norepinephrine plasma membrane transport proteins

Summary

Summary: Sodium chloride-dependent neurotransmitter symporters located primarily on the PLASMA MEMBRANE of noradrenergic neurons. They remove NOREPINEPHRINE from the EXTRACELLULAR SPACE by high affinity reuptake into PRESYNAPTIC TERMINALS. The norepinephrine transporter regulates signal amplitude and duration at noradrenergic synapses and is the target of ADRENERGIC UPTAKE INHIBITORS.

Top Publications

  1. Hall F, Li X, Randall Thompson J, Sora I, Murphy D, Lesch K, et al. Cocaine-conditioned locomotion in dopamine transporter, norepinephrine transporter and 5-HT transporter knockout mice. Neuroscience. 2009;162:870-80 pubmed publisher
  2. Wersinger C, Jeannotte A, Sidhu A. Attenuation of the norepinephrine transporter activity and trafficking via interactions with alpha-synuclein. Eur J Neurosci. 2006;24:3141-52 pubmed
  3. Zhao G, Li S, Qin G, Fei J, Guo L. Inhibitive effects of Fructus Psoraleae extract on dopamine transporter and noradrenaline transporter. J Ethnopharmacol. 2007;112:498-506 pubmed
  4. Retz W, Rosler M, Kissling C, Wiemann S, Hünnerkopf R, Coogan A, et al. Norepinephrine transporter and catecholamine-O-methyltransferase gene variants and attention-deficit/hyperactivity disorder symptoms in adults. J Neural Transm (Vienna). 2008;115:323-9 pubmed
    ..Results do not support the hypothesis that common variants in the SLC6A2 and COMT genes in particular are associated with ADHD, but might give some evidence for interactive effects between these gene variants on ADHD severity. ..
  5. Jayanthi L, Annamalai B, Samuvel D, Gether U, Ramamoorthy S. Phosphorylation of the norepinephrine transporter at threonine 258 and serine 259 is linked to protein kinase C-mediated transporter internalization. J Biol Chem. 2006;281:23326-40 pubmed
    ..These results suggest that Thr-258 and Ser-259 serve as a PKC-specific phospho-acceptor site and that phosphorylation of this motif is linked to PKC-induced NET internalization. ..
  6. Mayer A, Schroeder C, Heusser K, Tank J, Diedrich A, Schmieder R, et al. Influences of norepinephrine transporter function on the distribution of sympathetic activity in humans. Hypertension. 2006;48:120-6 pubmed
    ..All of these changes are physiologically relevant because they lead to corresponding changes in organ function. ..
  7. Ding Y, Singhal T, Planeta Wilson B, Gallezot J, Nabulsi N, Labaree D, et al. PET imaging of the effects of age and cocaine on the norepinephrine transporter in the human brain using (S,S)-[(11)C]O-methylreboxetine and HRRT. Synapse. 2010;64:30-8 pubmed publisher
  8. Haenisch B, Linsel K, Bruss M, Gilsbach R, Propping P, Nothen M, et al. Association of major depression with rare functional variants in norepinephrine transporter and serotonin1A receptor genes. Am J Med Genet B Neuropsychiatr Genet. 2009;150B:1013-6 pubmed publisher
    ..In conclusion, our results favor the hypothesis that monoaminergic neurotransmission in general and the F528C NET and R219L 5-HT(1A) receptor variants in particular are involved in the pathogenesis of depression. ..
  9. Song D, Jhung K, Song J, Cheon K. The 1287 G/A polymorphism of the norepinephrine transporter gene (NET) is involved in commission errors in Korean children with attention deficit hyperactivity disorder. Behav Brain Funct. 2011;7:12 pubmed publisher
    ..These findings suggest a protective role of the G/G genotype of the NET polymorphisms in the deficits of response inhibition in ADHD children. ..

More Information

Publications62

  1. Solich J, Faron Górecka A, Kusmider M, Palach P, Gaska M, Dziedzicka Wasylewska M. Norepinephrine transporter (NET) knock-out upregulates dopamine and serotonin transporters in the mouse brain. Neurochem Int. 2011;59:185-91 pubmed publisher
  2. Renner T, Nguyen T, Romanos M, Walitza S, Roser C, Reif A, et al. No evidence for association between a functional promoter variant of the Norepinephrine Transporter gene SLC6A2 and ADHD in a family-based sample. Atten Defic Hyperact Disord. 2011;3:285-9 pubmed publisher
    ..5%, P = 0.55). We conclude that A-3081T is not a major risk variant in our ADHD sample, though SLC6A2 remains an interesting candidate gene in ADHD, especially for the inattentive subtype. ..
  3. Kollins S, Anastopoulos A, Lachiewicz A, Fitzgerald D, Morrissey Kane E, Garrett M, et al. SNPs in dopamine D2 receptor gene (DRD2) and norepinephrine transporter gene (NET) are associated with continuous performance task (CPT) phenotypes in ADHD children and their families. Am J Med Genet B Neuropsychiatr Genet. 2008;147B:1580-8 pubmed publisher
    ..Results also shed light on the molecular genetic basis of specific processes that may underlie the disorder. ..
  4. Trivedi M, Desaiah D, Ossanna M, Pritchett Y, Brannan S, Detke M. Clinical evidence for serotonin and norepinephrine reuptake inhibition of duloxetine. Int Clin Psychopharmacol. 2008;23:161-9 pubmed publisher
    ..In summary, the data presented in this report provide clinical evidence of a mechanism for duloxetine involving both 5-HT and NE reuptake inhibition in humans and are consistent with preclinical evidence for 5-HT/NE reuptake inhibition. ..
  5. Haenisch B, Gilsbach R, Bonisch H. Neurotrophin and neuropeptide expression in mouse brain is regulated by knockout of the norepinephrine transporter. J Neural Transm (Vienna). 2008;115:973-82 pubmed publisher
    ..We could delineate NT-3, NGF and CRF as being regulated in distinct brain regions by KO of the NET. ..
  6. Jørgensen S, Nielsen E, Peters D, Dyhring T. Validation of a fluorescence-based high-throughput assay for the measurement of neurotransmitter transporter uptake activity. J Neurosci Methods. 2008;169:168-76 pubmed publisher
    ..The described assay enables monitoring of dynamic transport activity of DAT, NET and SERT and is amenable for high-throughput screening and compound characterization. ..
  7. Hahn M, Blackford J, Haman K, Mazei Robison M, English B, Prasad H, et al. Multivariate permutation analysis associates multiple polymorphisms with subphenotypes of major depression. Genes Brain Behav. 2008;7:487-95 pubmed
    ..74 (1.05-7.18)]}. These relationships illustrate an approach to the elucidation of gene influences on trait components of MDD and with replication, may help identify MDD subpopulations that can benefit from more targeted pharmacotherapy. ..
  8. Kooij J, Boonstra A, Vermeulen S, Heister A, Burger H, Buitelaar J, et al. Response to methylphenidate in adults with ADHD is associated with a polymorphism in SLC6A3 (DAT1). Am J Med Genet B Neuropsychiatr Genet. 2008;147B:201-8 pubmed
    ..The polymorphisms in DRD4 and the SLC6A2 were not associated with treatment response. This study supports a role of the SLC6A3 genotype in determining the response to MPH in the treatment of adults with ADHD. ..
  9. Kim J, Biederman J, McGrath C, Doyle A, Mick E, Fagerness J, et al. Further evidence of association between two NET single-nucleotide polymorphisms with ADHD. Mol Psychiatry. 2008;13:624-30 pubmed
    ..This is the first time that identical alleles of NET from different studies were implicated, and thus our report provides further evidence that the NET gene is involved in the etiology of ADHD. ..
  10. Lambert E, Eikelis N, Esler M, Dawood T, Schlaich M, Bayles R, et al. Altered sympathetic nervous reactivity and norepinephrine transporter expression in patients with postural tachycardia syndrome. Circ Arrhythm Electrophysiol. 2008;1:103-9 pubmed publisher
    ..Paradoxically, whole-body NE spillover to plasma during rest in the supine position and in response to head-up tilt is not altered despite excessive nerve firing rate in response to the head-up tilt. ..
  11. Tsuruda P, Yung J, Martin W, Chang R, Mai N, Smith J. Influence of ligand binding kinetics on functional inhibition of human recombinant serotonin and norepinephrine transporters. J Pharmacol Toxicol Methods. 2010;61:192-204 pubmed publisher
    ..Such information can serve as a foundation for understanding the in vitro profiles of monoamine reuptake inhibitors in the context of their clinical efficacy and tolerability. ..
  12. Gulyas B, Brockschnieder D, Nag S, Pavlova E, Kasa P, Beliczai Z, et al. The norepinephrine transporter (NET) radioligand (S,S)-[18F]FMeNER-D2 shows significant decreases in NET density in the human brain in Alzheimer's disease: a post-mortem autoradiographic study. Neurochem Int. 2010;56:789-98 pubmed publisher
  13. Keller N, Robertson D. Familial orthostatic tachycardia. Curr Opin Cardiol. 2006;21:173-9 pubmed
    ..Therefore, continued study of the relationships between genotype and phenotype are necessary to better understand this syndrome and others with associated dysautonomia. ..
  14. Schroeder C, Birkenfeld A, Mayer A, Tank J, Diedrich A, Luft F, et al. Norepinephrine transporter inhibition prevents tilt-induced pre-syncope. J Am Coll Cardiol. 2006;48:516-22 pubmed
    ..We tested the hypothesis that pharmacological norepinephrine reuptake transporter (NET) inhibition delays the onset of head-up tilt-induced presyncope in healthy subjects...
  15. Mick E, Neale B, Middleton F, McGough J, Faraone S. Genome-wide association study of response to methylphenidate in 187 children with attention-deficit/hyperactivity disorder. Am J Med Genet B Neuropsychiatr Genet. 2008;147B:1412-8 pubmed publisher
    ..These results should be considered preliminary until replicated in larger adequately powered, controlled samples but do suggest that noradrenergic and possibly glutaminergic genes may be involved with response to methylphenidate. ..
  16. Wehrwein E, Parker L, Wright A, Spitsbergen J, Novotny M, Babankova D, et al. Cardiac norepinephrine transporter protein expression is inversely correlated to chamber norepinephrine content. Am J Physiol Regul Integr Comp Physiol. 2008;295:R857-63 pubmed publisher
    ..In summary, there is a ventricular predominance of NET binding that corresponds to a high NE reuptake capacity in the ventricles, yet negatively correlates to tissue NE content...
  17. Hall F, Schwarzbaum J, Perona M, Templin J, Caron M, Lesch K, et al. A greater role for the norepinephrine transporter than the serotonin transporter in murine nociception. Neuroscience. 2011;175:315-27 pubmed publisher
    ..Collectively these data suggest that NET has a far greater role in determining baseline analgesia, and perhaps other analgesic effects, than SERT in mice. ..
  18. Esler M, Alvarenga M, Pier C, Richards J, El Osta A, Barton D, et al. The neuronal noradrenaline transporter, anxiety and cardiovascular disease. J Psychopharmacol. 2006;20:60-6 pubmed
  19. Dzirasa K, Phillips H, Sotnikova T, Salahpour A, Kumar S, Gainetdinov R, et al. Noradrenergic control of cortico-striato-thalamic and mesolimbic cross-structural synchrony. J Neurosci. 2010;30:6387-97 pubmed publisher
  20. Kim C, Hahn M, Joung Y, Anderson S, Steele A, Mazei Robinson M, et al. A polymorphism in the norepinephrine transporter gene alters promoter activity and is associated with attention-deficit hyperactivity disorder. Proc Natl Acad Sci U S A. 2006;103:19164-9 pubmed
  21. Mitchell H, Ahern T, Liles L, Javors M, Weinshenker D. The effects of norepinephrine transporter inactivation on locomotor activity in mice. Biol Psychiatry. 2006;60:1046-52 pubmed
    ..Acute or chronic inactivation of the norepinephrine transporter decreases spontaneous locomotor activity in novel and familiar environments unless coupled with dopamine transporter blockade. ..
  22. Raffel D, Chen W, Sherman P, Gildersleeve D, Jung Y. Dependence of cardiac 11C-meta-hydroxyephedrine retention on norepinephrine transporter density. J Nucl Med. 2006;47:1490-6 pubmed
    ..This finding is discussed in relation to clinical observations of the dependence of HED retention on cardiac nerve density in human subjects using PET. ..
  23. Lile J, Stoops W, Durell T, Glaser P, Rush C. Discriminative-stimulus, self-reported, performance, and cardiovascular effects of atomoxetine in methylphenidate-trained humans. Exp Clin Psychopharmacol. 2006;14:136-47 pubmed
    ..These data suggest that the behavioral effects of atomoxetine overlap to a small degree with psychomotor stimulants and that it has low abuse potential...
  24. Kim H, Lim S, Kim S, Kim J, Chang Y, Carroll B, et al. Monoamine transporter gene polymorphisms and antidepressant response in koreans with late-life depression. JAMA. 2006;296:1609-18 pubmed
    ..Combinations of polymorphisms were informative for response and nonresponse. Confirmation of these preliminary findings would permit refined pharmacogenetic selection of antidepressant treatment. ..
  25. Kim B, Kim J, Hong S, Cho S, Shin M, Yoo H. Possible association of norepinephrine transporter -3081(A/T) polymorphism with methylphenidate response in attention deficit hyperactivity disorder. Behav Brain Funct. 2010;6:57 pubmed publisher
    ..Our findings provide evidence for the involvement of the -3081(A/T) polymorphism of SLC6A2 in the modulation of the effectiveness of MPH treatment in ADHD. ..
  26. Song J, Song D, Jhung K, Cheon K. Norepinephrine transporter gene (SLC6A2) is involved with methylphenidate response in Korean children with attention deficit hyperactivity disorder. Int Clin Psychopharmacol. 2011;26:107-13 pubmed publisher
    ..008]. Our study found a significant association between the G1287A genotype of the NET gene and the MPH response in Korean children with ADHD. These findings support the significant role of the NET gene in ADHD treatment with MPH. ..
  27. Joung Y, Kim C, Moon J, Jang W, Yang J, Shin D, et al. Association studies of -3081(A/T) polymorphism of norepinephrine transporter gene with attention deficit/hyperactivity disorder in Korean population. Am J Med Genet B Neuropsychiatr Genet. 2010;153B:691-694 pubmed publisher
    ..The odds ratio for TT and AT genotypes was 4.57 (95% CI: 2.56-8.15) and 1.96 (95% CI: 0.96-3.78), respectively. Findings in the present study provided further evidence of association between ADHD and -3081(A/T) polymorphism of SLC6A2. ..
  28. Matthies H, Han Q, Shields A, Wright J, Moore J, Winder D, et al. Subcellular localization of the antidepressant-sensitive norepinephrine transporter. BMC Neurosci. 2009;10:65 pubmed publisher
    ..Moreover, NET is localized in presynaptic membranes in a manner that can take advantage of regulatory processes targeting lipid raft subdomains. ..
  29. Haenisch B, Bonisch H. Depression and antidepressants: insights from knockout of dopamine, serotonin or noradrenaline re-uptake transporters. Pharmacol Ther. 2011;129:352-68 pubmed publisher
    ..Thus, NATKO mice are an interesting tool to investigate the mechanisms beyond monoamines responsible for depression as well as for AD actions. ..
  30. Bourdet D, Tsuruda P, Obedencio G, Smith J. Prediction of human serotonin and norepinephrine transporter occupancy of duloxetine by pharmacokinetic/pharmacodynamic modeling in the rat. J Pharmacol Exp Ther. 2012;341:137-45 pubmed publisher
  31. Lee S, Kim S, Lee M, Yook K, Greenhill L, Fradin K, et al. Lack of association between response of OROS-methylphenidate and norepinephrine transporter (SLC6A2) polymorphism in Korean ADHD. Psychiatry Res. 2011;186:338-44 pubmed publisher
    ..05). Although there were no significant positive results, our findings may have several implications and offer direction for future studies. ..
  32. Goddard A, Ball S, Martinez J, Robinson M, Yang C, Russell J, et al. Current perspectives of the roles of the central norepinephrine system in anxiety and depression. Depress Anxiety. 2010;27:339-50 pubmed publisher
    ..Accordingly, pharmacological interventions targeting the NE system can result in anxiolytic, rather than anxiogenic, outcomes when used to treat patients with anxiety and depression. ..
  33. Bayles R, Harikrishnan K, Lambert E, Baker E, Agrotis A, Guo L, et al. Epigenetic modification of the norepinephrine transporter gene in postural tachycardia syndrome. Arterioscler Thromb Vasc Biol. 2012;32:1910-6 pubmed publisher
    ..We propose that chromatin-modifying events associated with SLC6A2 gene suppression may constitute a mechanism of POTS. ..
  34. Perona M, Waters S, Hall F, Sora I, Lesch K, Murphy D, et al. Animal models of depression in dopamine, serotonin, and norepinephrine transporter knockout mice: prominent effects of dopamine transporter deletions. Behav Pharmacol. 2008;19:566-74 pubmed publisher
  35. Kim C, Waldman I, Blakely R, Kim K. Functional gene variation in the human norepinephrine transporter: association with attention deficit hyperactivity disorder. Ann N Y Acad Sci. 2008;1129:256-60 pubmed publisher
    ..Moreover, we observed a significant association of the -3081(T) variant with ADHD. Altered transcription of SLC6A2 may therefore represent a novel risk factor for the development of ADHD. ..
  36. Cho S, Kim J, Kim B, Hwang J, Park M, Kim S, et al. No evidence of an association between norepinephrine transporter gene polymorphisms and attention deficit hyperactivity disorder: a family-based and case-control association study in a Korean sample. Neuropsychobiology. 2008;57:131-8 pubmed publisher
    ..Our findings do not support SLC6A2 as a major genetic susceptibility factor in ADHD. ..
  37. Sogawa C, Kumagai K, Sogawa N, Morita K, Dohi T, Kitayama S. C-terminal region regulates the functional expression of human noradrenaline transporter splice variants. Biochem J. 2007;401:185-95 pubmed
    ..These findings suggest that in addition to the function of the C-terminus, the common proximal region encoded by exon 14 regulates the functional expression of splice variants, such as hNET1 and hNET2. ..
  38. Haenisch B, Bilkei Gorzo A, Caron M, Bonisch H. Knockout of the norepinephrine transporter and pharmacologically diverse antidepressants prevent behavioral and brain neurotrophin alterations in two chronic stress models of depression. J Neurochem. 2009;111:403-16 pubmed publisher
    ..In addition, these mice represent a useful model to study depression-resistant behaviors, and they might help to provide deeper insights into the identification of downstream targets involved in the mechanisms of antidepressants. ..
  39. Logan J, Wang G, Telang F, Fowler J, Alexoff D, Zabroski J, et al. Imaging the norepinephrine transporter in humans with (S,S)-[11C]O-methyl reboxetine and PET: problems and progress. Nucl Med Biol. 2007;34:667-79 pubmed
    ..0 mg/kg/day), this would suggest that there may be additional targets for ATX's therapeutic actions. ..
  40. Zhou Z, Zhen J, Karpowich N, Goetz R, Law C, Reith M, et al. LeuT-desipramine structure reveals how antidepressants block neurotransmitter reuptake. Science. 2007;317:1390-3 pubmed publisher
    ..Mutagenesis experiments on human SERT and DAT indicate that both the desipramine-binding site and its inhibition mechanism are probably conserved in the human neurotransmitter transporters...
  41. Zou M, Cao J, Kopajtic T, Desai R, Katz J, Newman A. Structure-activity relationship studies on a novel series of (S)-2beta-substituted 3alpha-[bis(4-fluoro- or 4-chlorophenyl)methoxy]tropane analogues for in vivo investigation. J Med Chem. 2006;49:6391-9 pubmed
  42. Dipace C, Sung U, Binda F, Blakely R, Galli A. Amphetamine induces a calcium/calmodulin-dependent protein kinase II-dependent reduction in norepinephrine transporter surface expression linked to changes in syntaxin 1A/transporter complexes. Mol Pharmacol. 2007;71:230-9 pubmed
    ..Here, we demonstrate that AMPH stimulation of CAMKII stabilizes an hNET/SYN1A complex. This hNET/SYN1A complex rapidly redistributes, upon AMPH treatment, when mechanisms supported by the transporter's NH2 terminus are eliminated. ..
  43. Ramoz N, Boni C, Downing A, Close S, Peters S, Prokop A, et al. A haplotype of the norepinephrine transporter (Net) gene Slc6a2 is associated with clinical response to atomoxetine in attention-deficit hyperactivity disorder (ADHD). Neuropsychopharmacology. 2009;34:2135-42 pubmed publisher
  44. Stober G, Nöthen M, Porzgen P, Bruss M, Bonisch H, Knapp M, et al. Systematic search for variation in the human norepinephrine transporter gene: identification of five naturally occurring missense mutations and study of association with major psychiatric disorders. Am J Med Genet. 1996;67:523-32 pubmed
    ..The detection of a highly polymorphic silent 1287G/A polymorphism was utilized to demonstrate biallelic expression of the NET in adult human brain. ..
  45. Skolnick P, Popik P, Janowsky A, Beer B, Lippa A. Antidepressant-like actions of DOV 21,947: a "triple" reuptake inhibitor. Eur J Pharmacol. 2003;461:99-104 pubmed
  46. Sung U, Apparsundaram S, Galli A, Kahlig K, Savchenko V, Schroeter S, et al. A regulated interaction of syntaxin 1A with the antidepressant-sensitive norepinephrine transporter establishes catecholamine clearance capacity. J Neurosci. 2003;23:1697-709 pubmed
    ..These two contradictory roles of syntaxin 1A on NET appear to be linked and reveal a dynamic cycle of interactions that allow for the coordinated control between NE release and reuptake. ..
  47. Yamashita M, Fukushima S, Shen H, Hall F, Uhl G, Numachi Y, et al. Norepinephrine transporter blockade can normalize the prepulse inhibition deficits found in dopamine transporter knockout mice. Neuropsychopharmacology. 2006;31:2132-9 pubmed
  48. Smith H, Beveridge T, Porrino L. Distribution of norepinephrine transporters in the non-human primate brain. Neuroscience. 2006;138:703-14 pubmed publisher
  49. Kaminski R, Shippenberg T, Witkin J, Rocha B. Genetic deletion of the norepinephrine transporter decreases vulnerability to seizures. Neurosci Lett. 2005;382:51-5 pubmed
    ..For all drugs tested, the response of NET-HT mice was always intermediate. These data provide further support for a role of endogenous NE in the control of seizure susceptibility. ..
  50. Hahn M, Mazei Robison M, Blakely R. Single nucleotide polymorphisms in the human norepinephrine transporter gene affect expression, trafficking, antidepressant interaction, and protein kinase C regulation. Mol Pharmacol. 2005;68:457-66 pubmed
    ..These findings reveal functional deficits that are likely to compromise NE signaling in SNP carriers in the population and identify key regions of NET contributing to transporter biosynthesis, activity, and regulation. ..
  51. Sung U, Jennings J, Link A, Blakely R. Proteomic analysis of human norepinephrine transporter complexes reveals associations with protein phosphatase 2A anchoring subunit and 14-3-3 proteins. Biochem Biophys Res Commun. 2005;333:671-8 pubmed
    ..The transporter complexes described likely support mechanisms regulating transporter activity, localization, and trafficking. ..
  52. Hopfner M, Sutter A, Beck N, Barthel B, Maaser K, Jockers Scherübl M, et al. Meta-iodobenzylguanidine induces growth inhibition and apoptosis of neuroendocrine gastrointestinal tumor cells. Int J Cancer. 2002;101:210-6 pubmed
    ..Thus, monoamine transporters in the plasma membrane of neuroendocrine gastrointestinal tumor cells are promising targets for innovative and specific treatment strategies of these tumors. ..
  53. Barr C, Kroft J, Feng Y, Wigg K, Roberts W, Malone M, et al. The norepinephrine transporter gene and attention-deficit hyperactivity disorder. Am J Med Genet. 2002;114:255-9 pubmed
    ..8%) was similar to that previously reported in a control sample (2.2%), it is unlikely that this variant is related to the ADHD phenotype. Our results do not support the NET1 gene as a major genetic susceptibility factor in ADHD. ..