer S.A., Sims S.K., Edwards C.A., Ashurst J.L., RA Wilming L., Jones M.C., Horton R., Hunt S.E., Scott C.E., Gilbert J.G.R., RA Clamp M.E., Bethel G., Milne S., Ainscough R., Almeida J.P., Ambrose K.D., RA Andrews T.D., Ashwell R.I.S., Babbage A.K., Bagguley C.L., Bailey J., RA Banerjee R., Barker D.J., Barlow K.F., Bates K., Beare D.M., Beasley H., RA Beasley O., Bird C.P., Blakey S.E., Bray-Allen S., Brook J., Brown A.J., RA Brown J.Y., Burford D.C., Burrill W., Burton J., Carder C., Carter N.P., RA Chapman J.C., Clark S.Y., Clark G., Clee C.M., Clegg S., Cobley V., RA Collier R.E., Collins J.E., Colman L.K., Corby N.R., Coville G.J., RA Culley K.M., Dhami P., Davies J., Dunn M., Earthrowl M.E., Ellington A.E., RA Evans K.A., Faulkner L., Francis M.D., Frankish A., Frankland J., RA French L., Garner P., Garnett J., Ghori M.J., Gilby L.M., Gillson C.J., RA Glithero R.J., Grafham D.V., Grant M., Gribble S., Griffiths C., RA Griffiths M.N.D., Hall R., Halls K.S., Hammond S., Harley J.L., Hart E.A., RA Heath P.D., Heathcott R., Holmes S.J., Howden P.J., Howe K.L., Howell G.R., RA Huckle E., Humphray S.J., Humphries M.D., Hunt A.R., Johnson C.M., RA Joy A.A., Kay M., Keenan S.J., Kimberley A.M., King A., Laird G.K., RA Langford C., Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C.R., RA Lloyd D.M., Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M., RA Maslen G.L., Matthews L., McCann O.T., McLaren S.J., McLay K., McMurray A., RA Moore M.J.F., Mullikin J.C., Niblett D., Nickerson T., Novik K.L., RA Oliver K., Overton-Larty E.K., Parker A., Patel R., Pearce A.V., Peck A.I., RA Phillimore B.J.C.T., Phillips S., Plumb R.W., Porter K.M., Ramsey Y., RA Ranby S.A., Rice C.M., Ross M.T., Searle S.M., Sehra H.K., Sheridan E., RA Skuce C.D., Smith S., Smith M., Spraggon L., Squares S.L., Steward C.A., RA Sycamore N., Tamlyn-Hall G., Tester J., Theaker A.J., Thomas D.W., RA Thorpe A., Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M., RA West A.P., White S.S., Whitehead S.L., Whittaker H., Wild A., Willey D.J., RA Wilmer T.E., Wood J.M., Wray P.W., Wyatt J.C., Young L., Younger R.M., RA Bentley D.R., Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Dunham I., RA Rogers J., Beck S.; RT "The DNA sequence and analysis of human chromosome 6."; RL Nature 425:805-811(2003). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [5] {ECO:0000305} RP NUCLEOTIDE SEQUENCE [MRNA] OF 513-556, AND TISSUE SPECIFICITY. 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 [6] {ECO:0000305} RP FUNCTION, SUBCELLULAR LOCATION, AND TISSUE 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 [7] RP FUNCTION, TRANSPORTER ACTIVITY, AND BIOPHYSICOCHEMICAL PROPERTIES. RX PubMed=12538837; DOI=10.1124/jpet.102.044404; RA Grundemann D., Hahne C., Berkels R., Schomig E.; RT "Agmatine is efficiently transported by non-neuronal monoamine transporters RT extraneuronal monoamine transporter (EMT) and organic cation transporter 2 RT (OCT2)."; RL J. Pharmacol. Exp. Ther. 304:810-817(2003). RN [8] RP SUBCELLULAR LOCATION, TISSUE SPECIFICITY, AND MISCELLANEOUS. RX PubMed=15817714; DOI=10.1165/rcmb.2004-0363oc; RA Lips K.S., Volk C., Schmitt B.M., Pfeil U., Arndt P., Miska D., Ermert L., RA Kummer W., Koepsell H.; RT "Polyspecific cation transporters mediate luminal release of acetylcholine RT from bronchial epithelium."; RL Am. J. Respir. Cell Mol. Biol. 33:79-88(2005). RN [9] RP SUBCELLULAR LOCATION, TISSUE SPECIFICITY, AND MISCELLANEOUS. RX PubMed=16263091; DOI=10.1016/j.bcp.2005.09.011; RA Mueller J., Lips K.S., Metzner L., Neubert R.H.H., Koepsell H., RA Brandsch M.; RT "Drug specificity and intestinal membrane localization of human organic RT cation transporters (OCT)."; RL Biochem. Pharmacol. 70:1851-1860(2005). RN [10] RP MISCELLANEOUS. RX PubMed=16914559; DOI=10.1124/jpet.106.110346; RA Yonezawa A., Masuda S., Yokoo S., Katsura T., Inui K.; RT "Cisplatin and oxaliplatin, but not carboplatin and nedaplatin, are RT substrates for human organic cation transporters (SLC22A1-3 and multidrug RT and toxin extrusion family)."; RL J. Pharmacol. Exp. Ther. 319:879-886(2006). RN [11] RP FUNCTION, TRANSPORTER ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, AND RP MISCELLANEOUS. RX PubMed=16581093; DOI=10.1016/j.neuropharm.2006.01.005; RA Amphoux A., Vialou V., Drescher E., Bruess M., Mannoury La Cour C., RA Rochat C., Millan M.J., Giros B., Boenisch H., Gautron S.; RT "Differential pharmacological in vitro properties of organic cation RT transporters and regional distribution in rat brain."; RL Neuropharmacology 50:941-952(2006). RN [12] RP FUNCTION, TRANSPORTER ACTIVITY, AND BIOPHYSICOCHEMICAL PROPERTIES. RX PubMed=17460754; DOI=10.1371/journal.pone.0000385; RA Taubert D., Grimberg G., Stenzel W., Schoemig E.; RT "Identification of the endogenous key substrates of the human organic RT cation transporter OCT2 and their implication in function of dopaminergic RT neurons."; RL PLoS ONE 2:e385-e385(2007). RN [13] RP FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, SUBCELLULAR RP LOCATION, TISSUE SPECIFICITY, AND MISCELLANEOUS. RX PubMed=20858707; DOI=10.1124/jpet.110.170142; RA Duan H., Wang J.; RT "Selective transport of monoamine neurotransmitters by human plasma RT membrane monoamine transporter and organic cation transporter 3."; RL J. Pharmacol. Exp. Ther. 335:743-753(2010). RN [14] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=22814378; DOI=10.1073/pnas.1210303109; RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A., RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E., Timmerman E., RA Prieto J., Arnesen T., Sherman F., Gevaert K., Aldabe R.; RT "N-terminal acetylome analyses and functional insights of the N-terminal RT acetyltransferase NatB."; RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012). RN [15] RP MUTAGENESIS OF PRO-289; VAL-363 AND TYR-380, AND DOMAIN. RX PubMed=26979622; DOI=10.1038/ncomms10880; RA Sprowl J.A., Ong S.S., Gibson A.A., Hu S., Du G., Lin W., Li L., RA Bharill S., Ness R.A., Stecula A., Offer S.M., Diasio R.B., Nies A.T., RA Schwab M., Cavaletti G., Schlatter E., Ciarimboli G., Schellens J.H.M., RA Isacoff E.Y., Sali A., Chen T., Baker S.D., Sparreboom A., Pabla N.; RT "A phosphotyrosine switch regulates organic cation transporters."; RL Nat. Commun. 7:10880-10880(2016). RN [16] RP FUNCTION, AND TISSUE SPECIFICITY. RX PubMed=35307651; DOI=10.1124/dmd.121.000748; RA Hau R.K., Klein R.R., Wright S.H., Cherrington N.J.; RT "Localization of Xenobiotic Transporters Expressed at the Human Blood- RT Testis Barrier."; RL Drug Metab. Dispos. 50:770-780(2022). 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:10196521, CC PubMed:10966924, PubMed:12538837, PubMed:17460754, PubMed:20858707). CC Cation cellular uptake or release is driven by the electrochemical CC potential, i.e. membrane potential and concentration gradient CC (PubMed:10966924). Functions as a Na(+)- and Cl(-)-independent, CC bidirectional uniporter (PubMed:12538837). Implicated in monoamine CC neurotransmitters uptake such as dopamine, adrenaline/epinephrine, CC noradrenaline/norepinephrine, histamine, serotonin and tyramine, CC thereby supporting a role in homeostatic regulation of aminergic CC neurotransmission in the brain (PubMed:10196521, PubMed:16581093, CC PubMed:20858707). Transports dopaminergic neuromodulators cyclo(his- CC pro) and salsolinol with low efficiency (PubMed:17460754). May be CC involved in the uptake and disposition of cationic compounds by renal CC clearance from the blood flow (PubMed:10966924). May contribute to CC regulate the transport of cationic compounds in testis across the CC blood-testis-barrier (Probable). Mediates the transport of polyamine CC spermidine and putrescine (By similarity). Mediates the bidirectional CC transport of polyamine agmatine (PubMed:12538837). Also transports CC guanidine (PubMed:10966924). May also mediate intracellular transport CC of organic cations, thereby playing a role in amine metabolism and CC intracellular signaling (By similarity). {ECO:0000250|UniProtKB:O88446, CC ECO:0000269|PubMed:10196521, ECO:0000269|PubMed:10966924, CC ECO:0000269|PubMed:12538837, ECO:0000269|PubMed:16581093, CC ECO:0000269|PubMed:17460754, ECO:0000269|PubMed:20858707, CC ECO:0000305|PubMed:35307651}. CC -!- CATALYTIC ACTIVITY: CC Reaction=(R)-noradrenaline(out) = (R)-noradrenaline(in); CC Xref=Rhea:RHEA:73871, ChEBI:CHEBI:72587; CC Evidence={ECO:0000269|PubMed:10196521, ECO:0000269|PubMed:16581093, CC ECO:0000269|PubMed:20858707}; CC -!- CATALYTIC ACTIVITY: CC Reaction=(R)-adrenaline(out) = (R)-adrenaline(in); CC Xref=Rhea:RHEA:73875, ChEBI:CHEBI:71406; CC Evidence={ECO:0000269|PubMed:10196521, ECO:0000269|PubMed:16581093, CC ECO:0000269|PubMed:20858707}; CC -!- CATALYTIC ACTIVITY: CC Reaction=serotonin(out) = serotonin(in); Xref=Rhea:RHEA:73867, CC ChEBI:CHEBI:350546; Evidence={ECO:0000269|PubMed:10196521, CC ECO:0000269|PubMed:20858707}; CC -!- CATALYTIC ACTIVITY: CC Reaction=dopamine(out) = dopamine(in); Xref=Rhea:RHEA:73863, CC ChEBI:CHEBI:59905; Evidence={ECO:0000269|PubMed:20858707}; CC -!- CATALYTIC ACTIVITY: CC Reaction=histamine(out) = histamine(in); Xref=Rhea:RHEA:73879, CC ChEBI:CHEBI:58432; Evidence={ECO:0000269|PubMed:16581093, CC ECO:0000269|PubMed:20858707}; CC -!- CATALYTIC ACTIVITY: CC Reaction=tyramine(in) = tyramine(out); Xref=Rhea:RHEA:74783, CC ChEBI:CHEBI:327995; Evidence={ECO:0000269|PubMed:10196521}; 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:0000269|PubMed:12538837}; 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:0000269|PubMed:17460754}; CC -!- CATALYTIC ACTIVITY: CC Reaction=(R)-salsolinol(in) = (R)-salsolinol(out); CC Xref=Rhea:RHEA:74791, ChEBI:CHEBI:194082; CC Evidence={ECO:0000269|PubMed:17460754}; CC -!- BIOPHYSICOCHEMICAL PROPERTIES: CC Kinetic parameters: CC KM=126 uM for cyclo(his-pro) {ECO:0000269|PubMed:17460754}; CC KM=139 uM for salsolinol {ECO:0000269|PubMed:17460754}; CC KM=220 uM for histamine {ECO:0000269|PubMed:16581093}; CC KM=641 uM for histamine {ECO:0000269|PubMed:20858707}; CC KM=240 uM for adrenaline {ECO:0000269|PubMed:16581093}; CC KM=458 uM for adrenaline {ECO:0000269|PubMed:20858707}; CC KM=923 uM for noradrenaline {ECO:0000269|PubMed:20858707}; CC KM=2630 uM for noradrenaline {ECO:0000269|PubMed:16581093}; CC KM=988 uM for serotonin {ECO:0000269|PubMed:20858707}; CC KM=1033 uM for dopamine {ECO:0000269|PubMed:20858707}; CC KM=2500 uM for agmatine {ECO:0000269|PubMed:12538837}; CC Vmax=0.4 nmol/min/mg enzyme for cyclo(his-pro) uptake CC {ECO:0000269|PubMed:17460754}; CC Vmax=0.5 nmol/min/mg enzyme for salsolinol uptake CC {ECO:0000269|PubMed:17460754}; CC Vmax=34.6 nmol/min/mg enzyme for histamine uptake CC {ECO:0000269|PubMed:20858707}; CC Vmax=12.76 nmol/min/mg enzyme for adrenaline uptake CC {ECO:0000269|PubMed:20858707}; CC Vmax=30.13 nmol/min/mg enzyme for noradrenaline uptake CC {ECO:0000269|PubMed:20858707}; CC Vmax=11.56 nmol/min/mg enzyme for serotonin uptake CC {ECO:0000269|PubMed:20858707}; CC Vmax=22.68 nmol/min/mg enzyme for dopamine uptake CC {ECO:0000269|PubMed:20858707}; CC Vmax=15.9 nmol/min/mg enzyme for agmatine uptake CC {ECO:0000269|PubMed:12538837}; CC pH dependence: CC Optimum pH is 8.5 for agmatine and MPP(+) transport. CC {ECO:0000269|PubMed:12538837}; CC -!- INTERACTION: CC O75751; P00519: ABL1; NbExp=2; IntAct=EBI-1752674, EBI-375543; CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:15817714, CC ECO:0000269|PubMed:20858707}; Multi-pass membrane protein CC {ECO:0000305}. Apical cell membrane {ECO:0000269|PubMed:15817714, CC ECO:0000269|PubMed:16263091}; Multi-pass membrane protein CC {ECO:0000305}. Basolateral cell membrane {ECO:0000269|PubMed:15817714}; CC Multi-pass membrane protein {ECO:0000305}. Mitochondrion membrane CC {ECO:0000250|UniProtKB:O88446}. Endomembrane system CC {ECO:0000250|UniProtKB:O88446}. Nucleus membrane CC {ECO:0000250|UniProtKB:O88446}. Nucleus outer membrane CC {ECO:0000250|UniProtKB:O88446}. Note=Localized to the apical/brush CC border membrane of enterocytes (PubMed:16263091). Localized to the CC luminal/apical membrane of ciliated epithelial cells in bronchi CC (PubMed:15817714). Localized to the basolateral membrane of CC intermediate cells in bronchi (PubMed:15817714). Localized to the CC entire plasma membrane of basal cells in bronchi (PubMed:15817714). CC {ECO:0000269|PubMed:15817714, ECO:0000269|PubMed:16263091}. CC -!- TISSUE SPECIFICITY: Expressed in liver (PubMed:10196521, CC PubMed:9933568). Expressed in intestine (PubMed:16263091, CC PubMed:20858707). Expressed in kidney in proximal tubular cells CC (PubMed:10966924). Expressed in placenta (PubMed:9933568, CC PubMed:10966924). Expressed throughout the brain, including cerebral CC cortex, cerebrellum, substancia nigra, medulla oblongata, hippocampus, CC caudate nucleus, nucleus accumbens and pons with low levels of CC expression detected in nearly all brain regions (PubMed:10196521, CC PubMed:20858707). In testis, mostly localized to peritubular myoid CC cells and Leydig cells, and weakly expressed in developing germ cells CC (PubMed:35307651). Expressed in tracheal and bronchial epithelium of CC the respiratory tract, where it localizes to the apical membrane of CC ciliated cells, the entire membrane of basal cells and the basolateral CC membrane of intermediate cells (PubMed:15817714). Expressed in skeletal CC muscle, adrenal gland, heart, prostate, aorta, salivary gland, adrenal CC gland, uterus, lymph node, lung, trachea and spinal cord CC (PubMed:10196521, PubMed:9933568, PubMed:20858707). Expressed in fetal CC lung and liver (PubMed:9933568). {ECO:0000269|PubMed:10196521, CC ECO:0000269|PubMed:10966924, ECO:0000269|PubMed:15817714, CC ECO:0000269|PubMed:16263091, ECO:0000269|PubMed:20858707, CC ECO:0000269|PubMed:35307651, ECO:0000269|PubMed:9933568}. CC -!- DOMAIN: Contains one proline-rich sequence (Pro-Glu-Ser-Pro-Arg) that CC is required for transport activity. {ECO:0000305|PubMed:26979622}. CC -!- MISCELLANEOUS: Mediates the uptake of clinically used drugs including CC neurotoxin 1-methyl-4-phenylpyridinium (MPP(+)) and platinum-based drug CC oxaliplatin (PubMed:10196521, PubMed:10966924, PubMed:12538837, CC PubMed:15817714, PubMed:16263091, PubMed:16914559, PubMed:16581093, CC PubMed:20858707). Plays a role in the anticancer activity of CC oxaliplatin and may contribute to antitumor specificity CC (PubMed:16914559). {ECO:0000269|PubMed:10196521, CC ECO:0000269|PubMed:10966924, ECO:0000269|PubMed:12538837, CC ECO:0000269|PubMed:15817714, ECO:0000269|PubMed:16263091, CC ECO:0000269|PubMed:16581093, ECO:0000269|PubMed:16914559, CC ECO:0000269|PubMed:20858707}. 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; AJ001417; CAA04751.1; -; mRNA. DR EMBL; AK314590; BAG37164.1; -; mRNA. DR EMBL; AL591069; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AL355506; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471051; EAW47599.1; -; Genomic_DNA. DR EMBL; AF078749; AAD20977.1; -; mRNA. DR CCDS; CCDS5277.1; -. DR RefSeq; NP_068812.1; NM_021977.3. DR PDB; 7ZH0; EM; 3.20 A; A=1-556. DR PDB; 7ZH6; EM; 3.67 A; A=1-556. DR PDB; 7ZHA; EM; 3.55 A; A=1-556. DR PDBsum; 7ZH0; -. DR PDBsum; 7ZH6; -. DR PDBsum; 7ZHA; -. DR AlphaFoldDB; O75751; -. DR EMDB; EMD-14716; -. DR EMDB; EMD-14725; -. DR EMDB; EMD-14728; -. DR SMR; O75751; -. DR BioGRID; 112468; 7. DR IntAct; O75751; 2. DR STRING; 9606.ENSP00000275300; -. DR BindingDB; O75751; -. DR ChEMBL; CHEMBL2073673; -. DR DrugBank; DB00718; Adefovir dipivoxil. DR DrugBank; DB08838; Agmatine. DR DrugBank; DB00182; Amphetamine. DR DrugBank; DB00122; Choline. DR DrugBank; DB14006; Choline salicylate. DR DrugBank; DB00501; Cimetidine. DR DrugBank; DB00575; Clonidine. DR DrugBank; DB01151; Desipramine. DR DrugBank; DB00988; Dopamine. DR DrugBank; DB00783; Estradiol. DR DrugBank; DB13952; Estradiol acetate. DR DrugBank; DB13953; Estradiol benzoate. DR DrugBank; DB13954; Estradiol cypionate. DR DrugBank; DB13955; Estradiol dienanthate. DR DrugBank; DB13956; Estradiol valerate. DR DrugBank; DB00983; Formoterol. DR DrugBank; DB00536; Guanidine. DR DrugBank; DB05381; Histamine. DR DrugBank; DB00458; Imipramine. DR DrugBank; DB00762; Irinotecan. DR DrugBank; DB00709; Lamivudine. DR DrugBank; DB00448; Lansoprazole. DR DrugBank; DB08882; Linagliptin. DR DrugBank; DB01042; Melphalan. DR DrugBank; DB01577; Metamfetamine. DR DrugBank; DB00331; Metformin. DR DrugBank; DB08893; Mirabegron. DR DrugBank; DB00184; Nicotine. DR DrugBank; DB00368; Norepinephrine. DR DrugBank; DB00526; Oxaliplatin. DR DrugBank; DB00925; Phenoxybenzamine. DR DrugBank; DB00413; Pramipexole. DR DrugBank; DB00457; Prazosin. DR DrugBank; DB01035; Procainamide. DR DrugBank; DB00396; Progesterone. DR DrugBank; DB00938; Salmeterol. DR DrugBank; DB00391; Sulpiride. DR DrugBank; DB13943; Testosterone cypionate. DR DrugBank; DB13944; Testosterone enanthate. DR DrugBank; DB08837; Tetraethylammonium. DR DrugBank; DB08841; Tyramine. DR DrugBank; DB00541; Vincristine. DR DrugCentral; O75751; -. DR GuidetoPHARMACOLOGY; 1021; -. DR TCDB; 2.A.1.19.24; the major facilitator superfamily (mfs). DR GlyCosmos; O75751; 4 sites, No reported glycans. DR GlyGen; O75751; 4 sites. DR iPTMnet; O75751; -. DR PhosphoSitePlus; O75751; -. DR SwissPalm; O75751; -. DR BioMuta; SLC22A3; -. DR jPOST; O75751; -. DR MassIVE; O75751; -. DR PaxDb; 9606-ENSP00000275300; -. DR PeptideAtlas; O75751; -. DR ProteomicsDB; 50179; -. DR Pumba; O75751; -. DR Antibodypedia; 20034; 244 antibodies from 34 providers. DR DNASU; 6581; -. DR Ensembl; ENST00000275300.3; ENSP00000275300.2; ENSG00000146477.6. DR GeneID; 6581; -. DR KEGG; hsa:6581; -. DR MANE-Select; ENST00000275300.3; ENSP00000275300.2; NM_021977.4; NP_068812.1. DR UCSC; uc003qti.5; human. DR AGR; HGNC:10967; -. DR CTD; 6581; -. DR DisGeNET; 6581; -. DR GeneCards; SLC22A3; -. DR HGNC; HGNC:10967; SLC22A3. DR HPA; ENSG00000146477; Tissue enhanced (skeletal). DR MIM; 604842; gene. DR neXtProt; NX_O75751; -. DR OpenTargets; ENSG00000146477; -. DR PharmGKB; PA330; -. DR VEuPathDB; HostDB:ENSG00000146477; -. DR eggNOG; KOG0255; Eukaryota. DR GeneTree; ENSGT00940000160810; -. DR HOGENOM; CLU_001265_33_5_1; -. DR InParanoid; O75751; -. DR OMA; NYWCRIP; -. DR OrthoDB; 1474205at2759; -. DR PhylomeDB; O75751; -. DR TreeFam; TF315847; -. DR PathwayCommons; O75751; -. DR Reactome; R-HSA-2161517; Abacavir transmembrane transport. DR Reactome; R-HSA-549127; Organic cation transport. DR SignaLink; O75751; -. DR BioGRID-ORCS; 6581; 14 hits in 1148 CRISPR screens. DR ChiTaRS; SLC22A3; human. DR GeneWiki; SLC22A3; -. DR GenomeRNAi; 6581; -. DR Pharos; O75751; Tchem. DR PRO; PR:O75751; -. DR Proteomes; UP000005640; Chromosome 6. DR RNAct; O75751; Protein. DR Bgee; ENSG00000146477; Expressed in thoracic aorta and 123 other cell types or tissues. DR GO; GO:0016324; C:apical plasma membrane; IDA:UniProtKB. DR GO; GO:0016323; C:basolateral plasma membrane; IDA:UniProtKB. DR GO; GO:0012505; C:endomembrane system; ISS:UniProtKB. DR GO; GO:0016020; C:membrane; TAS:ProtInc. DR GO; GO:0031966; C:mitochondrial membrane; ISS:UniProtKB. DR GO; GO:0043025; C:neuronal cell body; IEA:Ensembl. DR GO; GO:0005640; C:nuclear outer membrane; IEA:UniProtKB-SubCell. DR GO; GO:0005886; C:plasma membrane; IDA:ARUK-UCL. DR GO; GO:0098793; C:presynapse; IEA:GOC. DR GO; GO:0008504; F:monoamine transmembrane transporter activity; IDA:UniProtKB. DR GO; GO:0005326; F:neurotransmitter transmembrane transporter activity; IDA:UniProtKB. DR GO; GO:0008514; F:organic anion transmembrane transporter activity; ISS:ARUK-UCL. DR GO; GO:0015101; F:organic cation transmembrane transporter activity; IDA:UniProtKB. 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; IDA:ARUK-UCL. DR GO; GO:0015872; P:dopamine transport; IDA:UniProtKB. DR GO; GO:0090494; P:dopamine uptake; IDA:ARUK-UCL. DR GO; GO:0048241; P:epinephrine transport; IDA:UniProtKB. DR GO; GO:0051625; P:epinephrine uptake; IDA:ARUK-UCL. DR GO; GO:0001692; P:histamine metabolic process; TAS:ARUK-UCL. DR GO; GO:0051608; P:histamine transport; IDA:UniProtKB. DR GO; GO:0051615; P:histamine uptake; IDA:ARUK-UCL. DR GO; GO:0015844; P:monoamine transport; IMP:ARUK-UCL. DR GO; GO:0006811; P:monoatomic ion transport; IEA:UniProtKB-KW. DR GO; GO:0015718; P:monocarboxylic acid transport; IEA:Ensembl. DR GO; GO:0006836; P:neurotransmitter transport; IDA:ARUK-UCL. DR GO; GO:0015874; P:norepinephrine transport; IDA:UniProtKB. DR GO; GO:0051620; P:norepinephrine uptake; IDA:ARUK-UCL. DR GO; GO:0015711; P:organic anion transport; ISS:ARUK-UCL. DR GO; GO:0015695; P:organic cation transport; IDA:MGI. DR GO; GO:0072530; P:purine-containing compound transmembrane transport; TAS:Reactome. DR GO; GO:0015697; P:quaternary ammonium group transport; IDA:MGI. DR GO; GO:0032098; P:regulation of appetite; IEA:Ensembl. DR GO; GO:0006837; P:serotonin transport; IDA:UniProtKB. DR GO; GO:0051610; P:serotonin uptake; IDA:ARUK-UCL. DR GO; GO:0015848; P:spermidine transport; ISS:UniProtKB. DR GO; GO:1901998; P:toxin transport; IDA:ARUK-UCL. DR GO; GO:0150104; P:transport across blood-brain barrier; NAS:ARUK-UCL. DR GO; GO:0042908; P:xenobiotic transport; IDA:ARUK-UCL. DR CDD; cd17379; MFS_SLC22A1_2_3; 1. DR Gene3D; 1.20.1250.20; MFS general substrate transporter like domains; 1. DR InterPro; IPR011701; MFS. DR InterPro; IPR020846; MFS_dom. 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; PF07690; MFS_1; 1. DR SUPFAM; SSF103473; MFS general substrate transporter; 1. DR PROSITE; PS50850; MFS; 1. DR PROSITE; PS00216; SUGAR_TRANSPORT_1; 1. DR Genevisible; O75751; HS. PE 1: Evidence at protein level; KW 3D-structure; Cell membrane; Glycoprotein; Ion transport; Membrane; KW Mitochondrion; Nucleus; Reference proteome; Transmembrane; KW Transmembrane helix; Transport. FT CHAIN 1..556 FT /note="Solute carrier family 22 member 3" FT /id="PRO_0000220503" FT TRANSMEM 21..41 FT /note="Helical" FT /evidence="ECO:0000255" FT TRANSMEM 182..202 FT /note="Helical" FT /evidence="ECO:0000255" FT TRANSMEM 241..261 FT /note="Helical" FT /evidence="ECO:0000255" FT TRANSMEM 269..289 FT /note="Helical" FT /evidence="ECO:0000255" FT TRANSMEM 381..401 FT /note="Helical" FT /evidence="ECO:0000255" FT TRANSMEM 468..488 FT /note="Helical" FT /evidence="ECO:0000255" FT TRANSMEM 498..518 FT /note="Helical" FT /evidence="ECO:0000255" FT MOTIF 289..293 FT /note="Proline-rich sequence" FT /evidence="ECO:0000305|PubMed:26979622" 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 119 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 322 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT VARIANT 44 FT /note="T -> M (in dbSNP:rs8187715)" FT /id="VAR_020351" FT VARIANT 116 FT /note="A -> S (in dbSNP:rs8187717)" FT /id="VAR_020352" FT MUTAGEN 289 FT /note="P->A: Decreased TEA uptake." FT /evidence="ECO:0000269|PubMed:26979622" FT MUTAGEN 363 FT /note="V->F: Decreased TEA uptake." FT /evidence="ECO:0000269|PubMed:26979622" FT MUTAGEN 380 FT /note="Y->F: Decreased TEA uptake." FT /evidence="ECO:0000269|PubMed:26979622" FT HELIX 3..10 FT /evidence="ECO:0007829|PDB:7ZH0" FT HELIX 16..37 FT /evidence="ECO:0007829|PDB:7ZH0" FT HELIX 38..41 FT /evidence="ECO:0007829|PDB:7ZH0" FT STRAND 49..51 FT /evidence="ECO:0007829|PDB:7ZH0" FT HELIX 54..63 FT /evidence="ECO:0007829|PDB:7ZH0" FT HELIX 67..73 FT /evidence="ECO:0007829|PDB:7ZH0" FT STRAND 90..93 FT /evidence="ECO:0007829|PDB:7ZH0" FT HELIX 95..98 FT /evidence="ECO:0007829|PDB:7ZH0" FT STRAND 118..120 FT /evidence="ECO:0007829|PDB:7ZH0" FT STRAND 124..126 FT /evidence="ECO:0007829|PDB:7ZH0" FT STRAND 131..133 FT /evidence="ECO:0007829|PDB:7ZH0" FT HELIX 140..144 FT /evidence="ECO:0007829|PDB:7ZH0" FT HELIX 148..153 FT /evidence="ECO:0007829|PDB:7ZH0" FT HELIX 154..178 FT /evidence="ECO:0007829|PDB:7ZH0" FT HELIX 181..200 FT /evidence="ECO:0007829|PDB:7ZH0" FT HELIX 205..233 FT /evidence="ECO:0007829|PDB:7ZH0" FT HELIX 239..263 FT /evidence="ECO:0007829|PDB:7ZH0" FT HELIX 267..275 FT /evidence="ECO:0007829|PDB:7ZH0" FT HELIX 277..282 FT /evidence="ECO:0007829|PDB:7ZH0" FT HELIX 285..287 FT /evidence="ECO:0007829|PDB:7ZH0" FT HELIX 292..295 FT /evidence="ECO:0007829|PDB:7ZH0" FT TURN 296..299 FT /evidence="ECO:0007829|PDB:7ZH0" FT HELIX 302..311 FT /evidence="ECO:0007829|PDB:7ZH0" FT HELIX 338..341 FT /evidence="ECO:0007829|PDB:7ZH0" FT HELIX 345..372 FT /evidence="ECO:0007829|PDB:7ZH0" FT HELIX 379..388 FT /evidence="ECO:0007829|PDB:7ZH0" FT HELIX 390..404 FT /evidence="ECO:0007829|PDB:7ZH0" FT HELIX 407..425 FT /evidence="ECO:0007829|PDB:7ZH0" FT STRAND 426..428 FT /evidence="ECO:0007829|PDB:7ZH0" FT HELIX 434..460 FT /evidence="ECO:0007829|PDB:7ZH0" FT STRAND 463..465 FT /evidence="ECO:0007829|PDB:7ZH0" FT HELIX 466..469 FT /evidence="ECO:0007829|PDB:7ZH0" FT HELIX 472..494 FT /evidence="ECO:0007829|PDB:7ZH0" FT HELIX 498..508 FT /evidence="ECO:0007829|PDB:7ZH0" FT HELIX 510..513 FT /evidence="ECO:0007829|PDB:7ZH0" FT TURN 514..516 FT /evidence="ECO:0007829|PDB:7ZH0" FT HELIX 528..531 FT /evidence="ECO:0007829|PDB:7ZH0" SQ SEQUENCE 556 AA; 61280 MW; C3CA2D77DD21C658 CRC64; MPSFDEALQR VGEFGRFQRR VFLLLCLTGV TFAFLFVGVV FLGTQPDHYW CRGPSAAALA ERCGWSPEEE WNRTAPASRG PEPPERRGRC QRYLLEAAND SASATSALSC ADPLAAFPNR SAPLVPCRGG WRYAQAHSTI VSEFDLVCVN AWMLDLTQAI LNLGFLTGAF TLGYAADRYG RIVIYLLSCL GVGVTGVVVA FAPNFPVFVI FRFLQGVFGK GTWMTCYVIV TEIVGSKQRR IVGIVIQMFF TLGIIILPGI AYFIPNWQGI QLAITLPSFL FLLYYWVVPE SPRWLITRKK GDKALQILRR IAKCNGKYLS SNYSEITVTD EEVSNPSFLD LVRTPQMRKC TLILMFAWFT SAVVYQGLVM RLGIIGGNLY IDFFISGVVE LPGALLILLT IERLGRRLPF AASNIVAGVA CLVTAFLPEG IAWLRTTVAT LGRLGITMAF EIVYLVNSEL YPTTLRNFGV SLCSGLCDFG GIIAPFLLFR LAAVWLELPL IIFGILASIC GGLVMLLPET KGIALPETVD DVEKLGSPHS CKCGRNKKTP VSRSHL //