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Function and Regulation of Monoamine Transporters: Focus on the Norepinephrine Transporter

Published online by Cambridge University Press:  07 November 2014

Subbu Apparsundaram
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Abstract

Presynaptic norepinephrine transporters (NETs) mediate the rapid clearance of norepinephrine from synaptic spaces. NET is a member of the Na+ and Cl− -coupled neurotransmitter transporter gene family, which also includes the serotonin and dopamine transporters. Recent studies reveal that these transporter molecules might be a dynamic component of synaptic plasticity, rather than a constitutive determinant of neurotransmitter levels in synaptic spaces. Recognition that cellular signaling molecules and transporter ligands, including cocaine, amphetamines, and antidepressants, can modify transporter intrinsic activity, trafficking, phosphorylation, and protein levels suggests opportunities for revealing unknown mechanisms of drug action. Control of these properties of transporter function may allow for the development of new strategies to modulate monoaminergic neurotransmission and identify regulatory pathways that may be compromised in psychiatric, neurologic, and neurodegenerative disorders.

Type
Feature Articles
Information
CNS Spectrums , Volume 6 , Issue 8: Advances in the Neurobiology of Norepinephrine and its Relevance to Psychiatric Disorders , August 2001 , pp. 671 - 678
Copyright
Copyright © Cambridge University Press 2001

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References

REFERENCES

1. Axelrod, J. Noradrenaline: fate and control of its biosynthesis. Science. 1971; 173: 598–606.CrossRefGoogle ScholarPubMed
2. Schomig, A, Haass, M, Richardt, G. Catecholamine release and arrhythmias in acute myocardial ischaemia. Eur Heart J. 1991; 12(suppl F): 38–47.CrossRefGoogle ScholarPubMed
3. Hatta, E, Yasuda, K, Levi, R. Activation of histamine H3 receptors inhibits carrier-mediated norepinephrine release in a human model of protracted myocardial ischemia. J Pharmacol Exp Ther. 1997; 283: 494–500.Google Scholar
4. Pacholczyk, T, Blakely, RD, Amara, SG. Expression cloning of a cocaine- and antidepressant-sensitive human noradrenaline transporter. Nature. 1991; 350: 350–354.CrossRefGoogle ScholarPubMed
5. Nelson, N. The family of Na+/Cl− neurotransmitter transporters. J Neurochem. 1998; 71: 1785–1803.CrossRefGoogle ScholarPubMed
6. Ramamoorthy, S, Bauman, AL, Moore, KR et al. , Antidepressant- and cocaine-sensitive human serotonin transporter: molecular cloning, expression, and chromosomal localization. Proc Natl Acad Sci U S A. 1993; 90: 2542–2546.CrossRefGoogle ScholarPubMed
7. Giros, B, El Mestikawy, S, Godinot, N et al. , Cloning, pharmacological characterization, and chromosome assignment of the human dopamine transporter. Mol Pharmacol. 1992; 42: 383–390.Google ScholarPubMed
8. Barker, EL, Blakely, RD. Norepinephrine and serotonin transporters: molecular targets of antidepressant drugs. In: Bloom, FE, Kupfer, DJ, eds. Psychopharmacology: The Fourth Generation of Progress. New York: Raven Press; 1995: 321–333.Google Scholar
9. Nelson, JC. A review of the efficacy of serotonergic and noradrenergic reuptake inhibitors for treatment of major depression. Biol Psychiatry. 1999; 46: 1301–1308.CrossRefGoogle ScholarPubMed
10. Burrows, GD, Maguire, KP, Norman, TR. Antidepressant efficacy and tolerability of the selective norepinephrine reuptake inhibitor reboxetine: a review. J Clin Psychiatry. 1998; 59(suppl 14): 4–7.Google ScholarPubMed
11. Xu, F, Gainetdinov, RR, Wetsel, WC et al. , Mice lacking the norepinephrine transporter are supersensitive to psychostimulants. Nat Neurosci. 2000; 3: 465–471.CrossRefGoogle ScholarPubMed
12. Bengel, D, Murphy, DL, Andrews, AM et al. , Altered brain serotonin homeostasis and locomotor insensitivity to 3, 4-methylenedioxymethamphetamine (“Ecstasy”) in serotonin transporter-deficient mice. Mol Pharmacol. 1998; 53: 649–655.CrossRefGoogle Scholar
13. Giros, B, Jaber, M, Jones, SR et al. , Hyperlocomotion and indifference to cocaine and amphetamine in mice lacking the dopamine transporter. Nature. 1996; 379: 606–612.CrossRefGoogle ScholarPubMed
14. Klimek, V, Stockmeier, C, Overholser, J et al. , Reduced levels of norepinephrine transporters in the locus coeruleus in major depression. J Neurosci. 1997; 17: 8451–8458.CrossRefGoogle ScholarPubMed
15. Esler, M, Jackman, G, Leonard, P et al. , Effect of norepinephrine uptake blockers on norepinephrine kinetics. Clin Pharmacol Ther. 1981; 29: 12–20.CrossRefGoogle ScholarPubMed
16. Bohm, M, La Rosee, K, Schwinger, RH et al. , Evidence for reduction of norepinephrine uptake sites in the failing human heart. J Am Coll Cardiol. 1995; 25: 146–153.CrossRefGoogle ScholarPubMed
17. Shannon, JR, Flattem, NL, Jordan, J et al. , Orthostatic intolerance and tachycardia associated with norepinephrine-transporter deficiency. N Engl J Med. 2000: 342: 541–549.CrossRefGoogle ScholarPubMed
18. Melikian, HE, Ramamoorthy, S, Tate, CG et al. , Inability to N-glycosylate the human norepinephrine transporter reduces protein stability, surface trafficking, and transport activity but not ligand recognition. Mol Pharmacol. 1996; 50: 266–276.Google Scholar
19. Nguyen, TT, Amara, SG. N-linked oligosaccharides are required for cell surface expression of the norepinephrine transporter but do not influence substrate or inhibitor recognition. J Neurochem. 1996; 67: 645–655.CrossRefGoogle ScholarPubMed
20. Gelernter, J, Kruger, S, Pakstis, AJ et al. , Assignment of the norepinephrine transporter protein (NET1) locus to chromosome 16. Genomics. 1993: 18: 690–692.CrossRefGoogle ScholarPubMed
21. Bruss, M, Kunz, J, Lingen, B et al. , Chromosomal mapping of the human gene for the tricyclic antidepressant-sensitive noradrenaline transporter. Hum Genet. 1993; 91: 278–280.CrossRefGoogle ScholarPubMed
22. Schroeter, S, Apparsundaram, S, Wiley, RG et al. , Immunolocalization of the cocaine- and antidepressant-sensitive 1-norepinephrine transporter. J Comp Neurol. 2000; 420: 211–232.3.0.CO;2-3>CrossRefGoogle Scholar
23. Carboni, E, Tanda, GL, Frau, R et al. , Blockade of the noradrenaline carrier increases extracellular dopamine concentrations in the prefrontal cortex: evidence that dopamine is taken up in vivo by noradrenergic terminals. J Neurochem. 1990; 55: 1067–1070.CrossRefGoogle ScholarPubMed
24. Daws, LC, Toney, GM, Gerhardt, GA et al. , In vivo chronoamperometric measures of extracellular serotonin clearance in rat dorsal hippocampus: contribution of serotonin and norepinephrine transporters. J Pharmacol Exp Ther. 1998; 286: 967–976.Google Scholar
25. Porzgen, P, Bonisch, H, Hammermann, R et al. , The human noradrenaline transporter gene contains multiple polyadenylation sites and two alternatively spliced C-terminal exons. Biochim Biophys Acta. 1998; 1398: 365–370.Google Scholar
26. Runkel, F, Bruss, M, Nothen, MM et al. , Pharmacological properties of naturally occurring variants of the human norepinephrine transporter. Pharmacogenetics. 2000; 10: 397–405.CrossRefGoogle ScholarPubMed
27. Rudnick, G, Clark, J. From synapse to vesicle: the reuptake and storage of biogenic amine neurotransmitters. Biochim Biophys Acta. 1993; 1144: 249–263.Google Scholar
28. DeFelice, LJ, Blakely, RD. Pore models for transporters? Biophys J. 1996; 70: 579–580.CrossRefGoogle ScholarPubMed
29. Galli, A, Blakely, RD, DeFelice, LJ. Patch-clamp and amperometric recordings from norepinephrine transporters: channel activity and voltage-dependent uptake. Proc Natl Acad Sci U S A. 1998; 95: 13260–13265.CrossRefGoogle ScholarPubMed
30. Mager, S, Min, C, Henry, DJ et al. , Conducting states of a mammalian serotonin transporter. Neuron. 1994; 12: 845–859.CrossRefGoogle ScholarPubMed
31. Sonders, MS, Zhu, SJ, Zahniser, NR et al. , Multiple ionic conductances of the human dopamine transporter: the actions of dopamine and psychostimulants. J Neurosci. 1997; 17: 960–974.CrossRefGoogle ScholarPubMed
32. Apparsundaram, S, Galli, A, DeFelice, LJ et al. , Acute regulation of norepinephrine transport: I. PKC-linked muscarinic receptors influence transport capacity and transporter density in SK-N-SH cells. J Pharmacol Exp Ther. 1998; 287: 733–743.Google Scholar
33. Apparsundaram, S, Schroeter, S, Blakely, RD. Acute regulation of norepinephrine transport. II. PKC-modulated surface expression of human norepinephrine transporter proteins. J Pharmacol Exp Ther. 1998; 287: 744–751.Google ScholarPubMed
34. Qian, Y, Galli, A, Ramamoorthy, S et al. , Protein kinase C activation regulates human serotonin transporters in HEK-293 cells via altered cell surface expression. J Neurosci. 1997; 17: 45–57.CrossRefGoogle ScholarPubMed
35. Huff, RA, Vaughan, RA, Kuhar, MJ et al. , Phorbol esters increase dopamine transporter phosphorylation and decrease transport Vmax. J Neurochem. 1997; 68: 225–232.CrossRefGoogle ScholarPubMed
36. Zhu, SJ, Kavanaugh, MP, Sonders, MS et al. , Activation of protein kinase C inhibits uptake, currents and binding associated with the human dopamine transporter expressed in Xenopus oocytes. J Pharmacol Exp Ther. 1997; 282: 1358–1365.Google ScholarPubMed
37. Blakely, RD, Ramamoorthy, S, Qian, Y et al. , Regulation of antidepressantsensitive serotonin transporters. In: Reith, MEA, ed. Neurotransmitter Transporters: Structure, Function, and Regulation. Totowa, NJ: Humana Press; 1997: 29–72.CrossRefGoogle Scholar
38. Melikian, HE, Buckley, KM. Membrane trafficking regulates the activity of the human dopamine transporter. J Neurosci. 1999; 19: 7699–7710.CrossRefGoogle ScholarPubMed
39. Daniels, GM, Amara, SG. Regulated trafficking of the human dopamine transporter: clathrin-mediated internalization and lysosomal degradation in response to phorbol esters. J Biol Chem. 1999; 274: 35794–35801.CrossRefGoogle ScholarPubMed
40. Saunders, C, Ferrer, JV, Shi, L et al. , Amphetamine-induced loss of human dopamine transporter activity: an internalization-dependent and cocaine-sensitive mechanism. Proc Natl Acad Sci U S A. 2000; 97: 6850–6855.CrossRefGoogle ScholarPubMed
41. Frazer, A, Gerhardt, GA, Daws, LC. New views of biogenic amine transporter function: implications for neuropsychopharmacology. Int J Neuropsychopharmacol. 1999; 2: 305–320.CrossRefGoogle Scholar
42. Blakely, RD, Ramamoorthy, S, Schroeter, S et al. , Regulated phosphorylation and trafficking of antidepressant-sensitive serotonin transporter proteins. Biol Psychiatry. 1998; 44: 169–178.CrossRefGoogle ScholarPubMed
43. Doolen, S, Zahniser, NR. Protein tyrosine kinase inhibitors alter human dopamine transporter activity in Xenopus oocytes. J Pharmacol Exp Ther. 2001; 296: 931–938.Google ScholarPubMed
44. Ramamoorthy, S, Giovanetti, E, Qian, Y et al. , Phosphorylation and regulation of antidepressant-sensitive serotonin transporters. J Biol Chem. 1998; 273: 2458–2466.CrossRefGoogle ScholarPubMed
45. Vaughan, RA, Huff, RA, Uhl, GR et al. , Protein kinase C-mediated phosphorylation and functional regulation of dopamine transporters in striatal synaptosomes. J Biol Chem. 1997; 272: 15541–15546.CrossRefGoogle ScholarPubMed
46. Ramamoorthy, S, Blakely, RD. Phosphorylation and sequestration of serotonin transporters differentially modulated by psychostimulants. Science. 1999; 285: 763–766.CrossRefGoogle ScholarPubMed
47. Lu, D, Yu, K, Paddy, MR et al. , Regulation of norepinephrine transport system by angiotensin II in neuronal cultures of normotensive and spontaneously hypertensive rat brains. Endocrinology. 1996; 137: 763–772.CrossRefGoogle ScholarPubMed
48. Ansah, TA, Ramamoorthy, S, Blakely, RD. Elucidation of alpha2-adrenergic receptor-mediated regulation of serotonin transport [abstract]. Soc Neurosci. 2000; 26: 17.6.Google Scholar
49. Mayfield, RD, Zahniser, NR. Dopamine D2 receptor regulation of the dopamine transporter expressed in Xenopus laevis oocytes is voltage-independent. Mol Pharmacol. 2001; 59: 113–121.CrossRefGoogle Scholar
50. Drew, AE, Werling, LL. Protein kinase C regulation of dopamine transporter initiated by nicotinic receptor activation in slices of rat prefrontal cortex. J Neurochem. 2001; 77: 839–848.CrossRefGoogle ScholarPubMed
51. Daws, LC, Gerhardt, GA, Frazer, A. 5-HT1B antagonists modulate clearance of extracellular serotonin in rat hippocampus. Neurosci Lett. 1999; 266: 165–168.CrossRefGoogle ScholarPubMed
52. Frazer, A, Daws, LC. Serotonin transporter function in vivo: assessment by chronoamperometry. Ann N Y Acad Sci. 1998; 861: 217–229.CrossRefGoogle ScholarPubMed
53. Cass, WA, Gerhardt, GA. Direct in vivo evidence that D2 dopamine receptors can modulate dopamine uptake. Neurosci Lett. 1994; 176: 259–263.CrossRefGoogle Scholar
54. Dickinson, SD, Sabeti, J, Larson, GA et al. , Dopamine D2 receptor-deficient mice exhibit decreased dopamine transporter function but no changes in dopamine release in dorsal striatum. J Neurochem. 1999; 72: 148–156.CrossRefGoogle ScholarPubMed
55. Ferguson, SS. Evolving concepts in G-protein-coupled receptor endocytosis: the role in receptor desensitization and signaling. Pharmacol Rev. 2001; 53: 1–24.Google ScholarPubMed
56. Bauman, AL, Apparsundaram, S, Ramamoorthy, S et al. , Cocaine and antidepressant-sensitive biogenic amine transporters exist in regulated complexes with protein phosphatase 2A. J Neurosci. 2000; 20: 7571–7578.CrossRefGoogle ScholarPubMed
57. Sung, U, Apparsundaram, S, Blakely, RD. Intracellular calcium regulates associations between norepinephrine transporter and syntaxin 1A [abstract]. Soc Neurosci. 2000; 26: 439.10.Google Scholar
58. Torres, GE, Yao, W, Mohn, AR et al. , Functional interaction between monoamine plasma membrane transporters and the synaptic PDZ domaincontaining protein PICK1. Neuron. 2001; 30: 121–134.CrossRefGoogle ScholarPubMed
59. Spillantini, MG, Schmidt, ML, Lee, VM et al. , Alpha-synuclein in Lewy bodies. Nature. 1997; 388: 839–840.CrossRefGoogle ScholarPubMed
60. Lee, FJ, Liu, F, Pristupa, ZB et al. , Direct binding and functional coupling of alpha-synuclein to the dopamine transporters accelerate dopamine-induced apoptosis. Faseb J. 2001; 15: 916–926.Google Scholar
61. Frazer, A. Pharmacology of antidepressants. J Clin Psychopharmacol. 1997; 17(suppl 1): 2S–18S.CrossRefGoogle ScholarPubMed
62. Benmansour, S, Tejani-Butt, SM, Hauptmann, M et al. , Lack of effect of high-dose cocaine on monoamine uptake sites in rat brain measured by quantitative autoradiography. Psychopharmacology. 1992; 106: 459–462.CrossRefGoogle ScholarPubMed
63. Shearman, LP, Meyer, JS. Cocaine up-regulates norepinephrine transporter binding in the rat placenta. Eur J Pharmacol. 1999; 386: 1–6.CrossRefGoogle ScholarPubMed
64. Zhu, MY, Shamburger, S, Li, J et al. , Regulation of the human norepinephrine transporter by cocaine and amphetamine. J Pharmacol Exp Ther. 2000; 295: 951–959.Google ScholarPubMed
65. Popoli, M, Brunello, N, Perez, J et al. , Second messenger-regulated protein kinases in the brain: their functional role and the action of antidepressant drugs. J Neurochem. 2000; 74: 21–33.CrossRefGoogle ScholarPubMed
66. Mori, S, Popoli, M, Brunello, N et al. , Effect of reboxetine treatment on brain cAMP- and calcium/calmodulin-dependent protein kinases. Neuropharmacology. 2001; 40: 448–456.CrossRefGoogle ScholarPubMed
67. Stober, G, Nothen, MM, Porzgen, P 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: 523–532.3.0.CO;2-I>CrossRefGoogle ScholarPubMed
68. Overton, MC, Blumer, KJ. G-protein-coupled receptors function as oligomers in vivo. Curr Biol. 2000; 10: 341–344.CrossRefGoogle ScholarPubMed
69. Chang, AS, Starnes, DM, Chang, SM. Possible existence of quaternary structure in the high-affinity serotonin transport complex. Biochem Biophys Res Commun. 1998; 249: 416–421.CrossRefGoogle ScholarPubMed
70. Kilic, F, Rudnick, G. Oligomerization of serotonin transporter and its functional consequences. Proc Natl Acad Sci U S A. 2000; 97: 3106–3111.CrossRefGoogle ScholarPubMed
71. De Felice, LJ, Adams, SV. Serotonin and norepinephrine transporters: possible relationship between oligomeric structure and channel modes of conduction. Mol Membr Biol. 2001; 18: 45–51.CrossRefGoogle ScholarPubMed
72. Hahn, MK, Mazei, M, Robertson, D et al. , Single nucleotide polymorphisms in the human norepinephrine transporter gene alter in vitro norepinephrine transport [abstract]. Soc Neurosci. 2000; 26: 17.Google Scholar
73. Kitayama, S, Ikeda, T, Mitsuhata, C et al. , Dominant negative isoform of rat norepinephrine transporter produced by alternative RNA splicing. J Biol Chem. 1999; 274: 10731–10736.CrossRefGoogle ScholarPubMed
74. Gu, H, Caplan, MJ, Rudnick, G. Cloned catecholamine transporters expressed in polarized epithelial cells: sorting, drug sensitivity, and ion-coupling stoichiometry. Adv Pharmacol. 1998; 42: 175–179.CrossRefGoogle ScholarPubMed
75. Ravary, A, Muzerelle, A, Darmon, M et al. , Abnormal trafficking and subcellular localization of an iV-terminally truncated serotonin transporter protein. Eur J Neurosci. 2001; 13: 1349–1362.CrossRefGoogle ScholarPubMed