P23975 (SC6A2_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Sodium-dependent noradrenaline transporter

Alternative name(s):
Norepinephrine transporter
Short name=NET
Solute carrier family 6 member 2

Gene names

Name:	SLC6A2
Synonyms:	NAT1, NET1, SLC6A5

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	617 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Amine transporter. Terminates the action of noradrenaline by its high affinity sodium-dependent reuptake into presynaptic terminals.
Subunit structure	Interacts with PRKCABP. Ref.7
Subcellular location	Membrane; Multi-pass membrane protein.
Involvement in disease	Orthostatic intolerance (OI) [MIM:604715]: Syndrome characterized by lightheadedness, fatigue, altered mentation and syncope. It is associated with postural tachycardia. Plasma norepinephrine concentration is abnormally high. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.8
Miscellaneous	This protein is the target of psychomotor stimulants such as amphetamines or cocaine.
Sequence similarities	Belongs to the sodium:neurotransmitter symporter (SNF) (TC 2.A.22) family. SLC6A2 subfamily. [View classification]

Ontologies

Keywords
Biological process	Neurotransmitter transport Symport Transport
Cellular component	Membrane
Coding sequence diversity	Alternative splicing Polymorphism
Disease	Disease mutation
Domain	Transmembrane Transmembrane helix
PTM	Glycoprotein
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	synaptic transmission Traceable author statement Ref.1. Source: ProtInc
Cellular_component	integral to plasma membrane Traceable author statement Ref.1. Source: ProtInc
Molecular_function	norepinephrine:sodium symporter activity Traceable author statement Ref.1. Source: ProtInc
Complete GO annotation...

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: P23975-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform 2 (identifier: P23975-2)

The sequence of this isoform differs from the canonical sequence as follows:
     611-617: LQHWLAI → MKTRQGRRRATNSCQISC

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 617	617	Sodium-dependent noradrenaline transporter		PRO_0000214748
Regions
	Topological domain	1 – 64	64	Cytoplasmic Potential
	Transmembrane	65 – 85	21	Helical; Name=1; Potential
	Transmembrane	93 – 112	20	Helical; Name=2; Potential
	Transmembrane	136 – 156	21	Helical; Name=3; Potential
	Topological domain	157 – 234	78	Extracellular Potential
	Transmembrane	235 – 253	19	Helical; Name=4; Potential
	Transmembrane	262 – 279	18	Helical; Name=5; Potential
	Transmembrane	315 – 332	18	Helical; Name=6; Potential
	Transmembrane	344 – 365	22	Helical; Name=7; Potential
	Transmembrane	398 – 417	20	Helical; Name=8; Potential
	Transmembrane	444 – 462	19	Helical; Name=9; Potential
	Transmembrane	478 – 498	21	Helical; Name=10; Potential
	Transmembrane	519 – 538	20	Helical; Name=11; Potential
	Transmembrane	557 – 575	19	Helical; Name=12; Potential
	Topological domain	576 – 617	42	Cytoplasmic Potential
Amino acid modifications
	Glycosylation	184	1	N-linked (GlcNAc...) Potential
	Glycosylation	192	1	N-linked (GlcNAc...) Potential
	Glycosylation	198	1	N-linked (GlcNAc...) Potential
Natural variations
	Alternative sequence	611 – 617	7	LQHWLAI → MKTRQGRRRATNSCQISC in isoform 2.		VSP_044479
	Natural variant	7	1	N → K. Corresponds to variant rs11568323 [ dbSNP | Ensembl ].		VAR_029157
	Natural variant	69	1	V → I. Corresponds to variant rs1805064 [ dbSNP | Ensembl ].		VAR_011756
	Natural variant	99	1	T → I. Corresponds to variant rs1805065 [ dbSNP | Ensembl ].		VAR_011757
	Natural variant	245	1	V → I. Corresponds to variant rs1805066 [ dbSNP | Ensembl ].		VAR_011758
	Natural variant	283	1	T → R. Corresponds to variant rs45564432 [ dbSNP | Ensembl ].		VAR_020048
	Natural variant	292	1	N → T. Corresponds to variant rs5563 [ dbSNP | Ensembl ].		VAR_011759
	Natural variant	356	1	V → L. Corresponds to variant rs5565 [ dbSNP | Ensembl ].		VAR_011760
	Natural variant	369	1	A → P. Corresponds to variant rs5566 [ dbSNP | Ensembl ].		VAR_011761
	Natural variant	375	1	N → S. Corresponds to variant rs5567 [ dbSNP | Ensembl ].		VAR_011762
	Natural variant	449	1	V → I. Corresponds to variant rs2234910 [ dbSNP | Ensembl ].		VAR_014800
	Natural variant	457	1	A → P in OI; loss of function. Ref.8		VAR_010022
	Natural variant	463	1	K → R. Corresponds to variant rs5570 [ dbSNP | Ensembl ].		VAR_011763
	Natural variant	478	1	G → S. Corresponds to variant rs1805067 [ dbSNP | Ensembl ].		VAR_011764
	Natural variant	528	1	F → C. Corresponds to variant rs5558 [ dbSNP | Ensembl ].		VAR_011765
	Natural variant	548	1	Y → H. Corresponds to variant rs5559 [ dbSNP | Ensembl ].		VAR_011766
	Natural variant	549	1	I → T. Corresponds to variant rs3743788 [ dbSNP | Ensembl ].		VAR_021861

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified March 1, 1992. Version 1. Checksum: BDC6DF31316907BB	FASTA	617	69,332
	10 20 30 40 50 60 MLLARMNPQV QPENNGADTG PEQPLRARKT AELLVVKERN GVQCLLAPRD GDAQPRETWG 70 80 90 100 110 120 KKIDFLLSVV GFAVDLANVW RFPYLCYKNG GGAFLIPYTL FLIIAGMPLF YMELALGQYN 130 140 150 160 170 180 REGAATVWKI CPFFKGVGYA VILIALYVGF YYNVIIAWSL YYLFSSFTLN LPWTDCGHTW 190 200 210 220 230 240 NSPNCTDPKL LNGSVLGNHT KYSKYKFTPA AEFYERGVLH LHESSGIHDI GLPQWQLLLC 250 260 270 280 290 300 LMVVVIVLYF SLWKGVKTSG KVVWITATLP YFVLFVLLVH GVTLPGASNG INAYLHIDFY 310 320 330 340 350 360 RLKEATVWID AATQIFFSLG AGFGVLIAFA SYNKFDNNCY RDALLTSSIN CITSFVSGFA 370 380 390 400 410 420 IFSILGYMAH EHKVNIEDVA TEGAGLVFIL YPEAISTLSG STFWAVVFFV MLLALGLDSS 430 440 450 460 470 480 MGGMEAVITG LADDFQVLKR HRKLFTFGVT FSTFLLALFC ITKGGIYVLT LLDTFAAGTS 490 500 510 520 530 540 ILFAVLMEAI GVSWFYGVDR FSNDIQQMMG FRPGLYWRLC WKFVSPAFLL FVVVVSIINF 550 560 570 580 590 600 KPLTYDDYIF PPWANWVGWG IALSSMVLVP IYVIYKFLST QGSLWERLAY GITPENEHHL 610 VAQRDIRQFQ LQHWLAI
	Isoform 2 [UniParc]. Checksum: 4CF79AD92F272587	FASTA	628	70,548
	10 20 30 40 50 60 MLLARMNPQV QPENNGADTG PEQPLRARKT AELLVVKERN GVQCLLAPRD GDAQPRETWG 70 80 90 100 110 120 KKIDFLLSVV GFAVDLANVW RFPYLCYKNG GGAFLIPYTL FLIIAGMPLF YMELALGQYN 130 140 150 160 170 180 REGAATVWKI CPFFKGVGYA VILIALYVGF YYNVIIAWSL YYLFSSFTLN LPWTDCGHTW 190 200 210 220 230 240 NSPNCTDPKL LNGSVLGNHT KYSKYKFTPA AEFYERGVLH LHESSGIHDI GLPQWQLLLC 250 260 270 280 290 300 LMVVVIVLYF SLWKGVKTSG KVVWITATLP YFVLFVLLVH GVTLPGASNG INAYLHIDFY 310 320 330 340 350 360 RLKEATVWID AATQIFFSLG AGFGVLIAFA SYNKFDNNCY RDALLTSSIN CITSFVSGFA 370 380 390 400 410 420 IFSILGYMAH EHKVNIEDVA TEGAGLVFIL YPEAISTLSG STFWAVVFFV MLLALGLDSS 430 440 450 460 470 480 MGGMEAVITG LADDFQVLKR HRKLFTFGVT FSTFLLALFC ITKGGIYVLT LLDTFAAGTS 490 500 510 520 530 540 ILFAVLMEAI GVSWFYGVDR FSNDIQQMMG FRPGLYWRLC WKFVSPAFLL FVVVVSIINF 550 560 570 580 590 600 KPLTYDDYIF PPWANWVGWG IALSSMVLVP IYVIYKFLST QGSLWERLAY GITPENEHHL 610 620 VAQRDIRQFQ MKTRQGRRRA TNSCQISC

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Expression cloning of a cocaine- and antidepressant-sensitive human noradrenaline transporter." Pacholczyk T., Blakely R.D., Amara S.G. Nature 350:350-354(1991) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
[2]	"Molecular cloning and organization of the coding region of the human norepinephrine transporter gene." Poerzgen P., Boenisch H., Bruss M. Biochem. Biophys. Res. Commun. 215:1145-1150(1995) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA]. Tissue: Lung.
[3]	"The human noradrenaline transporter gene contains multiple polyadenylation sites and two alternatively spliced C-terminal exons." Porzgen P., Bonisch H., Hammermann R., Bruss M. Biochim. Biophys. Acta 1398:365-370(1998) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM 2), ALTERNATIVE SPLICING. Tissue: Lung.
[4]	"Complete sequencing and characterization of 21,243 full-length human cDNAs." Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S. Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). Tissue: Testis.
[5]	"The sequence and analysis of duplication-rich human chromosome 16." Martin J., Han C., Gordon L.A., Terry A., Prabhakar S., She X., Xie G., Hellsten U., Chan Y.M., Altherr M., Couronne O., Aerts A., Bajorek E., Black S., Blumer H., Branscomb E., Brown N.C., Bruno W.J. , Buckingham J.M., Callen D.F., Campbell C.S., Campbell M.L., Campbell E.W., Caoile C., Challacombe J.F., Chasteen L.A., Chertkov O., Chi H.C., Christensen M., Clark L.M., Cohn J.D., Denys M., Detter J.C., Dickson M., Dimitrijevic-Bussod M., Escobar J., Fawcett J.J., Flowers D., Fotopulos D., Glavina T., Gomez M., Gonzales E., Goodstein D., Goodwin L.A., Grady D.L., Grigoriev I., Groza M., Hammon N., Hawkins T., Haydu L., Hildebrand C.E., Huang W., Israni S., Jett J., Jewett P.B., Kadner K., Kimball H., Kobayashi A., Krawczyk M.-C., Leyba T., Longmire J.L., Lopez F., Lou Y., Lowry S., Ludeman T., Manohar C.F., Mark G.A., McMurray K.L., Meincke L.J., Morgan J., Moyzis R.K., Mundt M.O., Munk A.C., Nandkeshwar R.D., Pitluck S., Pollard M., Predki P., Parson-Quintana B., Ramirez L., Rash S., Retterer J., Ricke D.O., Robinson D.L., Rodriguez A., Salamov A., Saunders E.H., Scott D., Shough T., Stallings R.L., Stalvey M., Sutherland R.D., Tapia R., Tesmer J.G., Thayer N., Thompson L.S., Tice H., Torney D.C., Tran-Gyamfi M., Tsai M., Ulanovsky L.E., Ustaszewska A., Vo N., White P.S., Williams A.L., Wills P.L., Wu J.-R., Wu K., Yang J., DeJong P., Bruce D., Doggett N.A., Deaven L., Schmutz J., Grimwood J., Richardson P., Rokhsar D.S., Eichler E.E., Gilna P., Lucas S.M., Myers R.M., Rubin E.M., Pennacchio L.A. Nature 432:988-994(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[6]	Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C. Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[7]	"Functional interaction between monoamine plasma membrane transporters and the synaptic PDZ domain-containing protein PICK1." Torres G.E., Yao W.-D., Mohn A.R., Quan H., Kim K.-M., Levey A.I., Staudinger J., Caron M.G. Neuron 30:121-134(2001) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH PRKCABP.
[8]	"Orthostatic intolerance and tachycardia associated with norepinephrine-transporter deficiency." Shannon J.R., Flattem N.L., Jordan J., Jacob G., Black B.K., Biaggioni I., Blakely R.D., Robertson D. N. Engl. J. Med. 342:541-549(2000) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT OI PRO-457.
+	Additional computationally mapped references.

Web resources

GeneReviews

Cross-references

Sequence databases
EMBL GenBank DDBJ	M65105 mRNA. Translation: AAA59943.1. X91117 , X91120, X91121, X91122, X91123, X91124, X91125, X91126, X91127, X91118, X91119 Genomic DNA. Translation: CAA62566.1. X91117 , X91118, X91119, X91120, X91121, X91122, X91123, X91124, X91125, X91126, X91127 Genomic DNA. Translation: CAC39181.1. AK312793 mRNA. Translation: BAG35654.1. AC136621 Genomic DNA. No translation available. CH471092 Genomic DNA. Translation: EAW82831.1. CH471092 Genomic DNA. Translation: EAW82833.1.
IPI	IPI00465438. IPI00743489.
PIR	S14278.
RefSeq	NP_001034.1. NM_001043.3. NP_001165972.1. NM_001172501.1. NP_001165975.1. NM_001172504.1.
UniGene	Hs.78036.
3D structure databases
ProteinModelPortal	P23975.
SMR	P23975. Positions 56-570.
ModBase	Search...
Protein-protein interaction databases
MINT	MINT-197872.
STRING	9606.ENSP00000369237.
Protein family/group databases
TCDB	2.A.22.1.2. neurotransmitter:sodium symporter (NSS) family.
PTM databases
PhosphoSite	P23975.
Polymorphism databases
DMDM	128616.
Proteomic databases
PaxDb	P23975.
PRIDE	P23975.
Protocols and materials databases
DNASU	6530.
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000219833; ENSP00000219833; ENSG00000103546. ENST00000379906; ENSP00000369237; ENSG00000103546. ENST00000568943; ENSP00000457473; ENSG00000103546.
GeneID	6530.
KEGG	hsa:6530.
UCSC	uc002eif.3. human.
Organism-specific databases
CTD	6530.
GeneCards	GC16P055745.
HGNC	HGNC:11048. SLC6A2.
HPA	HPA004057.
MIM	163970. gene. 604715. phenotype.
neXtProt	NX_P23975.
PharmGKB	PA310.
GenAtlas	Search...
Phylogenomic databases
eggNOG	COG0733.
HOGENOM	HOG000116406.
HOVERGEN	HBG071421.
KO	K05035.
OMA	PPWANWV.
OrthoDB	EOG46HG9B.
PhylomeDB	P23975.
Enzyme and pathway databases
Reactome	REACT_15518. Transmembrane transport of small molecules. REACT_20679. Amine compound SLC transporters.
Gene expression databases
ArrayExpress	P23975.
Bgee	P23975.
CleanEx	HS_NAT1. HS_NET1. HS_SLC6A2. HS_SLC6A5.
Genevestigator	P23975.
GermOnline	ENSG00000103546. Homo sapiens.
Family and domain databases
InterPro	IPR000175. Na/ntran_symport. IPR002435. Na/ntran_symport_noradrenaline. [Graphical view]
PANTHER	PTHR11616. PTHR11616. 1 hit.
Pfam	PF00209. SNF. 1 hit. [Graphical view]
PRINTS	PR00176. NANEUSMPORT. PR01201. NORTRANSPORT.
PROSITE	PS00610. NA_NEUROTRAN_SYMP_1. 1 hit. PS00754. NA_NEUROTRAN_SYMP_2. 1 hit. PS50267. NA_NEUROTRAN_SYMP_3. 1 hit. [Graphical view]
ProtoNet	Search...
Other
BindingDB	P23975.
ChEMBL	CHEMBL222.
DrugBank	DB04836. Amineptine. DB00321. Amitriptyline. DB00543. Amoxapine. DB00289. Atomoxetine. DB00217. Bethanidine. DB01156. Bupropion. DB01242. Clomipramine. DB00907. Cocaine. DB04840. Debrisoquin. DB01151. Desipramine. DB00937. Diethylpropion. DB01142. Doxepin. DB00476. Duloxetine. DB00696. Ergotamine. DB00226. Guanadrel Sulfate. DB01170. Guanethidine. DB00458. Imipramine. DB00934. Maprotiline. DB00579. Mazindol. DB00422. Methylphenidate. DB04896. Milnacipran. DB01149. Nefazodone. DB00368. Norepinephrine. DB00540. Nortriptyline. DB00715. Paroxetine. DB00830. Phenmetrazine. DB00191. Phentermine. DB00344. Protriptyline. DB00234. Reboxetine. DB01105. Sibutramine. DB00193. Tramadol. DB00656. Trazodone. DB00726. Trimipramine. DB00285. Venlafaxine.
GenomeRNAi	6530.
NextBio	25407.
SOURCE	Search...

Entry information

Entry name

SC6A2_HUMAN

Accession

Primary (citable) accession number: P23975
Secondary accession number(s): B2R707, Q96KH8

Entry history

Integrated into UniProtKB/Swiss-Prot:	March 1, 1992
Last sequence update:	March 1, 1992
Last modified:	May 1, 2013
This is version 128 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.