Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Plasma membrane monoamine transporters: structure, regulation and function

Key Points

  • About four decades ago, Julius Axelrod proposed that reuptake is an important mechanism for inactivating neurotransmitters. The genes that code for the transporters that are responsible for monoamine uptake were identified in the early 1990s.

  • Monoamine transporters have been shown to be involved both in the regulation of the extracellular concentrations of monoamines and in the homeostatic maintenance of presynaptic function. Recent studies indicate that their expression and activity is tightly regulated.

  • Transporters for dopamine, noradrenaline and 5-hydroxytryptamine (named DAT, NET and SERT, respectively) represent established targets for many pharmacological agents that affect brain function, including psychostimulants, antidepressants and neurotoxins.

  • Monoamine transporters are polytopic membrane proteins, containing 12 putative transmembrane domains (TMDs). Conservation of amino acid sequences seems to be highest in the TMDs, whereas the least conserved regions are at the amino and carboxyl termini.

  • The mechanism by which transporter proteins mediate monoamine uptake involves sequential binding and co-transport of Na+ and Cl ions. DAT transports two Na+ ions and one Cl ion with its substrate, whereas NET and SERT co-transport their substrates with one Na+ and one Cl ion.

  • Although most models of transporter function have assumed that they function as single subunits, early studies using radiation inactivation indicated that monoamine transporters might exist as oligomers, and this has recently been confirmed.

  • Transporter activity is regulated at the post-translational level, through modifications such as phosphorylation and N-linked glycosylation. There is also evidence that monoamine transporters undergo regulated trafficking in cells.

  • The disruption of monoamine transporter genes in mice by knockout technologies has provided an opportunity to investigate the physiological role of these proteins in vivo.

  • The identification of DAT as the cocaine receptor enhanced our understanding of the basic mechanisms of addictive processes, and provided strong support for the dopamine theory of addiction. Monoamine transporter genes have also received considerable attention as candidate genes for psychiatric and neurological disorders.

  • There are several outstanding questions in the field of monoamine transporters. We only have a partial knowledge of the proteins that are associated with monoamine transporters and of the factors that contribute to transporter regulation. Also, what is the physiological significance of their channel-like activity?

Abstract

The classical biogenic amine neurotransmitters — dopamine, noradrenaline, and 5-hydroxytryptamine — control a variety of functions including locomotion, autonomic function, hormone secretion, and the complex behaviours that are associated with affect, emotion and reward. A key step that determines the intensity and duration of monoamine signalling at synapses is the reuptake of the released transmitter into nerve terminals through high-affinity plasma membrane transporters. In recent years, molecular, pharmacological and genetic approaches have established the importance of monoamine transporters in the control of monoamine homeostasis and have provided insights into their regulation.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Schematic representation of dopamine, noradrenaline and 5-HT synaptic terminals.
Figure 2: Amino acid sequence and topology of monoamine transporter proteins.
Figure 3: Schematic representation of the trafficking mechanisms associated with plasma membrane monoamine transporters.
Figure 4: Interaction between monoamine transporters and the PDZ domain-containing synaptic protein PICK1.
Figure 5: Role of monoamine transporters in presynaptic homeostasis — lessons from knockout mice.

Similar content being viewed by others

References

  1. Hertting, G. & Axelrod, J. Fate of tritiated noradrenaline at the sympathetic nerve endings. Nature 192, 172–173 (1961). This study showed noradrenaline uptake by neurons for the first time.

    CAS  PubMed  Google Scholar 

  2. Iversen, L. L. Role of transporter uptake mechanisms in synaptic neurotransmission. Br. J. Pharmacol. 41, 571–591 (1971).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Amara, S. G. & Sonders, M. S. Neurotransmitter transporters as molecular targets for addictive drugs. Drug Alcohol Depend. 51, 87–96 (1998).

    CAS  PubMed  Google Scholar 

  4. Barker, E. L. & Blakely, R. D. in Psychopharmacology: The Fourth Generation of Progress (eds Bloom F. E. & Kupfer D. J.) 21–333 (Raven Press, Philadelphia, 1995).

    Google Scholar 

  5. Miller, G. W., Gainetdinov, R. R., Levey, A. I. & Caron, M. G. Dopamine transporters and neuronal injury. Trends Pharmacol. Sci. 20, 424–429 (1999).

    CAS  PubMed  Google Scholar 

  6. Giros, B. et al. Delineation of discrete domains for substrate, cocaine, and tricyclic antidepressant interactions using chimeric dopamine-norepinephrine transporters. J. Biol. Chem. 269, 15985–15988 (1994).

    CAS  PubMed  Google Scholar 

  7. Carboni, E., Tanda, G. L., Frau, R. & Di Chiara, G. 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. 55, 1067–1090 (1990).

    CAS  PubMed  Google Scholar 

  8. Moron, J. A., Brockington, A., Wise, R. A., Rocha, B. A. & Hope, B. T. Dopamine uptake through the norepinephrine transporter in brain regions with low levels of the dopamine transporter: evidence from knock-out mouse lines. J. Neurosci. 22, 389–395 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Ritz, M. C., Lamb, R. J., Goldberg, S. R. & Kuhar, M. J. Cocaine receptors on dopamine transporters are related to self-administration of cocaine. Science, 237, 1219–1223 (1987). This paper related the effects of cocaine with dopamine transporter inhibition.

    CAS  PubMed  Google Scholar 

  10. Seiden, L. S., Sabol, K. E. & Ricaurte, G. A. Amphetamine: effects on catecholamine systems and behavior. Annu. Rev. Pharmacol. Toxicol. 33, 639–677 (1993).

    CAS  PubMed  Google Scholar 

  11. Sulzer, D. et al. Amphetamine redistributes dopamine from synaptic vesicles to the cytosol and promotes reverse transport. J. Neurosci. 15, 4102–4108 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Jones, S. R., Gainetdinov, R. R., Wightman, R. M. & Caron, M. G. Mechanisms of amphetamine action revealed in mice lacking the dopamine transporter. J. Neurosci. 18, 1979–1986 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Kuhar, M. J. Molecular pharmacology of cocaine: a dopamine hypothesis and its implications. Ciba Found. Symp. 166, 81–89 (1992).

    CAS  PubMed  Google Scholar 

  14. Wise, R. A. Neurobiology of addiction. Curr. Opin. Neurobiol. 6, 243–251 (1996).

    CAS  PubMed  Google Scholar 

  15. Rudnick, G. & Wall, S. C. The molecular mechanism of 'ecstasy' 3,4-methylenedioxy-methamphetamine (MDMA): serotonin transporters are targets for MDMA-induced serotonin release. Proc. Natl Acad. Sci. USA 89, 1817–1821 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Javitch, J. A. & Snyder, S. H. Uptake of MPP+ by dopamine neurons explains selectivity of parkinsonism-inducing neurotoxin, MPTP. Eur. J. Pharmacol. 106, 455–456 (1984).

    CAS  PubMed  Google Scholar 

  17. Gainetdinov, R. R., Fumagalli, F., Jones, S. R. & Caron, M. G. Dopamine transporter is required for in vivo MPTP neurotoxicity: evidence from mice lacking the transporter. J. Neurochem. 69, 1322–1325 (1997).

    CAS  PubMed  Google Scholar 

  18. Pacholczyk, T., Blakely, R. D. & Amara, S. G. Expression cloning of a cocaine- and antidepressant-sensitive human noradrenaline transporter. Nature 350, 350–354 (1991).

    CAS  PubMed  Google Scholar 

  19. Guastella, J. et al. Cloning and expression of a rat brain GABA transporter. Science 249, 1303–1306 (1990). In references 18 and 19, the cloning of NET and the GABA transporter identified a new family of plasma membrane transporters, and provided the templates for the cloning of the related transporters DAT and SERT.

    CAS  PubMed  Google Scholar 

  20. Kilty, J. E., Lorang, D. & Amara, S. G. Cloning and expression of a cocaine-sensitive rat dopamine transporter. Science 254, 578–579 (1991).

    CAS  PubMed  Google Scholar 

  21. Shimada, S. et al. Cloning and expression of a cocaine-sensitive dopamine transporter complementary DNA. Science 254, 576–578 (1991).

    CAS  PubMed  Google Scholar 

  22. Usdin, T. B., Mezey, E., Chen, C., Brownstein, M. J. & Hoffman, B. J. Cloning of the cocaine-sensitive bovine dopamine transporter. Proc. Natl Acad. Sci. USA 88, 11168–11171 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Giros, B., el Mestikawy, S. Bertrand, L. & Caron, M. G. Cloning and functional characterization of a cocaine-sensitive dopamine transporter. FEBS Lett. 295, 149–154 (1991).

    CAS  PubMed  Google Scholar 

  24. Blakely, R. D. et al. Cloning and expression of a functional serotonin transporter from rat brain. Nature 354, 66–70 (1991).

    CAS  PubMed  Google Scholar 

  25. Hoffman, B. J., Mezey, E. & Brownstein, M. J. Cloning of a serotonin transporter affected by antidepressants. Science 254, 579–580 (1991). In references 20–25, the cloning of DAT and SERT provided the starting point for structural, functional and genetic studies.

    CAS  PubMed  Google Scholar 

  26. Giros, B. et al. Cloning, pharmacological characterization, and chromosome assignment of the human dopamine transporter. Mol. Pharmacol. 42, 383–390 (1992).

    CAS  PubMed  Google Scholar 

  27. Vandenbergh, D. J. et al. A human dopamine transporter cDNA predicts reduced glycosylation, displays a novel repetitive element and provides racially-dimorphic TaqI RFLPs. Brain Res. Mol. Brain Res. 15, 161–166 (1992).

    CAS  PubMed  Google Scholar 

  28. Ramamoorthy, S. et al. Antidepressant- and cocaine-sensitive human serotonin transporter: molecular cloning, expression, and chromosomal localization. Proc. Natl Acad. Sci. USA 90, 2542–2546 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Bruss, M., Kunz, J., Lingen, B. & Bonisch, H. Chromosomal mapping of the human gene for the tricyclic antidepressant-sensitive noradrenaline transporter. Hum. Genet. 91, 278–280 (1993).

    CAS  PubMed  Google Scholar 

  30. Corey, J. L., Quick, M. W., Davidson, N., Lester, H. A. & Guastella, J. A cocaine-sensitive Drosophila serotonin transporter: cloning, expression, and electrophysiological characterization. Proc. Natl Acad. Sci. USA 91, 1188–1192 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Demchyshyn, L. L. et al. Cloning, expression, and localization of a chloride-facilitated, cocaine-sensitive serotonin transporter from Drosophila melanogaster. Proc. Natl Acad. Sci. USA 91, 5158–5162 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Lingen, B., Bruss, M. & Bonisch, H. Cloning and expression of the bovine sodium- and chloride-dependent noradrenaline transporter. FEBS Lett. 342, 235–238 (1994).

    CAS  PubMed  Google Scholar 

  33. Porzgen, P., Bonisch, H. & Bruss, M. Molecular cloning and organization of the coding region of the human norepinephrine transporter gene. Biochem. Biophys. Res. Comm. 215, 1145–1150 (1995).

    CAS  PubMed  Google Scholar 

  34. Chang, A. S. et al. Cloning and expression of the mouse serotonin transporter. Brain Res. Mol. Brain Res. 43, 185–192 (1996).

    CAS  PubMed  Google Scholar 

  35. Bruss, M., Porzgen, P., Bryan-Lluka, L. J. & Bonisch, H. The rat norepinephrine transporter: molecular cloning from PC12 cells and functional expression. Brain Res. Mol. Brain Res. 52, 257–262 (1997).

    CAS  PubMed  Google Scholar 

  36. Fritz, J. D., Jayanthi, L. D., Thoreson, M. A. & Blakely, R. D. Cloning and chromosomal mapping of the murine norepinephrine transporter. J. Neurochem. 70, 2241–2251 (1998).

    CAS  PubMed  Google Scholar 

  37. Jayanthi, L. D. et al. The Caenorhabditis elegans gene T23G5.5 encodes an antidepressant- and cocaine-sensitive dopamine transporter. Mol. Pharmacol. 54, 601–609 (1998).

    CAS  PubMed  Google Scholar 

  38. Mortensen, O. V., Kristensen, A. S., Rudnick, G. & Wiborg, O. Molecular cloning, expression and characterization of a bovine serotonin transporter. Brain Res. Mol. Brain Res. 71, 120–126 (1999).

    CAS  PubMed  Google Scholar 

  39. Porzgen, P., Park, S. K., Hirsh, J., Sonders, M. S. & Amara, S. G. The antidepressant-sensitive dopamine transporter in Drosophila melanogaster: a primordial carrier for catecholamines. Mol. Pharmacol. 59, 83–95 (2001).

    CAS  PubMed  Google Scholar 

  40. Miller, G. M., Yatin, S. M., De La Garza, R., Goulet, M. & Madras, B. K. Cloning of dopamine, norepinephrine and serotonin transporters from monkey brain: relevance to cocaine sensitivity. Brain Res. Mol. Brain Res. 87, 124–143 (2001).

    CAS  PubMed  Google Scholar 

  41. Sandhu, S. K., Ross, L. S. & Gill, S. S. A cocaine insensitive chimeric insect serotonin transporter reveals domains critical for cocaine interaction. Eur. J. Biochem. 269, 3934–3944 (2002).

    CAS  PubMed  Google Scholar 

  42. Masson, J., Sagne, M., Hamon, M. & El Mestikawy, S. Neurotransmitter transporters in the central nervous system. Pharmacol. Rev. 51, 439–464 (1999).

    CAS  PubMed  Google Scholar 

  43. Vandenbergh, D. J., Persico, A. M. & Uhl, G. R. Human dopamine transporter gene (DAT1) maps to chromosome 5p15.3 and displays a VNTR. Genomics 14, 1104–1106 (1992).

    CAS  PubMed  Google Scholar 

  44. Bannon, M. J., Michelhaugh, S. K., Wang, J. & Sacchetti, P. The human dopamine transporter gene: gene organization, transcriptional regulation, and potential involvement in neuropsychiatric disorders. Eur. Neuropsychopharmacol. 11, 449–455 (2001).

    CAS  PubMed  Google Scholar 

  45. Kawarai, T., Kawakami, H., Yamamura, Y. & Nakamura, S. Structure and organization of the gene encoding human dopamine transporter. Gene 195, 11–18 (1997).

    CAS  PubMed  Google Scholar 

  46. Gelernter J. et al. Assignment of the norepinephrine transporter protein (NET1) locus to chromosome 16. Genomics 18, 690–692 (1993).

    CAS  PubMed  Google Scholar 

  47. Porzgen, P., Bonisch, H., Hammermann, R. & Bruss, M. The human noradrenaline transporter gene contains multiple polyadenylation sites and two alternatively spliced C-terminal exons. Biochim. Biophys. Acta 1398, 365–370 (1998).

    CAS  PubMed  Google Scholar 

  48. Kitayama, S., Morita, K. & Dohi, T. Functional characterization of the splicing variants of human norepinephrine transporter. Neurosci. Lett. 312, 108–112 (2001).

    CAS  PubMed  Google Scholar 

  49. Sacchetti, P., Brownschidle, L. A., Granneman, J. G. & Bannon, M. J. Characterization of the 5′-flanking region of the human dopamine transporter gene. Mol. Brain Res. 74, 167–174 (1999).

    CAS  PubMed  Google Scholar 

  50. Meyer, J. et al. Cloning and functional characterization of the human norepinephrine transporter gene promoter. J. Neural. Transm. 105, 1341–1350 (1998).

    CAS  PubMed  Google Scholar 

  51. Heils, A. et al. Functional promoter and polyadenylation site mapping of the human serotonin (5-HT) transporter gene. J. Neural Transm. 102, 247–254 (1995).

    CAS  Google Scholar 

  52. Kim, C. H., Kim, H. S., Cubells, J. F. & Kim, K. S. 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, 6507–6518 (1999).

    CAS  PubMed  Google Scholar 

  53. Bruss, M., Hammermann, R., Brimijoin, S. & Bonisch, H. Antipeptide antibodies confirm the topology of the human norepinephrine transporter. J. Biol. Chem. 270, 9197–9201 (1995).

    CAS  PubMed  Google Scholar 

  54. Hersch, S. M., Yi, H., Heilman, C. J., Edwards, R. H. & Levey, A. I. Subcellular localization and molecular topology of the dopamine transporter in the striatum and substantia nigra. J. Comp. Neurol. 388, 211–227 (1997).

    CAS  PubMed  Google Scholar 

  55. Chen, J. G., Liu-Chen, S. & Rudnick, G. Determination of external loop topology in the serotonin transporter by site-directed chemical labeling. J. Biol. Chem. 273, 12675–12681 (1998).

    CAS  PubMed  Google Scholar 

  56. Androutsellis-Theotokis, A. & Rudnick, G. Accessibility and conformational coupling in serotonin transporter predicted internal domains. J. Neurosci. 22, 8370–8378 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Buck, K. J. & Amara, S. G. Chimeric dopamine-norepinephrine transporters delineate structural domains influencing selectivity for catecholamines and 1-methyl-4-phenylpyridinium. Proc. Natl Acad. Sci. USA 91, 12584–12588 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Buck, K. J. & Amara, S. G. Structural domains of catecholamine transporter chimeras involved in selective inhibition by antidepressants and psychomotor stimulants. Mol. Pharmacol. 48, 1030–1037 (1995).

    CAS  PubMed  Google Scholar 

  59. Lee, S. H., Kang, S., Son, H. & Lee, Y. S. The region of dopamine transporter encompassing the 3rd transmembrane domain is crucial for function. Biochem. Biophys. Res. Commun. 246, 347–352 (1998).

    CAS  PubMed  Google Scholar 

  60. Ferrer, J. V. & Javitch, J. A. Cocaine alters the accessibility of endogenous cysteines in putative extracellular and intracellular loops of the human dopamine transporter. Proc. Natl Acad. Sci. USA 95, 9238–9243 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Chen, N., Ferrer, J. V., Javitch, J. A. & Justice, J. B. Transport-dependent accessibility of a cytoplasmic loop cysteine in the human dopamine transporter. J. Biol. Chem. 275, 1608–1614 (2000).

    CAS  PubMed  Google Scholar 

  62. Loland, C. J., Norregaard, L., Litman, T. & Gether, U. Generation of an activating Zn2+ switch in the dopamine transporter: mutation of an intracellular tyrosine constitutively alters the conformational equilibrium of the transport cycle. Proc. Natl Acad. Sci. USA 99, 1683–1638 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Norregaard, L., Frederiksen, D., Nielsen, E. O. & Gether, U. Delineation of an endogenous zinc-binding site in the human dopamine transporter. EMBO J. 17, 4266–4273 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Kitayama, S. et al. Dopamine transporter site-directed mutations differentially alter substrate transport and cocaine binding. Proc. Natl Acad. Sci. USA 89, 7782–7785 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Barker, E. L., Moore, K. R., Rakhshan, F. & Blakely, R. D. Transmembrane domain I contributes to the permeation pathway for serotonin and ions in the serotonin transporter. J. Neurosci. 19, 4705–4717 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Chen, N., Vaughan, R. A. & Reith, M. E. The role of conserved tryptophan and acidic residues in the human dopamine transporter as characterized by site-directed mutagenesis. J. Neurochem. 77, 1116–1127 (2001).

    CAS  PubMed  Google Scholar 

  67. Lin, Z., Wang, W., Kopajtic, T., Revay, R. S. & Uhl, G. R. Dopamine transporter: transmembrane phenylalanine mutations can selectively influence dopamine uptake and cocaine analog recognition. Mol. Pharmacol. 56, 434–447 (1999).

    CAS  PubMed  Google Scholar 

  68. Lin, Z., Wang, W. & Uhl, G. R. Dopamine transporter tryptophan mutants highlight candidate dopamine- and cocaine-selective domains. Mol. Pharmacol. 58, 1581–1592 (2000).

    CAS  PubMed  Google Scholar 

  69. Mitsuhata, C. et al. Tyrosine-533 of rat dopamine transporter: involvement in interactions with 1-methyl-4-phenylpyridinium and cocaine. Brain Res. Mol. Brain Res. 56, 84–88 (1998).

    CAS  PubMed  Google Scholar 

  70. Barker, E. L., Kimmel, H. L. & Blakely, R. D. Chimeric human and rat serotonin transporters reveal domains involved in recognition of transporter ligands. Mol. Pharmacol. 46, 799–807 (1994).

    CAS  PubMed  Google Scholar 

  71. Barker, E. L. et al. High affinity recognition of serotonin transporter antagonists defined by species-scanning mutagenesis. An aromatic residue in transmembrane domain I dictates species-selective recognition of citalopram and mazindol. J. Biol. Chem. 273, 19459–19466 (1998).

    CAS  PubMed  Google Scholar 

  72. Smicun, Y., Campbell, S. D., Chen, M. A., Gu, H. & Rudnick, G. The role of external loop regions in serotonin transport. Loop scanning mutagenesis of the serotonin transporter external domain. J. Biol. Chem. 274, 36058–36064 (1999).

    CAS  PubMed  Google Scholar 

  73. Mortensen, O. V., Kristensen, A. S. & Wiborg, O. Species-scanning mutagenesis of the serotonin transporter reveals residues essential in selective, high-affinity recognition of antidepressants. J. Neurochem. 79, 237–247 (2001).

    CAS  PubMed  Google Scholar 

  74. Chen, J. G., Sachpatzidis, A. & Rudnick, G. The third transmembrane domain of the serotonin transporter contains residues associated with substrate and cocaine binding J. Biol. Chem. 272, 28321–28327 (1997).

    CAS  PubMed  Google Scholar 

  75. Chen, J. G. & Rudnick, G. Permeation and gating residues in serotonin transporter. Proc. Natl Acad. Sci. USA 97, 1044–1049 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Androutsellis-Theotokis, A., Ghassemi, F. & Rudnick, G. A conformationally sensitive residue on the cytoplasmic surface of serotonin transporter. J. Biol. Chem. 276, 45933–45938 (2001).

    CAS  PubMed  Google Scholar 

  77. Stephan, M. M., Chen, M. A., Penado, K. M. & Rudnick, G. An extracellular loop region of the serotonin transporter may be involved in the translocation mechanism. Biochemistry 36, 1322–1328 (1997).

    CAS  PubMed  Google Scholar 

  78. Kamdar, G., Penado, K. M., Rudnick, G. & Stephan, M. M. Functional role of critical stripe residues in transmembrane span 7 of the serotonin transporter. Effects of Na+, Li+, and methanethiosulfonate reagents. J. Biol. Chem. 276, 4038–4045 (2001).

    CAS  PubMed  Google Scholar 

  79. Sur, C., Betz, H. & Schloss, P. A single serine residue controls the cation dependence of substrate transport by the rat serotonin transporter. Proc. Natl Acad. Sci. USA 94, 7639–7644 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Rudnick, G. & Clark, J. From synapse to vesicle: the reuptake and storage of biogenic amine neurotransmitters. Biochim. Biophys. Acta. 1144, 249–263 (1993).

    CAS  PubMed  Google Scholar 

  81. Gu, H., Wall, S. C. & Rudnick, G. Stable expression of biogenic amine transporters reveals differences in inhibitor sensitivity, kinetics, and ion dependence. J. Biol. Chem. 269, 7124–7130 (1994).

    CAS  PubMed  Google Scholar 

  82. Fischer, J. F. & Cho, A. K. Chemical release of dopamine from striatal homogenates: evidence for an exchange diffusion model. J. Pharmacol. Exp. Ther. 208, 203–209 (1979).

    CAS  PubMed  Google Scholar 

  83. Mager, S. et al. Conducting states of a mammalian serotonin transporter. Neuron 12, 845–859 (1994).

    CAS  PubMed  Google Scholar 

  84. Galli, A., Blakely, R. D. & DeFelice, L. J. Norepinephrine transporters have channel modes of conduction. Proc. Natl Acad. Sci. USA 93, 8671–8676 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Sonders, M. S., Zhu, S. J., Zahniser, N. R., Kavanaugh, M. P. & Amara, S. G. Multiple ionic conductances of the human dopamine transporter: the actions of dopamine and psychostimulants. J. Neurosci. 17, 960–974 (1997). References 83–85 show that monoamine transporters are associated with conductances that are similar to ion channels.

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Ingram, S. L., Prasad, B. M. & Amara, S. G. Dopamine transporter-mediated conductances increase excitability of midbrain dopamine neurons. Nature Neurosci. 5, 971–978 (2002).

    CAS  PubMed  Google Scholar 

  87. Milner, H. E., Beliveau, R. & Jarvis, S. M. The in situ size of the dopamine transporter is a tetramer as estimated by radiation inactivation. Biochim. Biophys. Acta. 1190, 185–187 (1994).

    CAS  PubMed  Google Scholar 

  88. Jess, U., El Far, O., Kirsch, J. & Betz, H. The membrane-bound rat serotonin transporter, SERT1, is an oligomeric protein. FEBS Lett. 394, 44–46 (1996).

    CAS  PubMed  Google Scholar 

  89. Chang, A. S., Starnes, D. M. & Chang, S. M. Possible existence of quaternary structure in the high-affinity serotonin transport complex. Biochem. Biophys. Res. Commun. 249, 416–421 (1998).

    CAS  PubMed  Google Scholar 

  90. Kilic, F. & Rudnick, G. Oligomerization of serotonin transporter and its functional consequences. Proc. Natl Acad. Sci. USA 97, 3106–3111 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Schmid, J. A. et al. Oligomerization of the human serotonin transporter and of the rat GABA transporter 1 visualized by fluorescence resonance energy transfer microscopy in living cells. J. Biol. Chem. 276, 3805–3810 (2001).

    CAS  PubMed  Google Scholar 

  92. Hastrup, H., Karlin, A. & Javitch, J. A. Symmetrical dimer of the human dopamine transporter revealed by cross-linking Cys-306 at the extracellular end of the sixth transmembrane segment. Proc. Natl Acad. Sci. USA 98, 10055–10060 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Torres G. E. et al. Oligomerization and trafficking of the human dopamine transporter: mutational analysis identifies critical domains important for the functional expression of the transporter. J. Biol. Chem. 11 November 2002 (doi:10.1074/jbc.m201926200).

  94. Vaughan, R. A., Huff, R. A., Uhl, G. R. & Kuhar, M. J. Protein kinase C-mediated phosphorylation and functional regulation of dopamine transporters in striatal synaptosomes. J. Biol. Chem. 272, 15541–15546 (1997).

    CAS  PubMed  Google Scholar 

  95. Zhang, L., Coffey, L. L. & Reith, M. E. Regulation of the functional activity of the human dopamine transporter by protein kinase C. Biochem. Pharmacol. 53, 677–688 (1997).

    CAS  PubMed  Google Scholar 

  96. Bonisch, H., Hammermann, R. & Bruss, M. Role of protein kinase C and second messengers in regulation of the norepinephrine transporter. Adv. Pharmacol. 42, 183–186 (1998).

    CAS  PubMed  Google Scholar 

  97. Ramamoorthy, S., Giovanetti, E., Qian, Y. & Blakely R. D. Phosphorylation and regulation of antidepressant-sensitive serotonin transporters. J. Biol. Chem. 273, 2458–2466 (1998).

    CAS  PubMed  Google Scholar 

  98. Qian, Y. et al. Protein kinase C activation regulates human serotonin transporters in HEK-293 cells via altered cell surface expression. J. Neurosci. 17, 45–57 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Zhu, S. J., Kavanaugh, M. P., Sonders, M. S., Amara, S. G. & Zahniser, N. R. Activation of protein kinase C inhibits uptake, currents and binding associated with the human dopamine transporter expressed in Xenopus oocytes. J. Pharmacol. Exp. Ther. 282, 1358–1365 (1997).

    CAS  PubMed  Google Scholar 

  100. Apparsundaram, S., Schroeter, S., Giovanetti, E. & Blakely, R. D. Acute regulation of norepinephrine transport: II. PKC-modulated surface expression of human norepinephrine transporter proteins. J. Pharmacol. Exp. Ther. 287, 744–751 (1998).

    CAS  PubMed  Google Scholar 

  101. Daniels, G. M. & Amara, S. G. Regulated trafficking of the human dopamine transporter. Clathrin-mediated internalization and lysosomal degradation in response to phorbol esters. J. Biol. Chem. 274, 35794–35801 (1999).

    CAS  PubMed  Google Scholar 

  102. Melikian, H. E. & Buckley, K. M. Membrane trafficking regulates the activity of the human dopamine transporter. J. Neurosci. 19, 7699–7710 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Ramamoorthy, S. & Blakely, R. D. Phosphorylation and sequestration of serotonin transporters differentially modulated by psychostimulants. Science 285, 763–736 (1999). This paper shows that substrates of SERT, such as serotonin and amphetamine, blocked the PKC-dependent SERT internalization, providing a new mechanism through which the activity of SERT is regulated.

    CAS  PubMed  Google Scholar 

  104. Saunders, C. et al. Amphetamine-induced loss of human dopamine transporter activity: an internalization-dependent and cocaine-sensitive mechanism. Proc. Natl Acad. Sci. USA 97, 6850–6855 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Daws, L. C. et al. Cocaine increases dopamine uptake and cell surface expression of dopamine transporters. Biochem. Biophys. Res. Comm. 290, 1545–1550 (2002).

    CAS  PubMed  Google Scholar 

  106. Little, K. Y., Elmer, L. W., Zhong, H., Scheys, J. O. & Zhang, L. Cocaine induction of dopamine transporter trafficking to the plasma membrane. Mol. Pharmacol. 61, 436–445 (2002).

    CAS  PubMed  Google Scholar 

  107. Chang, M. Y. et al. Protein kinase C-mediated functional regulation of dopamine transporter is not achieved by direct phosphorylation of the dopamine transporter protein. J. Neurochem. 77, 754–761 (2001).

    CAS  PubMed  Google Scholar 

  108. Sakai, N. et al. Modulation of serotonin transporter activity by a protein kinase C activator and an inhibitor of type 1 and 2A serine/threonine phosphatases. J. Neurochem. 68, 2618–2624 (1997).

    CAS  PubMed  Google Scholar 

  109. Foster, J. D., Pananusorn, B. & Vaughan, R. A. Dopamine transporters are phosphorylated on N-terminal serines in rat striatum. J. Biol. Chem. 277, 25178–25186 (2002).

    CAS  PubMed  Google Scholar 

  110. Zahniser, N. R. & Doolen, S. Chronic and acute regulation of Na+/Cl-dependent neurotransmitter transporters: drugs, substrates, presynaptic receptors, and signaling systems. Pharmacol. Ther. 92, 21–55 (2001). This is a comprehensive review of the regulatory mechanisms associated with monoamine transporters.

    CAS  PubMed  Google Scholar 

  111. Zhu, M. Y. & Ordway, G. A. Down-regulation of norepinephrine transporters on PC12 cells by transporter inhibitors. J. Neurochem. 68, 134–141 (1997).

    CAS  PubMed  Google Scholar 

  112. Zhu, M. Y., Blakely, R. D., Apparsundaram, S. & Ordway, G. A. Down-regulation of the human norepinephrine transporter in intact 293-hNET cells exposed to desipramine. J. Neurochem. 70, 1547–1555 (1998).

    CAS  PubMed  Google Scholar 

  113. Benmansour, S. et al. Effects of chronic antidepressant treatments on serotonin transporter function, density, and mRNA level. J. Neurosci. 19, 10494–10501 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Benmansour, S., Owens, W. A., Cecchi, M., Morilak, D. A. & Frazer, A. Serotonin clearance in vivo is altered to a greater extent by antidepressant-induced downregulation of the serotonin transporter than by acute blockade of this transporter. J. Neurosci. 22, 6766–6772 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Lew, R., Vaughan, R., Simantov, R., Wilson, A. & Kuhar, M. J. Dopamine transporters in the nucleus accumbens and the striatum have different apparent molecular weights. Synapse 8, 152–153 (1991).

    CAS  PubMed  Google Scholar 

  116. Patel, A., Uhl, G. R. & Kuhar, M. J. Species differences in dopamine transporters: postmortem changes and glycosylation differences. J. Neurochem. 61, 496–500 (1993).

    CAS  PubMed  Google Scholar 

  117. Patel, A. P., Cerruti, C., Vaughan, R. A. & Kuhar, M. J. Developmentally regulated glycosylation of dopamine transporter. Brain Res. Dev. Brain Res. 83, 53–58 (1994).

    CAS  PubMed  Google Scholar 

  118. Tate, C. G. & Blakely, R. D. The effect of N-linked glycosylation on activity of the Na+- and Cl-dependent serotonin transporter expressed using recombinant baculovirus in insect cells. J. Biol. Chem. 269, 26303–26310 (1994).

    CAS  PubMed  Google Scholar 

  119. Nguyen, T. T. & Amara, S. G. N-linked oligosaccharides are required for cell surface expression of the norepinephrine transporter but do not influence substrate or inhibitor recognition. J. Neurochem. 67, 645–655 (1996).

    CAS  PubMed  Google Scholar 

  120. Melikian, H. E., Ramamoorthy, S., Tate, C. G. & Blakely, R. D. Inability to N-glycosylate the human norepinephrine transporter reduces protein stability, surface trafficking, and transport activity but not ligand recognition. Mol. Pharmacol. 50, 266–276 (1996).

    CAS  PubMed  Google Scholar 

  121. Bauman, A. L. et al. Cocaine and antidepressant-sensitive biogenic amine transporters exist in regulated complexes with protein phosphatase 2A. J. Neurosci. 20, 7571–7578 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Jess, U., El Far, O., Kirsch, J. & Betz, H. Interaction of the C-terminal region of the rat serotonin transporter with MacMARCKS modulates 5-HT uptake regulation by protein kinase C. Biochem. Biophys. Res. Comm. 294, 272–279 (2002).

    CAS  PubMed  Google Scholar 

  123. Lee, F. J., Liu, F., Pristupa, Z. B. & Niznik, H. B. Direct binding and functional coupling of α-synuclein to the dopamine transporters accelerate dopamine-induced apoptosis. FASEB J. 15, 916–926 (2001).

    CAS  PubMed  Google Scholar 

  124. Gwinn-Hardy, K. Genetics of parkinsonism. Mov. Disord. 17, 645–656 (2002).

    PubMed  Google Scholar 

  125. Lehmensiek, V., Tan, E. M., Schwarz, J. & Storch, A. Expression of mutant α-synucleins enhances dopamine transporter-mediated MPP+ toxicity in vitro. Neuroreport 13, 1279–1283 (2002).

    CAS  PubMed  Google Scholar 

  126. Torres, G. E. et al. Functional interaction between monoamine plasma membrane transporters and the synaptic PDZ domain-containing protein PICK1. Neuron 30, 121–134 (2001).

    CAS  PubMed  Google Scholar 

  127. Carneiro, A. M. et al. The multiple LIM domain-containing adaptor protein Hic-5 synaptically colocalizes and interacts with the dopamine transporter. J. Neurosci. 22, 7045–7054 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Giros, B., Jaber, M., Jones, S. R., Wightman, R. M. & Caron, M. G. Hyperlocomotion and indifference to cocaine and amphetamine in mice lacking the dopamine transporter. Nature 379, 606–712 (1996).

    CAS  PubMed  Google Scholar 

  129. Xu, F. et al. Mice lacking the norepinephrine transporter are supersensitive to psychostimulants. Nature Neurosci. 3, 465–471 (2000).

    CAS  PubMed  Google Scholar 

  130. Bengel, D. et al. Altered brain serotonin homeostasis and locomotor insensitivity to 3, 4-methylenedioxymethamphetamine (“Ecstasy”) in serotonin transporter-deficient mice. Mol. Pharmacol. 53, 649–655 (1998). References 128–130 showed the essential role of monoamine transporters in the control of presynaptic homeostasis in mice lacking functional monoamine transporters.

    CAS  PubMed  Google Scholar 

  131. Jones, S. R. et al. Profound neuronal plasticity in response to inactivation of the dopamine transporter. Proc. Natl Acad. Sci. USA 95, 4029–4034 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Gainetdinov, R. R., Sotnikova, T. D. & Caron, M. G. Monoamine transporter pharmacology and mutant mice Trends Pharmacol. Sci. 23, 367–373 (2002).

    CAS  PubMed  Google Scholar 

  133. Gainetdinov, R. R. & Caron, M. G. Monoamine transporters: from genes to behavior. Annu. Rev. Pharmacol. Toxicol. 43, 261–284 (2003).

    CAS  PubMed  Google Scholar 

  134. Murphy, D. L. et al. Consequences of engineered and spontaneous genetic alterations of the 5-HT transporter in mice, men, and women. Behav. Pharmacol. 10, S65 (1999).

    Google Scholar 

  135. Fabre, V. et al. Altered expression and functions of serotonin 5-HT1A and 5-HT1B receptors in knock-out mice lacking the 5-HT transporter. Eur. J. Neurosci. 12, 2299–2310 (2000).

    CAS  PubMed  Google Scholar 

  136. Rocha, B. A. et al. Cocaine self-administration in dopamine transporter knockout mice. Nature Neurosci. 1, 132–133 (1998).

    CAS  PubMed  Google Scholar 

  137. Sora, I. et al. Cocaine reward models: conditioned place preference can be established in dopamine- and in serotonin-transporter knockout mice. Proc. Natl Acad. Sci. USA 95, 7699–7704 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Sora, I. et al. Molecular mechanisms of cocaine reward: combined dopamine and serotonin transporter knockouts eliminate cocaine place preference. Proc. Natl Acad. Sci. USA 98, 5300–5305 (2001). References 136 and 138 provide evidence that mechanisms other than DAT blockade might contribute to the rewarding properties of psychostimulants.

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Carboni, E. et al. Cocaine and amphetamine increase extracellular dopamine in the nucleus accumbens of mice lacking the dopamine transporter gene. J. Neurosci. 21, 1–4 (2001).

    Google Scholar 

  140. Budygin, E. A., John, C. E., Mateo, Y. & Jones, S. R. Lack of cocaine effect on dopamine clearance in the core and shell of the nucleus accumbens of dopamine-transporter knockout mice. J. Neurosci. 22, RC222 (2002).

    PubMed  PubMed Central  Google Scholar 

  141. Hall, F. S. et al. Cocaine mechanisms: enhanced cocaine, fluoxetine and nisoxetine place preferences following monoamine transporter deletions. Neuroscience 115, 153–161 (2002).

    CAS  PubMed  Google Scholar 

  142. Gainetdinov, R. R. et al. Role of serotonin in the paradoxical calming effect of psychostimulants on hyperactivity. Science 283, 397–401 (1999). This study showed that in the absence of a functional DAT, psychostimulants can inhibit hyperactivity primarily through their actions with SERT.

    CAS  PubMed  Google Scholar 

  143. Laakso, A. & Hietala, J. PET studies of brain monoamine transporters. Curr. Pharm. Des. 6, 1611–1623 (2000).

    CAS  PubMed  Google Scholar 

  144. Volkow, N. D. et al. Decreased dopamine transporters with age in health human subjects. Ann. Neurol. 36, 237–239 (1994).

    CAS  PubMed  Google Scholar 

  145. Kim, H. J. et al. Imaging and quantitation of dopamine transporters with iodine-123-IPT in normal and Parkinson's disease subjects. J. Nucl. Med. 38, 1703–1711 (1997).

    CAS  PubMed  Google Scholar 

  146. Jeon, B. et al. Dopamine transporter imaging with [123I]-β-CIT demonstrates presynaptic nigrostriatal dopaminergic damage in Wilson's disease. J. Neurol. Neurosurg. Psychiatry 65, 60–64 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Wong, D. F. et al. Dopamine transporters are markedly reduced in Lesch-Nyhan disease in vivo. Proc. Natl Acad. Sci. USA 93, 5539–5543 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Malison, R. T. et al. [123I]β–CIT SPECT imaging of striatal dopamine transporter binding in Tourette's disorder. Am. J. Psychiatry 152, 1359–1361 (1995).

    CAS  PubMed  Google Scholar 

  149. Laasonen-Balk, T. et al. Striatal dopamine transporter density in major depression. Psychopharmacology 144, 282–285 (1999).

    CAS  PubMed  Google Scholar 

  150. Dougherty, D. D. et al. Dopamine transporter density in patients with attention deficit hyperactivity disorder. Lancet 354, 2132–2133 (1999).

    CAS  PubMed  Google Scholar 

  151. Tiihonen, J. et al. Single-photon emission tomography imaging of monoamine transporters in impulsive violent behaviour. Eur. J. Nucl. Med. 24, 1253–1260 (1997).

    CAS  PubMed  Google Scholar 

  152. Heinz, A. et al. Reduced central serotonin transporters in alcoholism. Am. J. Psychiatry 155, 1544–1549 (1998).

    CAS  PubMed  Google Scholar 

  153. Malison, R. T. et al. Reduced brain serotonin transporter availability in major depression as measured by [123I]-2 β-carbomethoxy-3 β-(4-iodophenyl)tropane and single photon emission computed tomography. Biol. Psychiatry 44, 1090–1098 (1998).

    CAS  PubMed  Google Scholar 

  154. Klimek, V. et al. Reduced levels of norepinephrine transporters in the locus coeruleus in major depression. J. Neurosci. 17, 8451–8458 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  155. Cook, E. H. Jr et al. Association of attention-deficit disorder and the dopamine transporter gene. Am. J. Hum. Genet. 56, 993–998 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Lesch, K. P. et al. Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 274, 1527–1531 (1996). References 155 and 156 provided the initial suggestions that genetic variations in monoamine transporter genes might contribute to pathological conditions

    CAS  PubMed  Google Scholar 

  157. Bengel, D. et al. Association of the serotonin transporter promoter regulatory region polymorphism and obsessive-compulsive disorder. Mol. Psychiatry 4, 463–466 (1999).

    CAS  PubMed  Google Scholar 

  158. Seeger, G., Schloss, P. & Schmidt, M. H. Functional polymorphism within the promotor of the serotonin transporter gene is associated with severe hyperkinetic disorders. Mol. Psychiatry 6, 235–238 (2001).

    CAS  PubMed  Google Scholar 

  159. Manor, I. et al. Family-based association study of the serotonin transporter promoter region polymorphism (5-HTTLPR) in attention deficit hyperactivity disorder. Am. J. Med. Genet. 105, 91–95 (2001).

    CAS  PubMed  Google Scholar 

  160. Shannon, J. R. et al. Orthostatic intolerance and tachycardia associated with norepinephrine-transporter deficiency. N. Engl. J. Med. 342, 541–549 (2000). This study showed, for the first time, that a variant in the coding region of a monoamine transporter is associated with a human pathology.

    CAS  PubMed  Google Scholar 

  161. Hoffman, B. J., Hansson, S. R., Mezey, E. & Palkovits, M. Localization and dynamic regulation of biogenic amine transporters in the mammalian central nervous system. Front. Neuroendocrinol. 19, 187–231 (1998).

    CAS  PubMed  Google Scholar 

  162. Freed, C. et al. Dopamine transporter immunoreactivity in rat brain. J. Comp. Neurol. 359, 340–349 (1995).

    CAS  PubMed  Google Scholar 

  163. Ciliax, B. J. et al. The dopamine transporter: immunochemical characterization and localization in brain. J. Neurosci. 15, 1714–1723 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  164. Schroeter, S. et al. Immunolocalization of the cocaine- and antidepressant-sensitive L-norepinephrine transporter. J. Comp. Neurol. 420, 211–232 (2000).

    CAS  PubMed  Google Scholar 

  165. Qian, Y., Melikian, H. E., Rye, D. B., Levey, A. I. & Blakely, R. D. Identification and characterization of antidepressant-sensitive serotonin transporter proteins using site-specific antibodies. J. Neurosci. 15, 1261–1274 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  166. Sur, C., Betz, H. & Schloss, P. Immunocytochemical detection of the serotonin transporter in rat brain. Neuroscience 73, 217–231 (1996).

    CAS  PubMed  Google Scholar 

  167. Nirenberg, M. J. et al. The dopamine transporter: comparative ultrastructure of dopaminergic axons in limbic and motor compartments of the nucleus accumbens. J. Neurosci. 17, 6899–6997 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  168. Zhou, F. C., Tao-Cheng, J. H., Segu, L., Patel, T. & Wang, Y. Serotonin transporters are located on the axons beyond the synaptic junctions: anatomical and functional evidence. Brain Res. 805, 241–254 (1998).

    CAS  PubMed  Google Scholar 

  169. Pickel, V. M. & Chan, J. Ultrastructural localization of the serotonin transporter in limbic and motor compartments of the nucleus accumbens. J. Neurosci. 19, 7356–7366 (1999). References 167–169 showed that monoamine transporters are not localized to synapses, but to extrasynaptic sites away from sites of release.

    CAS  PubMed  PubMed Central  Google Scholar 

  170. Eisenhofer, G. The role of neuronal and extraneuronal plasma membrane transporters in the inactivation of peripheral catecholamines. Pharmacol. Ther. 91, 35–62 (2001).

    CAS  PubMed  Google Scholar 

  171. Talvenheimo, J. & Rudnick, G. Solubilization of the platelet plasma membrane serotonin transporter in an active form. J. Biol. Chem. 255, 8606–8611 (1980).

    CAS  PubMed  Google Scholar 

  172. Wade, P. R. et al. Localization and function of a 5-HT transporter in crypt epithelia of the astrointestinal tract. J. Neurosci. 16, 2352–2364 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  173. Schroeter, S., Levey, A. I. & Blakely, R. D. Polarized expression of the antidepressant-sensitive serotonin transporter in epinephrine-synthesizing chromaffin cells of the rat adrenal gland. Mol. Cell. Neurosci. 9, 170–184 (1997).

    CAS  PubMed  Google Scholar 

  174. Kimelberg, H. K. & Katz, D. M. High-affinity uptake of serotonin into immunocytochemically identified astrocytes. Science 228, 889–891 (1985).

    CAS  PubMed  Google Scholar 

  175. Chen, N. & Reith, M. A. in Neurotransmitter Transporters 2nd edn (ed. Reith, M. E. A.) 60 (Humana Press, New Jersey, 2002).

    Google Scholar 

Download references

Acknowledgements

We would like to thank V. Sandoval for helpful discussions and M. Reith for his contribution to the preparation of this article. We are also grateful to the National Institute on Drug Abuse and to the National Institute of Mental Health for support of work in the authors' laboratory. M.G.C. is an investigator of the Howard Hughes Medical Institute.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Marc G. Caron.

Related links

Related links

DATABASES

LocusLink

DAT

Hic-5

MacMARCKS

NET

PICK1

SERT

α-synuclein

OMIM

ADHD

FURTHER INFORMATION

Encyclopedia of Life Sciences

addiction

adrenaline and noradrenaline: introduction

amine neurotransmitters

ATPases: ion-motive

attention deficit–hyperactivity disorder

cocaine and amphetamines

dopamine

dopamine receptors: molecular pharmacology

G protein-coupled receptors

Hallucinogenic drugs

mouse knockouts

Parkinson disease

protein kinases

serotonin

serotonin receptors

Glossary

MICRODIALYSIS

Analytical technique that is used to monitor extracellular levels of neurotransmitters or other molecules in vivo. A cannula is inserted into the brain and test solution is perfused through it. Dialysis takes place between the test and the extracellular solutions, making it possible to measure the transmitter levels at the tissue surrounding the tip of the cannula.

TRICYCLIC ANTIDEPRESSANTS

Molecules that inhibit monoamine reuptake, therefore prolonging the period during which these neurotransmitters are active at the synaptic cleft.

EXPRESSION CLONING

Cloning strategy that is based on the transfection of cDNAs such that functional proteins are expressed, followed by a screening of the functional activity of the gene of interest.

SPLICE VARIANTS

Further forms of a protein derived from alternative processing of its mRNA.

POLYMORPHIC VARIANTS

Genotypic variants that exist in the same population in frequencies that cannot be explained by recurrent mutations.

POLYTOPIC

A term that refers to a transmembrane protein that traverses the membrane two or more times.

CHIMAERIC

Molecules that are constructed from functional domains that belong to homologue and orthologue proteins. They are commonly used to identify the structural determinants of the functional properties in the parental proteins.

SUBSTITUTED CYSTEINE ACCESSIBILITY METHOD (SCAM).

A method used to identify the residues that are probably exposed to a solvent, such as those that line the pore of a channel. It is based on the systematic replacement of native amino acids by cysteines to then test the ability of hydrophilic molecules to react with the added cysteines. If a cysteine is accessible to the hydrophilic reagent, then channel permeability will be affected.

SITE-DIRECTED MUTAGENESIS

The generation of a mutation at a predetermined position in a DNA sequence. The most common method involves the use of a chemically synthesized mutant DNA strand that can hybridize with the target molecule.

CONCATAMER

A linear array of identical molecules that are covalently linked in tandem. They can be useful to determine the stoichiometry of homomeric macromolecular complexes.

TAGGED PROTEIN

The lack of specific antibodies against many proteins makes it necessary to develop alternative methods for their visualization. Tagging the amino or carboxyl termini of proteins with short peptides that can then be used as epitopes is one of the most commonly used approaches.

FLUORESCENCE RESONANCE ENERGY TRANSFER (FRET).

A spectroscopic technique that is based on the transfer of energy from the excited state of a donor moiety to an acceptor. The transfer efficiency depends on the distance between the donor and the acceptor.

GLYCOPHORIN

Protein with a single transmembrane domain that has been shown to mediate the non-covalent dimerization of this molecule.

DOMINANT NEGATIVE

A mutant molecule that can form a heteromeric complex with the normal molecule, knocking out the activity of the entire complex.

LEUCINE REPEAT

A leucine-rich domain within a protein that binds to other proteins with a similar domain.

CLATHRIN

A major structural component of coated vesicles that are implicated in protein transport. Clathrin heavy and light chains form a triskelion, the main building element of clathrin coats.

DYNAMIN

A GTPase that takes part in endocytosis. It seems to be involved in severing the connection between the nascent vesicle and the donor membrane.

PDZ DOMAIN

A peptide-binding domain that is important for the organization of membrane proteins, particularly at cell–cell junctions, including synapses. It can bind to the carboxyl termini of proteins or can form dimers with other PDZ domains.

YEAST TWO-HYBRID SYSTEM

A system used to determine the existence of direct interactions between proteins. It involves the use of plasmids that encode two hybrid proteins; one of them is fused to the GAL4 DNA-binding domain and the other one is fused to the GAL4 activation domain. The two proteins are expressed together in yeast; if they interact, then the resulting complex will drive the expression of a reporter gene, commonly β-galactosidase.

LIM HOMEODOMAIN

A domain that is found in several proteins, many of which function as transcription factors. Many LIM-homeodomain-containing proteins are involved in developmental processes or cell differentiation.

PLACE PREFERENCE

In this experimental model, a drug with a rewarding effect is injected to an animal, which is then placed in a chamber with specific environmental cues. Over time, the animal develops an association between the rewarding effect of the drug and the environmental cues. In this way, if the animal is given the choice between a chamber containing drug-associated cues and a chamber with neutral cues, it spends more time in the chamber with the drug-associated cues.

FAST SCAN CYCLIC VOLTAMETRY

An analytical technique for the real-time measurement of evoked monoamine release and clearance in extracellular brain fluid.

PERSEVERATIVE ERRORS

Cases in which a subject sticks to a specific strategy when solving a problem despite the fact that the strategy is wrong or the rule of the task has changed.

SINGLE-PHOTON EMISSION COMPUTED TOMOGRAPHY

(SPECT). A method in which images are generated by using radionuclides that emit single photons of a given energy. Images are captured at multiple positions by rotating the sensor around the subject; the three-dimensional distribution of radionuclides is then used to reconstruct the images. SPECT can be used to observe biochemical and physiological processes, as well as the size and volume of structures.

WILSON'S DISEASE

Genetic disorder that causes excessive copper accumulation in the liver and brain, resulting in hepatitis, as well as in psychiatric and neurological symptoms.

LESCH–NYHAN SYNDROME

X-linked recessive disorder that is caused by alterations in the activity of the enzyme hypoxanthine-guanine phosphoribosyltransferase. It is characterized by self-mutilating behaviours such as lip and finger biting, and head banging.

TOURETTE'S SYNDROME

A disorder that is thought to be caused by abnormalities of the basal ganglia. It is characterized by facial and vocal tics and less frequently by verbal profanities.

ORTHOSTATIC INTOLERANCE

Condition that is characterized by light-headedness and fainting when the upright position is assumed. Its causes are unknown, but it might be related to low blood pressure and an inadequate supply of blood to the brain.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Torres, G., Gainetdinov, R. & Caron, M. Plasma membrane monoamine transporters: structure, regulation and function. Nat Rev Neurosci 4, 13–25 (2003). https://doi.org/10.1038/nrn1008

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrn1008

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing