The Vesicular Monoamine Transporters (VMATs): Role in the Chemical Coding of Neuronal Transmission and Monoamine Storage in Amine-Handling Immune and Inflammatory Cells

  • L. E. Eiden
  • B. Schütz
  • M. Anlauf
  • C. Depboylu
  • M. K.-H. Schäfer
  • E. Weihe
Part of the Advances in Behavioral Biology book series (ABBI, volume 53)


Monoamines can act as neurotransmitters, hormones, autocrine and paracrine factors, or autacoids. How they function depends on the locations of the cells that synthesize and store them, and the stimuli that release them. All amine transmitters are first sequestered in a storage vesicle or granule, from which they are secreted from the cell. This requires specific transporters that reside on the vesicle. All of the vesicular transporters for classical neurotransmitters inferred to exist as individual proteins based on functional studies, have been cloned and characterized in a detailed molecular way over the last ten years (see Table 1). As a result, an understanding has developed that the role of these transporters in the chemical coding of neurotransmission is dynamic, and a novel view of what constitutes a neurotransmitter phenotype for a given neuron has emerged. The purpose of this contribution is to highlight recent progress from our laboratories and others in understanding the evolution of vesicular transporter structure, transport properties and cell-specific expression, as these relate to the physiological and regulatory functions of mammalian monoamine-containing*** neuronal, endocrine, and hematopoietic cells.


Synaptic Vesicle Vesicular Transporter Eccrine Sweat Gland Vesicular Monoamine Transporter Nucleus Tractus Solitarious 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    B. I. Kanner and S. Schuldiner, Mechanism of transport and storage of neurotransmitters, CRC Crit. Rev. Biochem. 22, 1–38 (1987).PubMedCrossRefGoogle Scholar
  2. 2.
    R. G. Johnson Jr., Accumulation of biological amines into chromaffin granules: a model for hormone and neurotransmitter transport, Physiol. Revs. 68, 232–307 (1988).Google Scholar
  3. 3.
    P. R. Maycox, T. Deckwoerth, J. W. Hell, and R. Jahn, Glutamate uptake by brain synaptic vesicles, J. Biol. Chem. 263, 15423–15428 (1988).PubMedGoogle Scholar
  4. 4.
    P. M. Burger, J. Hell, E. Mehl, C. Krasel, F. Lottspeich, and R. Jahn, GABA and glycine in synaptic vesicles: Storage and transport characteristics, Neuron 7, 287–293 (1991).PubMedCrossRefGoogle Scholar
  5. 5.
    S. M. Parsons, Transport mechanisms in acetylcholine and monoamine storage, FASEB J. 14, 2423–2434 (2000).PubMedCrossRefGoogle Scholar
  6. 6.
    B. Rost, PHD: predicting one-dimensional protein structure by profile based neural networks, Meth. Enzymol. 266,525–539 (1996).PubMedCrossRefGoogle Scholar
  7. 7.
    B. Rost, P. Fariselli, and R. Casadio, Topology prediction for helical transmembrane proteins at 86% accuracy, Protein Science 7, 1704–1718 (1996).CrossRefGoogle Scholar
  8. 8.
    M. L. Gilmor, N. R. Nash, A. Roghani, R. H. Edwards, H. Yi, S. M. Hersch, and A. I. Levey, Expression of the putative vesicular acetylcholine transporter in rat brain and localization in cholinergic synaptic vesicles, J. Neurosci. 16, 2179–2190 (1996).PubMedGoogle Scholar
  9. 9.
    E. Weihe, J.-H. Tao-Cheng, M. K.-H. Schäfer, J. D. Erickson, and L. E. Eiden, Visualization of the vesicular acetylcholine transporter in cholinergic nerve terminals and its targeting to a specific population of small synaptic vesicles, Proc. Natl. Acad. Sci. USA 93, 3547–3552 (1996).PubMedCrossRefGoogle Scholar
  10. 10.
    S. Schuldiner, A. Shirvan, and M. Linial, Vesicular neurotransmitter transporters: From bacteria to humans, Physiol. Rev. 75, 369–392 (1995).PubMedGoogle Scholar
  11. 11.
    C. Sagné, S. E. Mestikaway, M.-F. Isambert, M. Hamon, J.-P. Nenry, B. Giros, and B. Gasnier, Cloning of a functional vesicular GABA and glycine transporter by screening of genome databases, 417, 177–183(1997).Google Scholar
  12. 12.
    S. L. McIntire, R. J. Reimer, K. Schuske, R. H. Edwards, and E. M. Jorgensen, Identification and characterization of the vesicular GABA transporter, Nature 389, 870–876 (1997).PubMedCrossRefGoogle Scholar
  13. 13.
    E. E. Bellochio, R. J. Reimer, R. T. Fremeau Jr., and R. H. Edwards, Uptake of glutamate into synaptic vesicles by an inorganic phosphate transporter, Science 289, 957–960 (2000).CrossRefGoogle Scholar
  14. 14.
    S. Takamori, J. S. Rhee, C. Rosenmund, and R. Jahn, Identification of a vesicular glutamate transporter that defines a glutamatergic phenotype in neurons, Nature 407, 189–194 (2000).PubMedCrossRefGoogle Scholar
  15. 15.
    J. D. Erickson, L. E. Eiden, and B. Hoffman, Expression cloning of a reserpine-sensitive vesicular monoamine transporter, Froc. Natl. Acad. Sci. USA 89, 10993–10997 (1992).CrossRefGoogle Scholar
  16. 16.
    Y. Liu, D. Peter, A. Roghani, S. Schuldiner, G. G. Prive, D. Eisenberg, N. Brecha, and R. H. Edwards, A cDNA that suppresses MPP+ toxicity encodes a vesicular amine transporter, Cell 70, 539–551 (1992).PubMedCrossRefGoogle Scholar
  17. 17.
    A. Alfonso, K. Grundahl, J. R. McManus, and J. B. Rand, Cloning and characterization of the choline acetyltransferase structural gene (cha-1) from C. elegans, J. Neurosci. 14, 2290–3300 (1994).PubMedGoogle Scholar
  18. 18.
    J. D. Erickson, H. Varoqui, M. Schäfer, M.-F. Diebler, E. Weihe, W. Modi, J. Rand, L. E. Eiden, T. I. Bonner, and T. Usdin, Functional characterization of the mammalian vesicular acetylcholine transporter and its expression from a ‘cholinergic’ gene locus, J. Biol. Chem. 269, 21929–21932 (1994).PubMedGoogle Scholar
  19. 19.
    S. Schuldiner, A molecular glimpse of vesicular transporters, J. Neurochem. 62, 2067–2078 (1994).PubMedCrossRefGoogle Scholar
  20. 20.
    M. K.-H. Schäfer, B. Schütz, E. Weihe, and L. E. Eiden, Target-independent cholinergic differentiation in the rat sympathetic nervous system, Proc. Natl. Acad. Sci. USA 94, 4149–4154 (1997).PubMedCrossRefGoogle Scholar
  21. 21.
    B. Schütz, M. K.-H. Schäfer, L. E. Eiden, and E. Weihe, Vesicular amine transporter expression and isoform selection in developing brain, peripheral nervous system and gut, Dev. Brain Res. 106, 181–204 (1998).CrossRefGoogle Scholar
  22. 22.
    S. E. Asmus, S. Parsons, and S. C. Landis, Developmental changes in the transmitter properties of sympathetic neurons that innervate the periosteum, J. Neurosci. 20, 1495–1504 (2000).PubMedGoogle Scholar
  23. 23.
    C. Goridis and J.-F. Brunet, Transcriptional control of neurotransmitter phenotype, Curr. Opin. Neurobiol. 9,47–53(1999).PubMedCrossRefGoogle Scholar
  24. 24.
    D. Frisby, J. McManus, J. Duerr, and J. Rand, Regulation of cholinergic gene expression in C. elegans, Soc. Neurosci. Abstr. 22, 1032 (1996).Google Scholar
  25. 25.
    C. Eastman, H. R. Horvitz, and Y. S. Jin, Coordinated transcriptional regulation of the unc-25 glutamic acid decarboxylase and the unc-47 GABA vesicular transporter by the Caenorhabditis elegans UNC-30 homeodomain protein, J. Neurosci. 9, 6225–6234 (1999).Google Scholar
  26. 26.
    J. J. Westmoreland, J. McEwen, B. A. Moore, Y. Jin, and B. G. Condie, Conserved function of C. elegans UNC-30 and mouse Pitx2 in controlling GABAergic neuron differentiation, J. Neurosci. in press, (2001).Google Scholar
  27. 27.
    M.-R. Hirsch, M.-C. Tiveron, F. Guillemot, J.-F. Brunet, and C. Goridis, Control of noradrenergic differentiation and Phox2a expression by MASH1 in the central and peripheral nervous system, Development 125, 599–608 (1998).PubMedGoogle Scholar
  28. 28.
    L. Lo, M.-C. Tiveron, and D. J. Anderson, MASH1 activates expression of the paired homeodomain transcription factor Phox2a, and couples pan-neuronal and subtype-specific components of autonomic neuronal identity, Development 125, 609–620 (1998).PubMedGoogle Scholar
  29. 29.
    J.-F. Brunet and A. Ghysen, Deconstructing cell determination: proneural genes and neuronal identity, Bio Essays 21, 313–318 (1999).Google Scholar
  30. 30.
    C. Yang, H.-S. Kim, H. Seo, C.-H. Kim, J.-F. Brunet, and K.-S. Kim, Paired-like homeodomain proteins, Phox2a and Phox2B., are responsible for noradrenergic cell-specific transcription of the dopamine ß- hydroxylase gene, J. Neurochem. 71, 1813–1826 (1998).PubMedCrossRefGoogle Scholar
  31. 31.
    M. Adachi, D. Browne, and E. J. Lewis, Paired-like homeodomain proteins Phox2a/Arix and Phox2b/NBPhox have similar genetic organization and independently regulate dopamine ß-hydroxylase gene transcription, DNA Cell Biol. 19, 539–554 (2000).PubMedCrossRefGoogle Scholar
  32. 32.
    C.-H. Kim, H.-S. Kim, J. F. Cubells, and K.-S. Kim, A previously undescribed intron and extensive 5’ upstreamm 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).PubMedCrossRefGoogle Scholar
  33. 33.
    J. D. Erickson, M. K.-H. Schäfer, T. I. Bonner, L. E. Eiden, and E. Weihe, Distinct pharmacological properties and distribution in neurons and endocrine cells of two isoforms of the human vesicular monoamine transporter, Proc. Natl. Acad. Sci. USA 93, 5166–5171 (1996).PubMedCrossRefGoogle Scholar
  34. 34.
    D. Peter, J. Jimenez, Y. Liu, J. Kim, and R. H. Edwards, The chromaffin granule and synaptic vesicle amine transporters differ in substrate recognition and sensitivity to inhibitors, J. Biol. Chem. 269, 7231–7237 (1994).PubMedGoogle Scholar
  35. 35.
    E. Weihe, M. K.-H. Schäfer, J. D. Erickson, and L. E. Eiden, Localization of vesicular monoamine transporter isoforms (VMAT1 and VMAT2) to endocrine cells and neurons in rat, J. Mol. Neurosci. 5, 149–164 (1994).PubMedCrossRefGoogle Scholar
  36. 36.
    J. D. Erickson, L. E. Eiden, M. K.-H. Schäfer, and E. Weihe, Reserpine- and tetrabenazine-sensitive transport of 3H-histamine by the neuronal isoform of the vesicular monoamine transporter, J. Mol. Neurosci. 6, 277–287 (1995).PubMedCrossRefGoogle Scholar
  37. 37.
    A. Merickel and R. H. Edwards, Transport of histamine by vesicular monoamine transporter-2, Neuropharmacol 34, 1543–1547 (1995).CrossRefGoogle Scholar
  38. 38.
    J. S. Duerr, D. L. Frisby, J. Gaskin, A. Duke, K. Asermely, D. Huddleston, L. E. Eiden, and J. B. Rand, The cat-1 gene of Caenorhabditis elegans encodes a vesicular monoamine transporter required for specific monoamine-dependent behaviors, J. Neurosci. 19, 72–84 (1999).PubMedGoogle Scholar
  39. 39.
    C. McClung and J. Hirsh, The trace amine tyramine is essential for sensitization to cocaine in Drosophila, Curr. Biol. 9, 853–860 (1999).PubMedCrossRefGoogle Scholar
  40. 40.
    M. Monastirioti, C. E. Linn, and K. White, Characterization of Drosophila tyramine beta-hydroxylase gene and isolation of mutant flies lacking octopamine, J. Neurosci. 16, 3900–3911 (1996).PubMedGoogle Scholar
  41. 41.
    J. F. Tallman, J. M. Saavedra, and J. Axelrod, Biosynthesis and metabolism of endogenous tyramine and its normal presence in sympathetic nerves, J. Pharmacol. Exp. Ther. 199, 216–221 (1976).PubMedGoogle Scholar
  42. 42.
    J. B. Rand, J. S. Duerr, and D. L. Frisby, Neurogenetics of vesicular transporters in C. elegans, FASEB J. 14,2414–2422(2000).PubMedCrossRefGoogle Scholar
  43. 43.
    M. A. Paulos and R. E. Tessel, Excretion of beta-phenethylamine is elevated in humans after profound stress, Science 215, 1127–1129 (1982).PubMedCrossRefGoogle Scholar
  44. 44.
    E. Weihe and L. E. Eiden, Vesicular amine transporter expression in amine-handling cells of the nervous, endocrine and inflammatory systems, FASEB J. 14, 2435–2449 (2000).PubMedCrossRefGoogle Scholar
  45. 45.
    E. Blaugrund, T. D. Pham, V. M. Tennyson, L. Lo, L. Sommer, D. J. Anderson, and M. D. Gershon, Distinct subpopulations of enteric neuronal progenitors defined by time of development, sympathoadrenal lineage markers and Mash-1 dependence, Development 122, 309–320 (1996).PubMedGoogle Scholar
  46. 46.
    C. Lebrand, O. Cases, C. Adelbrecht, A. Doye, C. Alvarez, S. El Mestikawy, I. Scif, and P. Gaspar, Transient uptake and storage of serotonin in developing thalamic neurons, Neuron 17, 823–835 (1996).PubMedCrossRefGoogle Scholar
  47. 47.
    K. Kitahama, N. Sakamoto, A. Jouvet, I. Nagatsu, and J. Pearson, Dopamine-beta-hydroxylase and tyrosine hydroxylase immunoreactive neurons in the human brainstem, J. Chem. Neuroanat. 10, 137–146 (1996).PubMedCrossRefGoogle Scholar
  48. 48.
    E. Weihe and L. E. Eiden, Chemical neuroanatomy of the vesicular transporters, FASEB J. 14, 2435–2449 (2000).PubMedCrossRefGoogle Scholar
  49. 49.
    I. S. Balan, M. V. Ugrumov, A. Calas, P. Mailly, M. Kreiger, and J. Thibault, Tyrosine hydroxylase- expressing and/or aromatic L-amino acid decarboxylase-expressing neurons in the mediobasal hypothalamus of perinatal rats: differentiation and sexual dimorphism, J. Comp. Neurol. 425, 167–176 (2000).PubMedCrossRefGoogle Scholar
  50. 50.
    G. Guidry and S. C. Landis, Target-dependent development of the vesicular acetylcholine transporter in rodent sweat gland innervation, Dev. Biol. 199, 175–184 (1998).PubMedCrossRefGoogle Scholar
  51. 51.
    S. A. Shields, K. A. MacDowell, S. B. Fairchild, and M. L. Campbell, Is mediation of sweating cholinergic, adrenergic, or both-A comment on the literature, Psychophysiology 24, 312–319 (1987).PubMedCrossRefGoogle Scholar
  52. 52.
    E. Weihe, M. Anlauf, M.-K. H. Schäfer, W. Hartschuh, and L. E. Eiden, VMAT2 is the transporter mediating sequestration of monoamines in rat and human platelets, mast cells, and cutaneous dendritic cells, Soc. Neurosci. Abstr. Nov. 7–12, #301.301 (1998).Google Scholar
  53. 53.
    M. da Prada, A. Pletscher, J. P. Tranzer, and H. Knuchel, Subcellular localization of 5-hydroxytryptamine and histamine in blood platelets, Nature 216, 1315–1317 (1967).PubMedCrossRefGoogle Scholar
  54. 54.
    M. H. Fukami, H. Holmsen, and K. Ugurbil, Histamine uptake in pig platelets and isolated dense granules, iochem. Pharmacol. 33, 3869–3874 (1984).CrossRefGoogle Scholar
  55. 55.
    A. Pletscher, M. Da Prada, K. H. Berneis, H. Steffen, B. Liitold, and H. G. Weder, Molecular organization f amine storage organelles of blood platelets and adrenal medulla, in Advances in Cytopharmacology, Ceccarelli, F. Clementi, and J. Meldolesi, Editors. 1974, Raven Press: New York. p. 257–264.Google Scholar
  56. 56.
    S. Tao-Cheng and L. E. Eiden, The vesicular monoamine transporter VMAT2 is targeted to large dense- ore vesicles, and the vesicular acetylcholine transporter VAChT to small synaptic vesicles, in PC 12 cells, Adv. Pharmacol. 42, 250–253 (1998).PubMedCrossRefGoogle Scholar
  57. 57.
    J. D. Erickson, D. Yao, H. Zhu, H. Ming, and H. Varoqui, Domains of vesicular amine transporters mportant for substrate recognition and targeting to secretory organelles, FASEB J. 14, 2450–2458 (2000).PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2002

Authors and Affiliations

  • L. E. Eiden
    • 1
  • B. Schütz
    • 2
  • M. Anlauf
    • 2
  • C. Depboylu
    • 2
  • M. K.-H. Schäfer
    • 2
  • E. Weihe
    • 1
  1. 1.Section on Molecular NeuroscienceNational Institute of Mental Health, NIHBethesdaUSA
  2. 2.Institute of Anatomy and Cell BiologyPhilipps-UniversitätMarburgGermany

Personalised recommendations