ID SC6A2_HUMAN Reviewed; 617 AA. AC P23975; B2R707; B4DX48; Q96KH8; DT 01-MAR-1992, integrated into UniProtKB/Swiss-Prot. DT 01-MAR-1992, sequence version 1. DT 24-JAN-2024, entry version 211. DE RecName: Full=Sodium-dependent noradrenaline transporter; DE AltName: Full=Norepinephrine transporter; DE Short=NET; DE AltName: Full=Solute carrier family 6 member 2; GN Name=SLC6A2; Synonyms=NAT1, NET1, SLC6A5; 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] (ISOFORM 1), FUNCTION, TRANSPORTER ACTIVITY, RP BIOPHYSICOCHEMICAL PROPERTIES, AND ACTIVITY REGULATION. RX PubMed=2008212; DOI=10.1038/350350a0; RA Pacholczyk T., Blakely R.D., Amara S.G.; RT "Expression cloning of a cocaine- and antidepressant-sensitive human RT noradrenaline transporter."; RL Nature 350:350-354(1991). RN [2] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RC TISSUE=Lung; RX PubMed=7488042; DOI=10.1006/bbrc.1995.2582; RA Poerzgen P., Boenisch H., Bruss M.; RT "Molecular cloning and organization of the coding region of the human RT norepinephrine transporter gene."; RL Biochem. Biophys. Res. Commun. 215:1145-1150(1995). RN [3] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM 2), AND ALTERNATIVE SPLICING. RC TISSUE=Lung; RX PubMed=9655936; DOI=10.1016/s0167-4781(98)00072-4; RA Porzgen P., Bonisch H., Hammermann R., Bruss M.; RT "The human noradrenaline transporter gene contains multiple polyadenylation RT sites and two alternatively spliced C-terminal exons."; RL Biochim. Biophys. Acta 1398:365-370(1998). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 3). RC TISSUE=Testis; 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 [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15616553; DOI=10.1038/nature03187; RA Martin J., Han C., Gordon L.A., Terry A., Prabhakar S., She X., Xie G., RA Hellsten U., Chan Y.M., Altherr M., Couronne O., Aerts A., Bajorek E., RA Black S., Blumer H., Branscomb E., Brown N.C., Bruno W.J., Buckingham J.M., RA Callen D.F., Campbell C.S., Campbell M.L., Campbell E.W., Caoile C., RA Challacombe J.F., Chasteen L.A., Chertkov O., Chi H.C., Christensen M., RA Clark L.M., Cohn J.D., Denys M., Detter J.C., Dickson M., RA Dimitrijevic-Bussod M., Escobar J., Fawcett J.J., Flowers D., Fotopulos D., RA Glavina T., Gomez M., Gonzales E., Goodstein D., Goodwin L.A., Grady D.L., RA Grigoriev I., Groza M., Hammon N., Hawkins T., Haydu L., Hildebrand C.E., RA Huang W., Israni S., Jett J., Jewett P.B., Kadner K., Kimball H., RA Kobayashi A., Krawczyk M.-C., Leyba T., Longmire J.L., Lopez F., Lou Y., RA Lowry S., Ludeman T., Manohar C.F., Mark G.A., McMurray K.L., Meincke L.J., RA Morgan J., Moyzis R.K., Mundt M.O., Munk A.C., Nandkeshwar R.D., RA Pitluck S., Pollard M., Predki P., Parson-Quintana B., Ramirez L., Rash S., RA Retterer J., Ricke D.O., Robinson D.L., Rodriguez A., Salamov A., RA Saunders E.H., Scott D., Shough T., Stallings R.L., Stalvey M., RA Sutherland R.D., Tapia R., Tesmer J.G., Thayer N., Thompson L.S., Tice H., RA Torney D.C., Tran-Gyamfi M., Tsai M., Ulanovsky L.E., Ustaszewska A., RA Vo N., White P.S., Williams A.L., Wills P.L., Wu J.-R., Wu K., Yang J., RA DeJong P., Bruce D., Doggett N.A., Deaven L., Schmutz J., Grimwood J., RA Richardson P., Rokhsar D.S., Eichler E.E., Gilna P., Lucas S.M., RA Myers R.M., Rubin E.M., Pennacchio L.A.; RT "The sequence and analysis of duplication-rich human chromosome 16."; RL Nature 432:988-994(2004). RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.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 (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [7] RP FUNCTION, TRANSPORTER ACTIVITY, AND BIOPHYSICOCHEMICAL PROPERTIES. RX PubMed=8125921; DOI=10.1016/s0021-9258(17)37256-3; RA Gu H., Wall S.C., Rudnick G.; RT "Stable expression of biogenic amine transporters reveals differences in RT inhibitor sensitivity, kinetics, and ion dependence."; RL J. Biol. Chem. 269:7124-7130(1994). RN [8] RP FUNCTION, TRANSPORTER ACTIVITY, AND BIOPHYSICOCHEMICAL PROPERTIES. RX PubMed=11093780; DOI=10.1124/mol.58.6.1404; RA Syringas M., Janin F., Mezghanni S., Giros B., Costentin J., Bonnet J.J.; RT "Structural domains of chimeric dopamine-noradrenaline human transporters RT involved in the Na(+)- and Cl(-)-dependence of dopamine transport."; RL Mol. Pharmacol. 58:1404-1411(2000). RN [9] RP INTERACTION WITH PRKCABP, AND SUBCELLULAR LOCATION. RX PubMed=11343649; DOI=10.1016/s0896-6273(01)00267-7; RA Torres G.E., Yao W.-D., Mohn A.R., Quan H., Kim K.-M., Levey A.I., RA Staudinger J., Caron M.G.; RT "Functional interaction between monoamine plasma membrane transporters and RT the synaptic PDZ domain-containing protein PICK1."; RL Neuron 30:121-134(2001). RN [10] RP VARIANT OI PRO-457. RX PubMed=10684912; DOI=10.1056/nejm200002243420803; RA Shannon J.R., Flattem N.L., Jordan J., Jacob G., Black B.K., Biaggioni I., RA Blakely R.D., Robertson D.; RT "Orthostatic intolerance and tachycardia associated with norepinephrine- RT transporter deficiency."; RL N. Engl. J. Med. 342:541-549(2000). CC -!- FUNCTION: Mediates sodium- and chloride-dependent transport of CC norepinephrine (also known as noradrenaline) (PubMed:2008212, CC PubMed:8125921). Can also mediate sodium- and chloride-dependent CC transport of dopamine (PubMed:8125921, PubMed:11093780). CC {ECO:0000269|PubMed:11093780, ECO:0000269|PubMed:2008212, CC ECO:0000269|PubMed:8125921}. CC -!- CATALYTIC ACTIVITY: CC Reaction=(R)-noradrenaline(out) + chloride(out) + Na(+)(out) = (R)- CC noradrenaline(in) + chloride(in) + Na(+)(in); Xref=Rhea:RHEA:70923, CC ChEBI:CHEBI:17996, ChEBI:CHEBI:29101, ChEBI:CHEBI:72587; CC Evidence={ECO:0000269|PubMed:2008212, ECO:0000269|PubMed:8125921}; CC -!- CATALYTIC ACTIVITY: CC Reaction=chloride(out) + dopamine(out) + Na(+)(out) = chloride(in) + CC dopamine(in) + Na(+)(in); Xref=Rhea:RHEA:70919, ChEBI:CHEBI:17996, CC ChEBI:CHEBI:29101, ChEBI:CHEBI:59905; CC Evidence={ECO:0000269|PubMed:11093780}; CC -!- CATALYTIC ACTIVITY: CC Reaction=chloride(out) + dopamine(out) + 2 Na(+)(out) = chloride(in) + CC dopamine(in) + 2 Na(+)(in); Xref=Rhea:RHEA:70931, ChEBI:CHEBI:17996, CC ChEBI:CHEBI:29101, ChEBI:CHEBI:59905; CC Evidence={ECO:0000269|PubMed:8125921}; CC -!- ACTIVITY REGULATION: Inhibited by mazindol, desipramine, nomifensine CC and nortriptyline. {ECO:0000269|PubMed:2008212}. CC -!- BIOPHYSICOCHEMICAL PROPERTIES: CC Kinetic parameters: CC KM=457 nM for noradrenaline {ECO:0000269|PubMed:2008212}; CC KM=0.58 uM for noradrenaline {ECO:0000269|PubMed:8125921}; CC KM=0.24 uM for dopamine {ECO:0000269|PubMed:8125921}; CC KM=100 mM for Na(+) in dopamine transport CC {ECO:0000269|PubMed:11093780}; CC KM=27 mM for Cl(-) in dopamine transport CC {ECO:0000269|PubMed:11093780}; CC Vmax=17 pmol/min/mg enzyme for noradrenaline CC {ECO:0000269|PubMed:8125921}; CC Vmax=32 pmol/min/mg enzyme for dopamine {ECO:0000269|PubMed:8125921}; CC -!- SUBUNIT: Interacts with PRKCABP. {ECO:0000269|PubMed:11343649}. CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:11343649}; CC Multi-pass membrane protein {ECO:0000255}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Name=1; CC IsoId=P23975-1; Sequence=Displayed; CC Name=2; CC IsoId=P23975-2; Sequence=VSP_044479; CC Name=3; CC IsoId=P23975-3; Sequence=VSP_054119; CC -!- DISEASE: Orthostatic intolerance (OI) [MIM:604715]: An autosomal CC dominant disorder characterized by lightheadedness, palpitations, CC fatigue, blurred vision and tachycardia following postural change from CC a supine to an upright position, in the absence of hypotension. A CC syncope with transient cognitive impairment and dyspnea may also occur. CC Plasma norepinephrine concentration is abnormally high. CC {ECO:0000269|PubMed:10684912}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- MISCELLANEOUS: This protein is the target of psychomotor stimulants CC such as amphetamines or cocaine. CC -!- SIMILARITY: Belongs to the sodium:neurotransmitter symporter (SNF) CC (TC 2.A.22) family. SLC6A2 subfamily. {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; M65105; AAA59943.1; -; mRNA. DR EMBL; X91117; CAA62566.1; -; Genomic_DNA. DR EMBL; X91120; CAA62566.1; JOINED; Genomic_DNA. DR EMBL; X91121; CAA62566.1; JOINED; Genomic_DNA. DR EMBL; X91122; CAA62566.1; JOINED; Genomic_DNA. DR EMBL; X91123; CAA62566.1; JOINED; Genomic_DNA. DR EMBL; X91124; CAA62566.1; JOINED; Genomic_DNA. DR EMBL; X91125; CAA62566.1; JOINED; Genomic_DNA. DR EMBL; X91126; CAA62566.1; JOINED; Genomic_DNA. DR EMBL; X91127; CAA62566.1; JOINED; Genomic_DNA. DR EMBL; X91118; CAA62566.1; JOINED; Genomic_DNA. DR EMBL; X91119; CAA62566.1; JOINED; Genomic_DNA. DR EMBL; X91117; CAC39181.1; -; Genomic_DNA. DR EMBL; X91118; CAC39181.1; JOINED; Genomic_DNA. DR EMBL; X91119; CAC39181.1; JOINED; Genomic_DNA. DR EMBL; X91120; CAC39181.1; JOINED; Genomic_DNA. DR EMBL; X91121; CAC39181.1; JOINED; Genomic_DNA. DR EMBL; X91122; CAC39181.1; JOINED; Genomic_DNA. DR EMBL; X91123; CAC39181.1; JOINED; Genomic_DNA. DR EMBL; X91124; CAC39181.1; JOINED; Genomic_DNA. DR EMBL; X91125; CAC39181.1; JOINED; Genomic_DNA. DR EMBL; X91126; CAC39181.1; JOINED; Genomic_DNA. DR EMBL; X91127; CAC39181.1; JOINED; Genomic_DNA. DR EMBL; AK301811; BAG63260.1; -; mRNA. DR EMBL; AK312793; BAG35654.1; -; mRNA. DR EMBL; AC136621; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471092; EAW82831.1; -; Genomic_DNA. DR EMBL; CH471092; EAW82833.1; -; Genomic_DNA. DR EMBL; CH471092; EAW82835.1; -; Genomic_DNA. DR CCDS; CCDS10754.1; -. [P23975-1] DR CCDS; CCDS54011.1; -. [P23975-2] DR CCDS; CCDS58463.1; -. [P23975-3] DR PIR; S14278; S14278. DR RefSeq; NP_001034.1; NM_001043.3. [P23975-1] DR RefSeq; NP_001165972.1; NM_001172501.1. [P23975-1] DR RefSeq; NP_001165973.1; NM_001172502.1. [P23975-3] DR RefSeq; NP_001165975.1; NM_001172504.1. [P23975-2] DR RefSeq; XP_006721326.1; XM_006721263.2. [P23975-2] DR RefSeq; XP_011521597.1; XM_011523295.1. [P23975-2] DR AlphaFoldDB; P23975; -. DR SMR; P23975; -. DR BioGRID; 112421; 3. DR MINT; P23975; -. DR STRING; 9606.ENSP00000219833; -. DR BindingDB; P23975; -. DR ChEMBL; CHEMBL222; -. DR DrugBank; DB04836; Amineptine. DR DrugBank; DB05964; Amitifadine. DR DrugBank; DB00321; Amitriptyline. DR DrugBank; DB00543; Amoxapine. DR DrugBank; DB00182; Amphetamine. DR DrugBank; DB00289; Atomoxetine. DR DrugBank; DB00245; Benzatropine. DR DrugBank; DB04889; Bicifadine. DR DrugBank; DB01156; Bupropion. DR DrugBank; DB01114; Chlorpheniramine. DR DrugBank; DB01242; Clomipramine. DR DrugBank; DB00907; Cocaine. DR DrugBank; DB05688; CRx-119. DR DrugBank; DB00924; Cyclobenzaprine. DR DrugBank; DB12305; Dasotraline. DR DrugBank; DB05642; DDP-225. DR DrugBank; DB04840; Debrisoquine. DR DrugBank; DB01151; Desipramine. DR DrugBank; DB06700; Desvenlafaxine. DR DrugBank; DB06701; Dexmethylphenidate. DR DrugBank; DB01576; Dextroamphetamine. DR DrugBank; DB00514; Dextromethorphan. DR DrugBank; DB00937; Diethylpropion. DR DrugBank; DB00988; Dopamine. DR DrugBank; DB09167; Dosulepin. DR DrugBank; DB01142; Doxepin. DR DrugBank; DB06262; Droxidopa. DR DrugBank; DB00476; Duloxetine. DR DrugBank; DB01363; Ephedra sinica root. DR DrugBank; DB01364; Ephedrine. DR DrugBank; DB01175; Escitalopram. DR DrugBank; DB09194; Etoperidone. DR DrugBank; DB01381; Ginkgo biloba. DR DrugBank; DB00226; Guanadrel. DR DrugBank; DB01170; Guanethidine. DR DrugBank; DB00458; Imipramine. DR DrugBank; DB06704; Iobenguane. DR DrugBank; DB09546; Iobenguane sulfate I-123. DR DrugBank; DB01221; Ketamine. DR DrugBank; DB08918; Levomilnacipran. DR DrugBank; DB00408; Loxapine. DR DrugBank; DB00934; Maprotiline. DR DrugBank; DB00579; Mazindol. DR DrugBank; DB00454; Meperidine. DR DrugBank; DB01577; Metamfetamine. DR DrugBank; DB00422; Methylphenidate. DR DrugBank; DB06148; Mianserin. DR DrugBank; DB01454; Midomafetamine. DR DrugBank; DB04896; Milnacipran. DR DrugBank; DB01442; MMDA. DR DrugBank; DB01149; Nefazodone. DR DrugBank; DB13931; Netarsudil. DR DrugBank; DB04821; Nomifensine. DR DrugBank; DB00368; Norepinephrine. DR DrugBank; DB00540; Nortriptyline. DR DrugBank; DB01173; Orphenadrine. DR DrugBank; DB00715; Paroxetine. DR DrugBank; DB01579; Phendimetrazine. DR DrugBank; DB00830; Phenmetrazine. DR DrugBank; DB00191; Phentermine. DR DrugBank; DB00721; Procaine. DR DrugBank; DB00344; Protriptyline. DR DrugBank; DB00852; Pseudoephedrine. DR DrugBank; DB09363; Rauwolfia serpentina root. DR DrugBank; DB00234; Reboxetine. DR DrugBank; DB16629; Serdexmethylphenidate. DR DrugBank; DB01104; Sertraline. DR DrugBank; DB01105; Sibutramine. DR DrugBank; DB14754; Solriamfetol. DR DrugBank; DB06204; Tapentadol. DR DrugBank; DB06156; Tesofensine. DR DrugBank; DB00193; Tramadol. DR DrugBank; DB00726; Trimipramine. DR DrugBank; DB06333; Trodusquemine. DR DrugBank; DB00285; Venlafaxine. DR DrugBank; DB09185; Viloxazine. DR DrugBank; DB09068; Vortioxetine. DR DrugBank; DB05012; XEN-2174. DR DrugBank; DB09225; Zotepine. DR DrugCentral; P23975; -. DR GuidetoPHARMACOLOGY; 926; -. DR TCDB; 2.A.22.1.2; the neurotransmitter:sodium symporter (nss) family. DR GlyCosmos; P23975; 3 sites, No reported glycans. DR GlyGen; P23975; 3 sites. DR iPTMnet; P23975; -. DR PhosphoSitePlus; P23975; -. DR BioMuta; SLC6A2; -. DR DMDM; 128616; -. DR MassIVE; P23975; -. DR MaxQB; P23975; -. DR PaxDb; 9606-ENSP00000219833; -. DR PeptideAtlas; P23975; -. DR ProteomicsDB; 5409; -. DR ProteomicsDB; 54172; -. [P23975-1] DR ProteomicsDB; 77077; -. DR Antibodypedia; 1363; 151 antibodies from 28 providers. DR DNASU; 6530; -. DR Ensembl; ENST00000219833.13; ENSP00000219833.8; ENSG00000103546.19. [P23975-2] DR Ensembl; ENST00000379906.6; ENSP00000369237.2; ENSG00000103546.19. [P23975-1] DR Ensembl; ENST00000567238.1; ENSP00000457375.1; ENSG00000103546.19. [P23975-3] DR Ensembl; ENST00000568943.6; ENSP00000457473.1; ENSG00000103546.19. [P23975-1] DR GeneID; 6530; -. DR KEGG; hsa:6530; -. DR MANE-Select; ENST00000568943.6; ENSP00000457473.1; NM_001172501.3; NP_001165972.1. DR UCSC; uc002eif.4; human. [P23975-1] DR AGR; HGNC:11048; -. DR CTD; 6530; -. DR DisGeNET; 6530; -. DR GeneCards; SLC6A2; -. DR HGNC; HGNC:11048; SLC6A2. DR HPA; ENSG00000103546; Tissue enhanced (adrenal gland, placenta, skin, testis). DR MalaCards; SLC6A2; -. DR MIM; 163970; gene. DR MIM; 604715; phenotype. DR neXtProt; NX_P23975; -. DR OpenTargets; ENSG00000103546; -. DR Orphanet; 443236; Postural orthostatic tachycardia syndrome due to NET deficiency. DR PharmGKB; PA310; -. DR VEuPathDB; HostDB:ENSG00000103546; -. DR eggNOG; KOG3659; Eukaryota. DR GeneTree; ENSGT00940000158960; -. DR HOGENOM; CLU_006855_9_5_1; -. DR InParanoid; P23975; -. DR OMA; NLWGFAY; -. DR OrthoDB; 3084493at2759; -. DR PhylomeDB; P23975; -. DR TreeFam; TF343812; -. DR PathwayCommons; P23975; -. DR Reactome; R-HSA-442660; Na+/Cl- dependent neurotransmitter transporters. DR Reactome; R-HSA-5619109; Defective SLC6A2 causes orthostatic intolerance (OI). DR SignaLink; P23975; -. DR SIGNOR; P23975; -. DR BioGRID-ORCS; 6530; 14 hits in 1152 CRISPR screens. DR ChiTaRS; SLC6A2; human. DR GeneWiki; Norepinephrine_transporter; -. DR GenomeRNAi; 6530; -. DR Pharos; P23975; Tclin. DR PRO; PR:P23975; -. DR Proteomes; UP000005640; Chromosome 16. DR RNAct; P23975; Protein. DR Bgee; ENSG00000103546; Expressed in placenta and 97 other cell types or tissues. DR ExpressionAtlas; P23975; baseline and differential. DR GO; GO:0009986; C:cell surface; IEA:Ensembl. DR GO; GO:0016020; C:membrane; TAS:ProtInc. DR GO; GO:0043005; C:neuron projection; IBA:GO_Central. DR GO; GO:0032809; C:neuronal cell body membrane; IBA:GO_Central. DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB. DR GO; GO:0042734; C:presynaptic membrane; IBA:GO_Central. DR GO; GO:0003779; F:actin binding; IPI:ARUK-UCL. DR GO; GO:0043014; F:alpha-tubulin binding; IEA:Ensembl. DR GO; GO:0048487; F:beta-tubulin binding; IEA:Ensembl. DR GO; GO:0005330; F:dopamine:sodium symporter activity; IDA:UniProtKB. DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW. DR GO; GO:0008504; F:monoamine transmembrane transporter activity; IDA:MGI. DR GO; GO:0005326; F:neurotransmitter transmembrane transporter activity; ISS:ARUK-UCL. DR GO; GO:0005328; F:neurotransmitter:sodium symporter activity; IEA:InterPro. DR GO; GO:0005334; F:norepinephrine:sodium symporter activity; IDA:UniProtKB. DR GO; GO:0007268; P:chemical synaptic transmission; TAS:ProtInc. DR GO; GO:0051583; P:dopamine uptake involved in synaptic transmission; IBA:GO_Central. DR GO; GO:0015844; P:monoamine transport; IDA:MGI. DR GO; GO:0070050; P:neuron cellular homeostasis; TAS:ARUK-UCL. DR GO; GO:0006836; P:neurotransmitter transport; ISS:ARUK-UCL. DR GO; GO:0015874; P:norepinephrine transport; IBA:GO_Central. DR GO; GO:0051620; P:norepinephrine uptake; ISS:ARUK-UCL. DR GO; GO:0048265; P:response to pain; IEA:Ensembl. DR GO; GO:0009410; P:response to xenobiotic stimulus; IEA:Ensembl. DR GO; GO:0035725; P:sodium ion transmembrane transport; IBA:GO_Central. DR CDD; cd11512; SLC6sbd_NET; 1. DR InterPro; IPR000175; Na/ntran_symport. DR InterPro; IPR002435; Na/ntran_symport_noradrenaline. DR InterPro; IPR037272; SNS_sf. DR PANTHER; PTHR11616:SF307; SODIUM-DEPENDENT NORADRENALINE TRANSPORTER; 1. DR PANTHER; PTHR11616; SODIUM/CHLORIDE DEPENDENT TRANSPORTER; 1. DR Pfam; PF00209; SNF; 1. DR PRINTS; PR00176; NANEUSMPORT. DR PRINTS; PR01201; NORTRANSPORT. DR SUPFAM; SSF161070; SNF-like; 1. DR PROSITE; PS00610; NA_NEUROTRAN_SYMP_1; 1. DR PROSITE; PS00754; NA_NEUROTRAN_SYMP_2; 1. DR PROSITE; PS50267; NA_NEUROTRAN_SYMP_3; 1. DR Genevisible; P23975; HS. PE 1: Evidence at protein level; KW Alternative splicing; Cell membrane; Disease variant; Disulfide bond; KW Glycoprotein; Membrane; Metal-binding; Neurotransmitter transport; KW Reference proteome; Sodium; Symport; Transmembrane; Transmembrane helix; KW Transport. FT CHAIN 1..617 FT /note="Sodium-dependent noradrenaline transporter" FT /id="PRO_0000214748" FT TOPO_DOM 1..62 FT /note="Cytoplasmic" FT /evidence="ECO:0000250|UniProtKB:Q7K4Y6" FT TRANSMEM 63..88 FT /note="Helical; Name=1" FT /evidence="ECO:0000250|UniProtKB:Q7K4Y6" FT TOPO_DOM 89..92 FT /note="Extracellular" FT /evidence="ECO:0000250|UniProtKB:Q7K4Y6" FT TRANSMEM 93..116 FT /note="Helical; Name=2" FT /evidence="ECO:0000250|UniProtKB:Q7K4Y6" FT TOPO_DOM 117..135 FT /note="Cytoplasmic" FT /evidence="ECO:0000250|UniProtKB:Q7K4Y6" FT TRANSMEM 136..166 FT /note="Helical; Name=3" FT /evidence="ECO:0000250|UniProtKB:Q7K4Y6" FT TOPO_DOM 167..233 FT /note="Extracellular" FT /evidence="ECO:0000250|UniProtKB:Q7K4Y6" FT TRANSMEM 234..254 FT /note="Helical; Name=4" FT /evidence="ECO:0000250|UniProtKB:Q7K4Y6" FT TOPO_DOM 255..257 FT /note="Cytoplasmic" FT /evidence="ECO:0000250|UniProtKB:Q7K4Y6" FT TRANSMEM 258..282 FT /note="Helical; Name=5" FT /evidence="ECO:0000250|UniProtKB:Q7K4Y6" FT TOPO_DOM 283..306 FT /note="Extracellular" FT /evidence="ECO:0000250|UniProtKB:Q7K4Y6" FT TRANSMEM 307..332 FT /note="Helical; Name=6" FT /evidence="ECO:0000250|UniProtKB:Q7K4Y6" FT TOPO_DOM 333..338 FT /note="Cytoplasmic" FT /evidence="ECO:0000250|UniProtKB:Q7K4Y6" FT TRANSMEM 339..362 FT /note="Helical; Name=7" FT /evidence="ECO:0000250|UniProtKB:Q7K4Y6" FT TOPO_DOM 363..402 FT /note="Extracellular" FT /evidence="ECO:0000250|UniProtKB:Q7K4Y6" FT TRANSMEM 403..428 FT /note="Helical; Name=8" FT /evidence="ECO:0000250|UniProtKB:Q7K4Y6" FT TOPO_DOM 429..443 FT /note="Cytoplasmic" FT /evidence="ECO:0000250|UniProtKB:Q7K4Y6" FT TRANSMEM 444..464 FT /note="Helical; Name=9" FT /evidence="ECO:0000250|UniProtKB:Q7K4Y6" FT TOPO_DOM 465 FT /note="Extracellular" FT /evidence="ECO:0000250|UniProtKB:Q7K4Y6" FT TRANSMEM 466..492 FT /note="Helical; Name=10" FT /evidence="ECO:0000250|UniProtKB:Q7K4Y6" FT TOPO_DOM 493..522 FT /note="Cytoplasmic" FT /evidence="ECO:0000250|UniProtKB:Q7K4Y6" FT TRANSMEM 523..545 FT /note="Helical; Name=11" FT /evidence="ECO:0000250|UniProtKB:Q7K4Y6" FT TOPO_DOM 546..548 FT /note="Extracellular" FT /evidence="ECO:0000250|UniProtKB:Q7K4Y6" FT TRANSMEM 549..569 FT /note="Helical; Name=12" FT /evidence="ECO:0000250|UniProtKB:Q7K4Y6" FT TOPO_DOM 570..617 FT /note="Cytoplasmic" FT /evidence="ECO:0000250|UniProtKB:Q7K4Y6" FT REGION 1..23 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT BINDING 71 FT /ligand="Na(+)" FT /ligand_id="ChEBI:CHEBI:29101" FT /ligand_label="1" FT /evidence="ECO:0000250|UniProtKB:Q7K4Y6" FT BINDING 73 FT /ligand="Na(+)" FT /ligand_id="ChEBI:CHEBI:29101" FT /ligand_label="2" FT /evidence="ECO:0000250|UniProtKB:Q7K4Y6" FT BINDING 74 FT /ligand="Na(+)" FT /ligand_id="ChEBI:CHEBI:29101" FT /ligand_label="1" FT /evidence="ECO:0000250|UniProtKB:Q7K4Y6" FT BINDING 78 FT /ligand="Na(+)" FT /ligand_id="ChEBI:CHEBI:29101" FT /ligand_label="2" FT /evidence="ECO:0000250|UniProtKB:Q7K4Y6" FT BINDING 318 FT /ligand="Na(+)" FT /ligand_id="ChEBI:CHEBI:29101" FT /ligand_label="2" FT /evidence="ECO:0000250|UniProtKB:Q7K4Y6" FT BINDING 350 FT /ligand="Na(+)" FT /ligand_id="ChEBI:CHEBI:29101" FT /ligand_label="2" FT /evidence="ECO:0000250|UniProtKB:Q7K4Y6" FT BINDING 415 FT /ligand="Na(+)" FT /ligand_id="ChEBI:CHEBI:29101" FT /ligand_label="1" FT /evidence="ECO:0000250|UniProtKB:Q7K4Y6" FT BINDING 418 FT /ligand="Na(+)" FT /ligand_id="ChEBI:CHEBI:29101" FT /ligand_label="1" FT /evidence="ECO:0000250|UniProtKB:Q7K4Y6" FT BINDING 419 FT /ligand="Na(+)" FT /ligand_id="ChEBI:CHEBI:29101" FT /ligand_label="1" FT /evidence="ECO:0000250|UniProtKB:Q7K4Y6" FT CARBOHYD 184 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 192 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 198 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT DISULFID 176..185 FT /evidence="ECO:0000250|UniProtKB:Q7K4Y6" FT VAR_SEQ 1..135 FT /note="MLLARMNPQVQPENNGADTGPEQPLRARKTAELLVVKERNGVQCLLAPRDGD FT AQPRETWGKKIDFLLSVVGFAVDLANVWRFPYLCYKNGGGAFLIPYTLFLIIAGMPLFY FT MELALGQYNREGAATVWKICPFFK -> MGVQWWSHTQGEVAVGLGLGDSYLTPCPCP FT (in isoform 3)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_054119" FT VAR_SEQ 611..617 FT /note="LQHWLAI -> MKTRQGRRRATNSCQISC (in isoform 2)" FT /evidence="ECO:0000305" FT /id="VSP_044479" FT VARIANT 7 FT /note="N -> K (in dbSNP:rs11568323)" FT /id="VAR_029157" FT VARIANT 69 FT /note="V -> I (in dbSNP:rs1805064)" FT /id="VAR_011756" FT VARIANT 99 FT /note="T -> I (in dbSNP:rs1805065)" FT /id="VAR_011757" FT VARIANT 245 FT /note="V -> I (in dbSNP:rs1805066)" FT /id="VAR_011758" FT VARIANT 283 FT /note="T -> R (in dbSNP:rs45564432)" FT /id="VAR_020048" FT VARIANT 292 FT /note="N -> T (in dbSNP:rs5563)" FT /id="VAR_011759" FT VARIANT 356 FT /note="V -> L (in dbSNP:rs5565)" FT /id="VAR_011760" FT VARIANT 369 FT /note="A -> P (in dbSNP:rs5566)" FT /id="VAR_011761" FT VARIANT 375 FT /note="N -> S (in dbSNP:rs5567)" FT /id="VAR_011762" FT VARIANT 449 FT /note="V -> I (in dbSNP:rs2234910)" FT /id="VAR_014800" FT VARIANT 457 FT /note="A -> P (in OI; loss of function; dbSNP:rs121918126)" FT /evidence="ECO:0000269|PubMed:10684912" FT /id="VAR_010022" FT VARIANT 463 FT /note="K -> R (in dbSNP:rs5570)" FT /id="VAR_011763" FT VARIANT 478 FT /note="G -> S (in dbSNP:rs1805067)" FT /id="VAR_011764" FT VARIANT 528 FT /note="F -> C (in dbSNP:rs5558)" FT /id="VAR_011765" FT VARIANT 548 FT /note="Y -> H (in dbSNP:rs5559)" FT /id="VAR_011766" FT VARIANT 549 FT /note="I -> T (in dbSNP:rs3743788)" FT /id="VAR_021861" SQ SEQUENCE 617 AA; 69332 MW; BDC6DF31316907BB CRC64; MLLARMNPQV QPENNGADTG PEQPLRARKT AELLVVKERN GVQCLLAPRD GDAQPRETWG KKIDFLLSVV GFAVDLANVW RFPYLCYKNG GGAFLIPYTL FLIIAGMPLF YMELALGQYN REGAATVWKI CPFFKGVGYA VILIALYVGF YYNVIIAWSL YYLFSSFTLN LPWTDCGHTW NSPNCTDPKL LNGSVLGNHT KYSKYKFTPA AEFYERGVLH LHESSGIHDI GLPQWQLLLC LMVVVIVLYF SLWKGVKTSG KVVWITATLP YFVLFVLLVH GVTLPGASNG INAYLHIDFY RLKEATVWID AATQIFFSLG AGFGVLIAFA SYNKFDNNCY RDALLTSSIN CITSFVSGFA IFSILGYMAH EHKVNIEDVA TEGAGLVFIL YPEAISTLSG STFWAVVFFV MLLALGLDSS MGGMEAVITG LADDFQVLKR HRKLFTFGVT FSTFLLALFC ITKGGIYVLT LLDTFAAGTS ILFAVLMEAI GVSWFYGVDR FSNDIQQMMG FRPGLYWRLC WKFVSPAFLL FVVVVSIINF KPLTYDDYIF PPWANWVGWG IALSSMVLVP IYVIYKFLST QGSLWERLAY GITPENEHHL VAQRDIRQFQ LQHWLAI //