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Mechanisms of Biogenic Amine Neurotransmitter Transporters

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Book cover Neurotransmitter Transporters

Part of the book series: Contemporary Neuroscience ((CNEURO))

Abstract

The biogenic amine transporters, as described in Chapters 1, 4, 5, and 12 terminate the action of released biogenic amine neurotransmitters. These transporters utilize norepinephrine (NE), dopamine (DA), and serotonin (5-HT), and are referred to as NET, DAT, and SERT, respectively. Interruption of their function by agents, such as antidepressants and stimulants, causes profound changes in mood and behavior. In addition to their importance in regulating the extra-cellular concentration of neurotransmitters, these proteins are fascinating molecular machines that utilize the energy from trans-membrane ion gradients to accumulate intracellular neurotransmitters. The pharmacology and molecular biology of these proteins is well covered in Chapters 1, 9, 11, and 12. This chapter focuses on the mechanism of neurotransmitter transport. Researchers are still far from completely understanding how these proteins work; however, recent advances give insight into the mechanism and encourage the hope that more understanding of the transport mechanism will issue from current and future research.

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References

  1. Azzaro, A. J., Ziance, R. J., and Rutledge, C. O. The importance of neuronal uptake of amines for amphetamine-induced release of 3H-norepinephrine from isolated brain tissue. J. Pharmacol. Exp. Ther. 189 (1974) 110–118.

    PubMed  CAS  Google Scholar 

  2. Balkovetz, D. F., Tirruppathi, C., Leibach, F. H., Mahesh, V. B., and Ganapathy, V. Evidence for an imipramine-sensitive serotonin transporter in human placental brush-border membranes. J. Biol. Chem. 264 (1989) 2195–2198.

    PubMed  CAS  Google Scholar 

  3. Bennett, J. P., Jr., Logan, W. J., and Snyder, S. H. Amino acid neurotransmitter candidates: sodium-dependent high-affinity uptake by unique synaptosomal fractions. Science 178 (1972) 997–999.

    Article  PubMed  CAS  Google Scholar 

  4. Bouvier, M., Szatkowski, M., Amato, A., and Attwell, D. The glial cell glutamate uptake carrier countertransports pH-changing anions. Nature 360 (1992) 471–474.

    Article  PubMed  CAS  Google Scholar 

  5. Brown, C. D., Bodmer, M., Biber, J., and Murer, H. Sodium-dependent phosphate transport by apical membrane vesicles from a cultured renal epithelial cell line (LLC-PK1). Biochim. Biophys. Acta 769 (1984) 471–478.

    Article  PubMed  CAS  Google Scholar 

  6. Cammack, J. N., Rakhilin, S. V., and Schwartz, E. A. A GAGA transporter operates asymmetrically and with variable stoichiometry. Neuron 13 (1994) 949–960.

    Article  PubMed  CAS  Google Scholar 

  7. Cammack, J. N. and Schwartz, E. A. Channel behavior in a GABA transporter. Proc. Natl. Acad. Sci. USA 93 (1996) 723–727.

    Article  PubMed  CAS  Google Scholar 

  8. Cool, D. A., Leibach, F. H., and Ganapathy, V. High-affinity paroxetine binding to the human placental serotonin transporter. Am. J. Physiol. 259 (1990) C196 — C204.

    PubMed  CAS  Google Scholar 

  9. Cool, D. R., Leibach, F. H., and Ganapathy, V. Modulation of serotonin uptake kinetics by ions and ion gradients in human placental brush-border membrane vesicles. Biochemistry 29 (1990) 1818–1822.

    Article  PubMed  CAS  Google Scholar 

  10. Crane, R. K., Forstner, G., and Eichholz, A. Studies on the mechanism of the intestinal absorption of sugars. Biochim. Biophys. Acta 109 (1965) 467–477.

    Article  PubMed  CAS  Google Scholar 

  11. Curtis, D. and Johnston, G. Amino acid transmitters in the mammalian central nervous system. Rev. Physiol. Biochem. Exp. Pharm. 69 (1974) 97–188.

    CAS  Google Scholar 

  12. Fairman, W. A., Vandenberg, R. J., Arriza, J. L., Kavanaugh, M. P., and Amara, S. G. An excitatory amino-acid transporter with properties of a ligand-gated chloride channel. Nature 375 (1995) 599–603.

    Article  PubMed  CAS  Google Scholar 

  13. Fischer, J. F. and Cho, A. K. Chemical release of dopamine from striatal homogenates: evidence for an exchange diffusion model. J. Pharm. Exp. Therap. 208 (1979) 203–209.

    CAS  Google Scholar 

  14. Friedrich, U. and Bonisch, H. The neuronal noradrenaline transport system of PC-12 cells: kinetic analysis of the interaction between noradrenaline, Nat and Cl-in transport. Naunyn-Schmiedegergs Arch. Pharmacol. 333 (1986) 246–252.

    Article  CAS  Google Scholar 

  15. Galli, A., Blakely, R. D., and DeFelice, L. J. Norepinephrine transporters have channel modes of conduction. Proc. Natl. Acad. Sci. USA (1996) in press.

    Google Scholar 

  16. Galli, A., DeFelice, L. J., Duke, B. J., Moore, K. R., and Blakely, R. D. Sodium-dependent norepinephrine-induced currents in norepinephrine-transportertransfected Hek-293 cells blocked By cocaine and antidepressants. J. Exp. Biol. 198 (1995) 2197–2212.

    PubMed  CAS  Google Scholar 

  17. Gu, H. H., Wall, S. C., and Rudnick, G. Ion coupling stoichiometry for the nor-epinephrine transporter in membrane vesicles from stably transfected cells. J. Biol. Chem. 271 (1996), 6911–6916.

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  19. Harder, R. and Bonisch, H. Effects of monovalent ions on the transport of noradrenaline across the plasma membrane of neuronal cells (PC-12 cells), J. Neurochem. 45 (1985) 1154–1162.

    Article  PubMed  CAS  Google Scholar 

  20. Higgins, C. Volume-activated chloride currents associated with the multidrug resistance P-glycoprotein. J. Physiol. (Lond.) 482 (1995) 31S - 365.

    CAS  Google Scholar 

  21. Humphreys, C. J., Beidler, D., and Rudnick, G. Substrate and inhibitor binding and translocation by the platelet plasma membrane serotonin transporter. Biochem. Soc. Trans. 19 (1991) 95–98.

    PubMed  CAS  Google Scholar 

  22. Humphreys, C. J., Wall, S. C., and Rudnick, G. Ligand binding to the serotonin transporter: equilibria, kinetics and ion dependence. Biochemistry 33 (1994) 9118–9125.

    Article  PubMed  CAS  Google Scholar 

  23. Iversen, L. L. Neuronal uptake processes for amines and amino acids. Adv. Biochem. Psychopharmacol. 2 (1970) 109–132.

    PubMed  CAS  Google Scholar 

  24. Iversen, L. L. The Uptake and Storage of Noradrenaline in Sympathetic Nerves. Cambridge University Press, Cambridge, UK, 1967.

    Google Scholar 

  25. Johnson, R. G. and Scarpa, A. Protonmotive force and catecholamine transport in isolated chromaffin granules. J. Biol. Chem. 254 (1979) 3750–3760.

    PubMed  CAS  Google Scholar 

  26. Jones, E. M. C. Nat-and Cl--dependent neurotransmitter transporters in bovine retina-identification and localization by in situ hybridization histochemistry. Vis. Neurosci. 12 (1995) 1135–1142.

    Article  PubMed  CAS  Google Scholar 

  27. Kanner, B. I. Active transport of y-aminobutyric acid by membrane vesicles isolated from rat brain. Biochemistry 17 (1978) 1207–1211.

    Article  PubMed  CAS  Google Scholar 

  28. Kanner, B. I. and Bendahan, A. Transport of 5-hydroxytryptamine in membrane vesicles from rat basophillic leukemia cells. Biochim. Biophys. Acta 816 (1985) 403–410.

    Article  PubMed  CAS  Google Scholar 

  29. Kanner, B. I. and Sharon, I. Active transport of i-glutamate by membrane vesicles isolated from rat brain. Biochemistry 17 (1978) 3949–3953.

    Article  PubMed  CAS  Google Scholar 

  30. Keyes, S. R. and Rudnick, G. Coupling of transmembrane proton gradients to platelet serotonin transport. J. Biol. Chem. 257 (1982) 1172–1176.

    PubMed  CAS  Google Scholar 

  31. Keynan, S. and Kanner, B. I. y-aminobutyric acid transport in reconstituted preparations from rat brain: coupled sodium and chloride fluxes. Biochemistry 27 (1988) 12–17.

    Article  PubMed  CAS  Google Scholar 

  32. Keynan, S., Suh, Y. J., Kanner, B. I., and Rudnick, G. Expression of a cloned y-aminobutyric acid transporter in mammalian cells. Biochemistry 31 (1992) 1974–1979.

    Article  PubMed  CAS  Google Scholar 

  33. Knoth, J., Isaacs, J., and Njus, D. Amine transport in chromaffin granule ghosts. pH dependence implies cationic form is translocated. J. Biol. Chem. 256 (1981) 6541–6543.

    PubMed  CAS  Google Scholar 

  34. Kobold, G., Langer, R., and Burger, A. Does the carrier of chromaffin granules transport the protonated or the uncharged species of catecholamines? NauynSchmiedegergs Arch. Pharmacol. 331 (1985) 209–219.

    Article  CAS  Google Scholar 

  35. Krnjevic, K. Chemical nature of synaptic transmission in vertebrates. Physiol. Rev. 54 (1974) 418–540.

    CAS  Google Scholar 

  36. Kuhar, M. J. Neurotransmitter uptake: a tool in identifying neurotransmitter-specific pathways. Life Sci. 13 (1973) 1623–1634.

    Article  PubMed  CAS  Google Scholar 

  37. Kuhar, M. J. and Zarbin, M. A. Synaptosomal transport: a chloride dependence for choline, GABA, glycine and several other compounds. J. Neurochem. 31 (1978) 251–256.

    Article  PubMed  CAS  Google Scholar 

  38. Lee, C. M., Javitch, J. A., and Snyder, S. H. Characterization of [3H]desipramine binding associated with neuronal norepinephrine uptake sites in rat brain membranes. J. Neurosci. 2 (1982) 1515–1525.

    PubMed  CAS  Google Scholar 

  39. Levi, G. and Raiteri, M. Synaptosomal transport processes. Int. Rev. Neurobiol. 19 (1976) 51–74.

    Article  PubMed  CAS  Google Scholar 

  40. Lin, F., Lester, H. A., and Mager, S. Single channel currents at the serotonin transporter reveal an amino acid in the permeation pathway. Submitted for publication (1996).

    Google Scholar 

  41. Lin, F., Lester, H. A., and Mager, S. Single channel studies of the serotonin transporter: (A) Different conducting states and (B) An amino acid in the permeation pathway. Soc. Neurosci. Abstract 21 (1995) 781.

    Google Scholar 

  42. Mager, S., Min, C., Henry, D. J., Chavkin, C., Hoffman, B. J., Davidson, N., and Lester, H. A. Conducting states of a mammalian serotonin transporter. Neuron 12 (1994) 845–859.

    Article  PubMed  CAS  Google Scholar 

  43. Mager, S., Naeve, J., Quick, M., Labarca, C., Davidson, N., and Lester, H. A. Steady states, charge movements, and rates for a cloned GAGA transporter expressed in Xenopus oocytes. Neuron 10 (1993) 177–188.

    Article  PubMed  CAS  Google Scholar 

  44. Mamounas, L. A., Mullen, C., Ohearn, E., and Molliver, M. E. Dual serotoninergic projections to forebrain in the rat-morphologically distinct 5-HT axon terminals exhibit differential vulnerability to nerutotoxic amphetamine derivatives. J. Comp. Neurol. 314 (1991) 558–586.

    Article  PubMed  CAS  Google Scholar 

  45. McElvain, J. S. and Schenk, J. O. A multisubstrate mechanism of striatal dopamine uptake and its inhibition by cocaine. Biochem. Pharmacol. 43 (1992) 2189–2199.

    Article  PubMed  CAS  Google Scholar 

  46. Nelson, P. J., Dean, G. E., Aronson, P. S., and Rudnick, G. Hydrogen ion cotransport by the renal brush border glutamate transporter. Biochemistry 22 (1983) 5459–5463.

    Article  PubMed  CAS  Google Scholar 

  47. Nelson, P. J. and Rudnick, G. Anion-dependent sodium ion conductance of platelet plasma membranes. Biochemistry 20 (1981) 4246–4249.

    Article  PubMed  CAS  Google Scholar 

  48. Nelson, P. J. and Rudnick, G. Coupling between platelet 5-hydroxytryptamine and potassium transport. J. Biol. Chem. 254 (1979) 10,084–10,089.

    Google Scholar 

  49. Nelson, P. J. and Rudnick, G. The role of chloride ion in platelet serotonin transport. J. Biol. Chem. 257 (1982) 6151–6155.

    PubMed  CAS  Google Scholar 

  50. O’Reilly, C. A. and Reith, M. E. A. Uptake of [3H]serotonin into plasma membrane vesicles from mouse cortex. J. Biol. Chem. 263 (1988) 6115–6121.

    PubMed  Google Scholar 

  51. Peter, D., Jimenez, J., Liu, Y. J., Kim, J., and Edwards, R. H. The chromaffin granule and synaptic vesicle amine transporters differ in substrate recognition and sensitivity to inhibitors. J. Biol. Chem. 269 (1994) 7231–7237.

    PubMed  CAS  Google Scholar 

  52. Peyer, M. and Pletscher, A. Liberation of catecholamines and 5-hydroxytryptamine from human blood-platelets. Naunyn Schmiedebergs Arch. Pharmacol. 316 (1981) 81–86.

    Article  PubMed  CAS  Google Scholar 

  53. Radian, R. and Kanner, B. I. Stoichiometry of Na+ and Cl-coupled GABA transport by synaptic plasma membrane vesicles isolated from rat brain. Biochemistry 22 (1983) 1236–1241.

    Article  PubMed  CAS  Google Scholar 

  54. Ramamoorthy, S., Leibach, F. H., Mahesh, V. B., and Ganapathy, V. Active transport of dopamine in human placental brush-border membrane vesicles. Am. J. Physiol. 262 (1992) C1189 - C1196.

    PubMed  CAS  Google Scholar 

  55. Ramamoorthy, S., Prasad, P., Kulanthaivel, P., Leibach, F. H., Blakely, R. D., and Ganapathy, V. Expression of a cocaine-sensitive norepinephrine transporter in the human placental syncytiotrophoblast. Biochemistry 32 (1993) 1346–1353.

    Article  PubMed  CAS  Google Scholar 

  56. Reith, M. E. A., Zimanyi, I., and O’Reilly, C. A. Role of ions and membrane potential in uptake of serotonin into plasma membrane vesicles from mouse brain. Biochem. Pharmacol. 38 (1989) 2091–2097.

    Article  PubMed  CAS  Google Scholar 

  57. Ritz, M. C., Lamb, R. J., Goldberg, S. R., and Kuhar, M. J. Cocaine receptors on dopamine transporters are related to self-administration of cocaine. Science 237 (1987) 1219–1223.

    Article  PubMed  CAS  Google Scholar 

  58. Rudnick, G. Active transport of 5-hydroxytryptamine by plasma membrane vesicles isolated from human blood platelets, J. Biol. Chem. 252 (1977) 2170–2174.

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  60. Rudnick, G., Kirk, K. L., Fishkes, H., and Schuldiner, S. Zwitterionic and anionic forms of a serotonin analog as transport substrates. J. Biol. Chem. 264 (1989) 14,865–14,868.

    Google Scholar 

  61. Rudnick, G. and Nelson, P. J. Platelet 5-hydroxytryptamine transport an electroneutral mechanism coupled to potassium. Biochemistry 17 (1978) 4739–4742.

    Article  PubMed  CAS  Google Scholar 

  62. Rudnick, G. and Wall, S. C. Binding of the cocaine analog 2-beta-[H-3] carbomethoxy-3-beta-[4-fluorophenyl]tropane to the serotonin transporter. Mol. Pharm. 40 (1991) 421–426.

    CAS  Google Scholar 

  63. Rudnick, G. and Wall, S. C. The molecular mechanism of ecstasy [3,4-methylenedioxymethamphetamine (MDMA)]-serotonin transporters are targets for MDMA-induced serotonin release. Proc. Natl. Acad. Sci. USA 89 (1992) 1817–1821.

    Article  PubMed  CAS  Google Scholar 

  64. Rudnick, G. and Wall, S. C. Non-neurotoxic amphetamine derivatives release serotonin through serotonin transporters. Molecular Pharmacology 43 (1993) 271–276.

    PubMed  CAS  Google Scholar 

  65. Rudnick, G. and Wall, S. C. p-Chloroamphetamine induces serotonin release through serotonin transporters. Biochemistry 31 (1992) 6710–6718.

    Article  PubMed  CAS  Google Scholar 

  66. Rudnick, G. and Wall, S. C. The platelet plasma membrane serotonin transporter catalyzes exchange between neurotoxic amphetamines and serotonin. Ann. NY Acad. Sci 648 (1992) 345–347.

    Article  PubMed  CAS  Google Scholar 

  67. Scherman, D. and Henry, J.-P. pH Dependence of the ATP-dependent uptake of noradrenaline by bovine chromaffin granule ghosts. Eur. J. Biochem. 116 (1981) 535–539.

    Article  PubMed  CAS  Google Scholar 

  68. Schuldiner, S., Steiner-Mordoch, S., Yelin, R., Wall, S. C., and Rudnick, G. Amphetamine derivatives interact with both plasma membrane and secretory vesicle biogenic amine transporters. Mol. Pharmacol. 44 (1993) 1227–1231.

    PubMed  CAS  Google Scholar 

  69. Sneddon, J. M. Sodium-dependent accumulation of 5-hydroxytryptamine by rat blood platelets. Br. J. Pharmacol. 37 (1969) 680–688.

    Article  PubMed  CAS  Google Scholar 

  70. Steele, T., Nichols, D., and Yim, G. Stereochemical effects of 3,4-methylenedioxymethamphetamine (MDMA) and related amphetamine derivatives on inhibition of uptake of [3H]monoamines into synaptosomes from different regions of rat brain. Biochem. Pharmacol. 36 (1987) 2297–2303.

    Article  PubMed  CAS  Google Scholar 

  71. Stephan, M. M., Chen, M. A., and Rudnick, G. An extracellular loop region of the serotonin transporter may be involved in the translocation mechanism. Submitted for publication (1996).

    Google Scholar 

  72. Sulzer, D., Chen, T. K., Lau, Y. Y., Kristensen, H., Rayport, S., and Ewing, A. Amphetamine redistributes dopamine from synaptic vesicles to the cytosol and promotes reverse transport. J. Neurosci. 15 (1995) 4102–4108.

    PubMed  CAS  Google Scholar 

  73. Sulzer, D. and Rayport, S. Amphetamine and other psychostimulants reduce pH gradient in midbrain dopaminergic neurons and chromaffin granules: a mechanism of action. Neuron 5 (1990) 797–808.

    Article  PubMed  CAS  Google Scholar 

  74. Talvenheimo, J., Fishkes, H., Nelson, P. J., and Rudnick, G. The serotonin transporter-imipramine “receptor”: different sodium requirements for imipramine binding and serotonin translocation. J. Biol. Chem. 258 (1983) 6115–6119.

    PubMed  CAS  Google Scholar 

  75. Talvenheimo, J., Nelson, P. J., and Rudnick, G. Mechanism of imipramine inhibition of platelet 5-hydroxytryptamine transport. J. Biol. Chem. 254 (1979) 4631–4635.

    PubMed  CAS  Google Scholar 

  76. Wadiche, J. I., Amara, S. G., and Kavanaugh, M. P. Ion fluxes associated with excitatory amino acid transport. Neuron 15 (1995) 721–728.

    Article  PubMed  CAS  Google Scholar 

  77. Wall, S. C., Gu, H. H., and Rudnick, G. Biogenic amine flux mediated by cloned transporters stably expressed in cultured cell lines: amphetamine specificity for inhibition and efflux. Mol. Pharmacol. 47 (1995) 544–550.

    PubMed  CAS  Google Scholar 

  78. Wall, S. C., Innis, R. B., and Rudnick, G. Binding of the cocaine analog [125]-2ßcarbomethoxy-30-(4-iodophenyl) tropane (ß-CIT) to serotonin and dopamine transporters: different ionic requirements for substrate and ß-CIT binding. Mol. Pharmacol. 43 (1993) 264–270.

    PubMed  CAS  Google Scholar 

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  1. Gary Rudnick
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  1. College of Medicine, University of Illinois, Peoria, IL, USA

    Maarten E. A. Reith

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Rudnick, G. (1997). Mechanisms of Biogenic Amine Neurotransmitter Transporters. In: Reith, M.E.A. (eds) Neurotransmitter Transporters. Contemporary Neuroscience. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-59259-470-2_3

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  • DOI: https://doi.org/10.1007/978-1-59259-470-2_3

  • Publisher Name: Humana Press, Totowa, NJ

  • Print ISBN: 978-1-4757-5980-8

  • Online ISBN: 978-1-59259-470-2

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