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Solute carrier family 6 (neurotransmitter transporter, noradrenalin), member 2
Identifiers
Symbols SLC6A2; NAT1; NET; NET1; SLC6A5
External IDs OMIM163970 MGI1270850 HomoloGene816 GeneCards: SLC6A2 Gene
RNA expression pattern
PBB GE SLC6A2 210353 s at tn.png
PBB GE SLC6A2 216611 s at tn.png
PBB GE SLC6A2 217621 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 6530 20538
Ensembl ENSG00000103546 ENSMUSG00000055368
UniProt P23975 Q6NZB4
RefSeq (mRNA) NM_001043 NM_009209
RefSeq (protein) NP_001034 NP_033235
Location (UCSC) Chr 16:
54.25 - 54.3 Mb
Chr 8:
95.85 - 95.89 Mb
PubMed search [1] [2]

The norepinephrine transporter or NET (or noradrenaline transporter (NAT)) is a monoamine transporter that transports the neurotransmitter norepinephrine (noradrenaline) from the synapse back to its vesicles for storage until later use. It also appears to transport the neurotransmitter dopamine in the same way, but to a lesser degree. NET is 617 amino acids in length, contains 12 transmembrane domains,[1] and is encoded by the SLC6A2 gene.

Certain antidepressant medications act to raise noradrenaline, such as the SNRIs and the tricyclic antidepressants (TCAs). In other words, these medications prevent the noradrenaline transporter from doing its job. Noradrenaline therefore remains in the synapse longer, allowing it to reach more normal levels. Since the noradrenaline transporter is also thought to transport dopamine to some extent, SNRIs would also raise dopamine levels in the synapse.

"The involvement of the norepinephrine transporter (NET) in the pathophysiology and treatment of attention deficit hyperactivity disorder (ADHD), substance abuse, neurodegenerative disorders (e.g., Alzheimer's disease (AD) and Parkinson's disease (PD)) and clinical depression has long been recognized. [2006]"[2]

Contents

Genetics

The norepinephrine transporter is coded by a gene called "solute carrier family 6, member 2" with the gene symbol SLC6A2. In humans it is located on chromosome 16 locus 16q12.2. There are several variations in the gene,[3] e.g., these single nucleotide polymorphism (SNP):

  • T-182C (rs2242446), a promoter variant
  • A1287G[4] (rs5569)
  • A-3081T in the promoter region[5]
  • Ala457Pro (C1369G) in exon 9
  • rs3785143
  • rs11568324

The Ala457Pro rare missense mutation results in a loss of function and has been associated with orthostatic intolerance (associated with postural orthostatic tachycardia syndrome) in one kindred.[6] Orthostatic intolerance is, however, not typically associated with the mutation.[7]

An epigenetic mechanism (hypermethylation of CpG islands in the NET gene promoter region)[8] that results in reduced expression of the noradrenaline transporter and consequently a phenotype of impaired neuronal reuptake of noradrenaline has been implicated in both postural orthostatic tachycardia syndrome and panic disorder.

The SNPs rs3785143 and rs11568324 have been related to the attention-deficit hyperactivity disorder.[9]

See also

References

  1. ^ Tahir Tellioglu and David Robertson, The molecular structure of the norepinephrine transporter protein.
  2. ^ Information Hyperlinked Over Proteins (IHOP)
  3. ^ Mary Jeanne Kreek, Gavin Bart, Charles Lilly, K. Steven LaForge & David A. Nielsen (March 2005). "Pharmacogenetics and human molecular genetics of opiate and cocaine addictions and their treatments". Pharmacological Reviews 57 (1): 1–6. doi:10.1124/pr.57.1.1. PMID 15734726. http://pharmrev.aspetjournals.org/cgi/content/full/57/1/1.  
  4. ^ E. G. Jonsson, M. M. Nothen, J. P. Gustavsson, H. Neidt, R. Bunzel, P. Propping & G. C. Sedvall (June 1998). "Polymorphisms in the dopamine, serotonin, and norepinephrine transporter genes and their relationships to monoamine metabolite concentrations in CSF of healthy volunteers". Psychiatry Research 79 (1): 1–9. doi:10.1016/S0165-1781(98)00027-4. PMID 9676821.  
  5. ^ Chun-Hyung Kim, Maureen K. Hahn, Yoosook Joung, Susan L. Anderson, Angela H. Steele, Michelle S. Mazei-Robinson, Ian Gizer, Martin H. Teicher, Bruce M. Cohen, David Robertson, Irwin D. Waldman, Randy D. Blakely & Kwang-Soo Kim (December 2006). "A polymorphism in the norepinephrine transporter gene alters promoter activity and is associated with attention-deficit hyperactivity disorder". Proceedings of the National Academy of Sciences of the United States of America 103 (50): 19164–19169. doi:10.1073/pnas.0510836103. PMID 17146058.  
  6. ^ J. R. Shannon, N. L. Flattem, J. Jordan, G. Jacob, B. K. Black, I. Biaggioni, R. D. Blakely & D. Robertson (February 2000). "Orthostatic intolerance and tachycardia associated with norepinephrine-transporter deficiency". The New England Journal of Medicine 342 (8): 541–549. doi:10.1056/NEJM200002243420803. PMID 10684912.  
  7. ^ Sabine Ivancsits, Arthur Heider, Hugo W. Rudiger & Robert Winker (February 2003). "Orthostatic intolerance is not necessarily related to a specific mutation (Ala457Pro) in the human norepinephrine transporter gene". The American journal of the medical sciences 325 (2): 63–65. doi:10.1097/00000441-200302000-00002. PMID 12589229.  
  8. ^ Esler M, Alvarenga M, Pier C, Richards J, El-Osta A, Barton D, Haikerwal D, Kaye D, Schlaich M, Guo L, Jennings G, Socratous F, Lambert G (2006). "The neuronal noradrenaline transporter, anxiety and cardiovascular disease". J Psychopharmacol 20 (4 Suppl): 60–6. doi:10.1177/1359786806066055. PMID 16785272.  
  9. ^ J. W. Kim, J. Biederman, C. L. McGrath, A. E. Doyle, E. Mick, J. Fagerness, S. Purcell, J. W. Smoller, P. Sklar & S. V. Faraone (June 2008). "Further evidence of association between two NET single-nucleotide polymorphisms with ADHD". Molecular Psychiatry 13 (6): 624–620. doi:10.1038/sj.mp.4002090. PMID 17876324.  

Further reading

  • Eisenhofer G (2001). "The role of neuronal and extraneuronal plasma membrane transporters in the inactivation of peripheral catecholamines.". Pharmacol. Ther. 91 (1): 35–62. doi:10.1016/S0163-7258(01)00144-9. PMID 11707293.  
  • Pacholczyk T, Blakely RD, Amara SG (1991). "Expression cloning of a cocaine- and antidepressant-sensitive human noradrenaline transporter.". Nature 350 (6316): 350–4. doi:10.1038/350350a0. PMID 2008212.  
  • Pörzgen P, Bönisch H, Brüss M (1995). "Molecular cloning and organization of the coding region of the human norepinephrine transporter gene.". Biochem. Biophys. Res. Commun. 215 (3): 1145–50. doi:10.1006/bbrc.1995.2582. PMID 7488042.  
  • Gelernter J, Kruger S, Pakstis AJ, et al. (1994). "Assignment of the norepinephrine transporter protein (NET1) locus to chromosome 16.". Genomics 18 (3): 690–2. doi:10.1016/S0888-7543(05)80375-1. PMID 7905857.  
  • Brüss M, Kunz J, Lingen B, Bönisch H (1993). "Chromosomal mapping of the human gene for the tricyclic antidepressant-sensitive noradrenaline transporter.". Hum. Genet. 91 (3): 278–80. doi:10.1007/BF00218272. PMID 8478011.  
  • Pörzgen P, Bönisch H, Hammermann R, Brüss M (1998). "The human noradrenaline transporter gene contains multiple polyadenylation sites and two alternatively spliced C-terminal exons.". Biochim. Biophys. Acta 1398 (3): 365–70. PMID 9655936.  
  • Apparsundaram S, Schroeter S, Giovanetti E, Blakely RD (1998). "Acute regulation of norepinephrine transport: II. PKC-modulated surface expression of human norepinephrine transporter proteins.". J. Pharmacol. Exp. Ther. 287 (2): 744–51. PMID 9808705.  
  • Kim CH, Kim HS, Cubells JF, Kim KS (1999). "A previously undescribed intron and extensive 5' upstream sequence, but not Phox2a-mediated transactivation, are necessary for high level cell type-specific expression of the human norepinephrine transporter gene.". J. Biol. Chem. 274 (10): 6507–18. doi:10.1074/jbc.274.10.6507. PMID 10037744.  
  • Shannon JR, Flattem NL, Jordan J, et al. (2000). "Orthostatic intolerance and tachycardia associated with norepinephrine-transporter deficiency.". N. Engl. J. Med. 342 (8): 541–9. doi:10.1056/NEJM200002243420803. PMID 10684912.  
  • Torres GE, Yao WD, Mohn AR, et al. (2001). "Functional interaction between monoamine plasma membrane transporters and the synaptic PDZ domain-containing protein PICK1.". Neuron 30 (1): 121–34. doi:10.1016/S0896-6273(01)00267-7. PMID 11343649.  
  • Gu HH, Wu X, Giros B, et al. (2002). "The NH(2)-terminus of norepinephrine transporter contains a basolateral localization signal for epithelial cells.". Mol. Biol. Cell 12 (12): 3797–807. PMID 11739781.  
  • Paczkowski FA, Bryan-Lluka LJ (2002). "Tyrosine residue 271 of the norepinephrine transporter is an important determinant of its pharmacology.". Brain Res. Mol. Brain Res. 97 (1): 32–42. doi:10.1016/S0169-328X(01)00295-9. PMID 11744160.  
  • Paczkowski FA, Bönisch H, Bryan-Lluka LJ (2002). "Pharmacological properties of the naturally occurring Ala(457)Pro variant of the human norepinephrine transporter.". Pharmacogenetics 12 (2): 165–73. doi:10.1097/00008571-200203000-00010. PMID 11875370.  
  • Barr CL, Kroft J, Feng Y, et al. (2002). "The norepinephrine transporter gene and attention-deficit hyperactivity disorder.". Am. J. Med. Genet. 114 (3): 255–9. doi:10.1002/ajmg.10193. PMID 11920844.  
  • Zill P, Engel R, Baghai TC, et al. (2002). "Identification of a naturally occurring polymorphism in the promoter region of the norepinephrine transporter and analysis in major depression.". Neuropsychopharmacology 26 (4): 489–93. doi:10.1016/S0893-133X(01)00386-4. PMID 11927173.  
  • Leszczyńska-Rodziewicz A, Czerski PM, Kapelski P, et al. (2002). "A polymorphism of the norepinephrine transporter gene in bipolar disorder and schizophrenia: lack of association.". Neuropsychobiology 45 (4): 182–5. doi:10.1159/000063668. PMID 12097806.  
  • Bauman PA, Blakely RD (2002). "Determinants within the C-terminus of the human norepinephrine transporter dictate transporter trafficking, stability, and activity.". Arch. Biochem. Biophys. 404 (1): 80–91. doi:10.1016/S0003-9861(02)00232-1. PMID 12127072.  
  • Urwin RE, Bennetts B, Wilcken B, et al. (2003). "Anorexia nervosa (restrictive subtype) is associated with a polymorphism in the novel norepinephrine transporter gene promoter polymorphic region.". Mol. Psychiatry 7 (6): 652–7. doi:10.1038/sj.mp.4001080. PMID 12140790.  
  • McEvoy B, Hawi Z, Fitzgerald M, Gill M (2003). "No evidence of linkage or association between the norepinephrine transporter (NET) gene polymorphisms and ADHD in the Irish population.". Am. J. Med. Genet. 114 (6): 665–6. doi:10.1002/ajmg.10416. PMID 12210284.  

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