Skip to main content
SpringerLink
Log in

Molecular model of the neural dopamine transporter

  • Published:
Journal of Computer-Aided Molecular Design Aims and scope Submit manuscript

Abstract

The dopamine transporter (DAT) regulates the action of dopamine by reuptake of the neurotransmitter into presynaptic neurons, and is the main molecular target of amphetamines and cocaine. DAT and the Na+/H+ antiporter (NhaA) are secondary transporter proteins that carry small molecules across a cell membrane against a concentration gradient, using ion gradients as energy source. A 3-dimensional projection map of the E. coli NhaA has confirmed a topology of 12 membrane spanning domains, and was previously used to construct a 3-dimensional NhaA model with 12 trans-membrane α-helices (TMHs). The NhaA model, and site directed mutagenesis data on DAT, were used to construct a detailed 3-dimensional DAT model using interactive molecular graphics and empiric force field calculations. The model proposes a dopamine transport mechanism involving TMHs 1, 3, 4, 5, 7 and 11. Asp79, Tyr252 and Tyr274 were the primary cocaine binding residues. Binding of cocaine or its analogue, (−)-2β-carbomethoxy-3β-(4-fluorophenyl)tropane (CFT), seemed to lock the transporter in an inactive state, and thus inhibit dopamine transport. The present model may be used to design further experimental studies of the molecular structure and mechanisms of DAT and other secondary transporter proteins.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Reizer, J., Reizer, A. and Saier, M.H., Jr., Biochim. Biophys. Acta, 1197 (1994) 133.

    Google Scholar 

  2. Saier, M.H., Jr., Microbiol Mol Biol Rev, 64 (2000) 354.

    Google Scholar 

  3. Rothman, A., Padan, E. and Schuldiner, S., J. Biol. Chem., 271 (1996) 32288.

    Google Scholar 

  4. Kaback, H.R. and Wu, J., Q. Rev. Biophys., 30 (1997) 333.

    Google Scholar 

  5. Chen, J.G., Liu-Chen, S. and Rudnick, G., J. Biol. Chem., 273 (1998) 12675.

    Google Scholar 

  6. Giros, B., el Mestikawy, S., Godinot, N., Zheng, K., Han, H., Yang-Feng, T. and Caron, M.G., Mol. Pharmacol., 42 (1992) 383.

    Google Scholar 

  7. Edvardsen, O. and Dahl, S.G., Brain Res. Mol. Brain. Res., 27 (1994) 265.

    Google Scholar 

  8. Ravna, A.W. and Edvardsen, O., J. Mol. Graph. Model., 20 (2001) 133.

    Google Scholar 

  9. Ravna, A.W., Sylte, I. and Dahl, S.G., Receptors and Channels, 7 (2001) 319.

    Google Scholar 

  10. Zeng, H., Parthasarathy, R., Rampal, A.L. and Jung, C.Y., Biophys. J., 70 (1996) 14.

    Google Scholar 

  11. Dwyer, D.S., Proteins, 42 (2001) 531.

    Google Scholar 

  12. Uhl, G., Lin, Z., Metzger, T. and Dar, D.E., Methods Enzymol., 296 (1998) 456.

    Google Scholar 

  13. Boja, J.W., Vaughan, R., Patel, A., Shaya, E.K. and Kuhar, M.J., In Boja, J.W., Vaughan, R., Patel, A., Shaya, E.K. and Kuhar, M.J. (Eds), Dopamine receptors and transporters, Marcel Dekker, New York, 1994, 611.

    Google Scholar 

  14. Williams, K.A., Nature, 403 (2000) 112.

    Google Scholar 

  15. Hrynchuk, R.J., Barton, R.J. and Robertson, B.E., Can. J. Chem., 61 (1983) 481.

    Google Scholar 

  16. Frisch, M.J., Trucks, G.W., Schlegel, H.B., Gill, W., Johnson, B.G., Robb, M.A., Cheeseman, J.R., Keith, T., Petersson, G.A., Montgomery, J.A., Raghavachari, K., Al-Laham, M.A., Zakrzewski, V.G., Ortiz, J.V., Foresman, J.B., Cioslowski, J., Stefanov, B.B., Nanayakkara, A., Challacombe, M., Peng, C.Y., Ayala, P.Y., Chen, W., Wong, M.W., Andre, J.L., Replogle, E.S., Gomperts, R., Martin, R.L., Fox, D.J., Binkley, J.S., Defrees, D.J., Baker, J., Stewart, J.P., Head-Gordon, M., Gonzales, C. and Pople, J.A., Gaussian 94, 1995, Gaussian Inc: Pittsburg PA.

    Google Scholar 

  17. Ravna, A.W., Schroder, K.E. and Edvardsen, O., Comput. Chem., 23 (1999) 435.

    Google Scholar 

  18. Kristiansen, K., Edvardsen, O. and Dahl, S.G., Med. Chem. Res., 3 (1993) 370.

    Google Scholar 

  19. Charifson, P.S., Hiskey, R.G. and Pedersen, L.G., J. Comput. Chem., 11 (1990) 1181.

    Google Scholar 

  20. Giesecke, J., Acta Crystallogr., B36 (1980) 178.

    Google Scholar 

  21. Ferrin, T.E., Huang, C.C., Jarvis, L.E. and Langridge, R., J. Mol. Graphics, 6 (1988) 13.

    Google Scholar 

  22. Cornell, W.D., Cieplak, P., Bayly, C.I., Gould, I.R., Merz, K.M., Ferguson, D.M., Spellmeyer, D.C., Fox, T., Caldwell, J.W. and Kollman, P.A., J. Am. Chem. Soc., 117 (1995) 5179.

    Google Scholar 

  23. Christensen, I.T. and Jorgensen, F.S., J Biomol Struct Dyn, 15 (1997) 473.

    Google Scholar 

  24. Fanelli, F., Menziani, C., Scheer, A., Cotecchia, S. and De Benedetti, P.G., Methods, 14 (1998) 302.

    Google Scholar 

  25. Sylte, I., Bronowska, A. and Dahl, S.G., Eur. J. Pharmacol., 416 (2001) 33.

    Google Scholar 

  26. Berman, H.M., Westbrook, J., Feng, Z., Gilliland, G., Bhat, T.N., Weissig, H., Shindyalov, I.N. and Bourne, P.E., Nucleic Acids Res., 28 (2000) 235.

    Google Scholar 

  27. Lin, Z., Wang, W., Kopajtic, T., Revay, R.S. and Uhl, G.R., Mol. Pharmacol., 56 (1999) 434.

    Google Scholar 

  28. Lin, Z., Itokawa, M. and Uhl, G.R., Faseb. J., 14 (2000) 715.

    Google Scholar 

  29. Kitayama, S., Shimada, S., Xu, H., Markham, L., Donovan, D.M. and Uhl, G.R., Proc. Natl. Acad. Sci. U S A, 89 (1992) 7782.

    Google Scholar 

  30. Kitayama, S., Wang, J.B. and Uhl, G.R., Synapse, 15 (1993) 58.

    Google Scholar 

  31. Kitayama, S., Morita, K., Dohi, T., Wang, J.B., Davis, S.C. and Uhl, G.R., Ann. N. Y. Acad. Sci., 801 (1996) 388.

    Google Scholar 

  32. Barker, E.L., Perlman, M.A., Adkins, E.M., Houlihan, W.J., Pristupa, Z.B., Niznik, H.B. and Blakely, R.D., J. Biol. Chem., 273 (1998) 19459.

    Google Scholar 

  33. Chen, J.G., Sachpatzidis, A. and Rudnick, G., J. Biol. Chem., 272 (1997) 28321.

    Google Scholar 

  34. Mitsuhata, C., Kitayama, S., Morita, K., Vandenbergh, D., Uhl, G.R. and Dohi, T., Brain Res. Mol. Brain Res., 56 (1998) 84.

    Google Scholar 

  35. Sur, C., Betz, H. and Schloss, P., Proc. Natl. Acad. Sci. U S A, 94 (1997) 7639.

    Google Scholar 

  36. Sur, C., Schloss, P. and Betz, H., Biochem. Biophys. Res. Commun., 241 (1997) 68.

    Google Scholar 

  37. Barker, E.L. and Blakely, R.D., Mol. Pharmacol., 50 (1996) 957.

    Google Scholar 

  38. Lee, S.H., Chang, M.Y., Lee, K.H., Park, B.S., Lee, Y.S. and Chin, H.R., Mol. Pharmacol., 57 (2000) 883.

    Google Scholar 

  39. Smicun, Y., Campbell, S.D., Chen, M.A., Gu, H. and Rudnick, G., J. Biol. Chem., 274 (1999) 36058.

    Google Scholar 

  40. Chen, J.G. and Rudnick, G., Proc. Natl. Acad. Sci. U S A, 97 (2000) 1044.

    Google Scholar 

  41. Bairoch, A. and Apweiler, R., Nucleic. Acids. Res., 27 (1999) 49.

    Google Scholar 

  42. Rost, B., Meth. Enzymol., 266 (1996) 525.

    Google Scholar 

  43. Kuroda, T., Shimamoto, T., Mizushima, T. and Tsuchiya, T., J. Bacteriol., 179 (1997) 7600.

    Google Scholar 

  44. Noumi, T., Inoue, H., Sakurai, T., Tsuchiya, T. and Kanazawa, H., J. Biochem. (Tokyo), 121 (1997) 661.

    Google Scholar 

  45. Inoue, H., Noumi, T., Tsuchiya, T. and Kanazawa, H., FEBS Lett., 363 (1995) 264.

    Google Scholar 

  46. Gerchman, Y., Olami, Y., Rimon, A., Taglicht, D., Schuldiner, S. and Padan, E., Proc. Natl. Acad. Sci. U S A, 90 (1993) 1212.

    Google Scholar 

  47. Gerchman, Y., Rimon, A. and Padan, E., J. Biol. Chem., 274 (1999) 24617.

    Google Scholar 

  48. Olami, Y., Rimon, A., Gerchman, Y., Rothman, A. and Padan, E., J. Biol. Chem., 272 (1997) 1761.

    Google Scholar 

  49. Rimon, A., Gerchman, Y., Kariv, Z. and Padan, E., J. Biol. Chem., 273 (1998) 26470.

    Google Scholar 

  50. Carroll, F.I., Gao, Y.G., Rahman, M.A., Abraham, P., Parham, K., Lewin, A.H., Boja, J.W. and Kuhar, M.J., J. Med. Chem., 34 (1991) 2719.

    Google Scholar 

  51. Pearson, W.R. and Lipman, D.J., Proc. Natl. Acad. Sci. USA, 85 (1988) 2444.

    Google Scholar 

  52. Loland, C.J., Norregaard, L. and Gether, U., J. Biol. Chem., 274 (1999) 36928.

    Google Scholar 

  53. Nicholls, A., Sharp, K.A. and Honig, B., Proteins, 11 (1991) 281.

    Google Scholar 

  54. Nicholls, A., GRASP: Graphical Representation and Analysis of Surface Properties, 1992.

  55. Chang, G. and Roth, C.B., Science, 293 (2001) 1793.

    Google Scholar 

  56. Murakami, S., Nakashima, R., Yamashita, E. and Yamaguchi, A., Nature, 419 (2002) 587.

    Google Scholar 

  57. Kawabe, T., Fujihira, E. and Yamaguchi, A., J. Biochem. (Tokyo), 128 (2000) 195.

    Google Scholar 

  58. Hirai, T., Heymann, J.A., Shi, D., Sarker, R., Maloney, P.C. and Subramaniam, S., Nat. Struct. Biol., 9 (2002) 597.

    Google Scholar 

  59. Bennett, E.R. and Kanner, B.I., J. Biol. Chem., 272 (1997) 1203.

    Google Scholar 

  60. Olivares, L., Aragon, C., Gimenez, C. and Zafra, F., J. Biol. Chem., 272 (1997) 1211.

    Google Scholar 

  61. Yu, N., Cao, Y., Mager, S. and Lester, H.A., FEBS Lett., 426 (1998) 174.

    Google Scholar 

  62. Hruz, P.W. and Mueckler, M.M., Biochemistry, 39 (2000) 9367.

    Google Scholar 

  63. Kleinberger-Doron, N. and Kanner, B.I., J. Biol. Chem., 269 (1994) 3063.

    Google Scholar 

  64. Larsen, N.A., Turner, J.M., Stevens, J., Rosser, S.J., Basran, A., Lerner, R.A., Bruce, N.C. and Wilson, I.A., Nat Struct Biol, 9 (2002) 17.

    Google Scholar 

  65. Rasmussen, S.G., Carroll, F.I., Maresch, M.J., Jensen, A.D., Tate, C.G. and Gether, U., J. Biol. Chem., 276 (2001) 4717.

    Google Scholar 

  66. Mortensen, O.V., Kristensen, A.S. and Wiborg, O., J. Neurochem., 79 (2001) 237.

    Google Scholar 

  67. Ferrer, J.V. and Javitch, J.A., Proc. Natl. Acad. Sci. USA, 95 (1998) 9238.

    Google Scholar 

  68. Loland, C.J., Norregaard, L., Litman, T. and Gether, U., Proc. Natl. Acad. Sci. USA, 99 (2002) 1683.

    Google Scholar 

  69. Fischer, J.F. and Cho, A.K., J. Pharmacol. Exp. Ther., 208 (1979) 203.

    Google Scholar 

  70. Liang, N.Y. and Rutledge, C.O., Biochem. Pharmacol., 31 (1982) 983.

    Google Scholar 

  71. Faivre, V., Manivet, P., Callaway, J.C., Airaksinen, M.M., Morimoto, H., Baszkin, A., Launay, J.M. and Rosilio, V., FEBS Lett., 471 (2000) 56.

    Google Scholar 

  72. Chen, N., Ferrer, J.V., Javitch, J.A. and Justice, J.B., Jr., J. Biol. Chem., 275 (2000) 1608.

    Google Scholar 

  73. Reith, M.E., Berfield, J.L., Wang, L.C., Ferrer, J.V. and Javitch, J.A., J. Biol. Chem., 276 (2001) 29012.

    Google Scholar 

  74. Schmid, J.A., Scholze, P., Kudlacek, O., Freissmuth, M., Singer, E.A. and Sitte, H.H., J. Biol. Chem., 276 (2001) 3805.

    Google Scholar 

  75. Kilic, F. and Rudnick, G., Proc. Natl. Acad. Sci. USA, 97 (2000) 3106.

    Google Scholar 

  76. Hastrup, H., Karlin, A. and Javitch, J.A., Proc. Natl. Acad. Sci. USA, 98 (2001) 10055.

    Google Scholar 

  77. Chang, A.S., Starnes, D.M. and Chang, S.M., Biochem. Biophys. Res. Commun., 249 (1998) 416.

    Google Scholar 

  78. Thompson, J.D., Higgins, D.G. and Gibson, T.J., Nucleic Acids Res., 22 (1994) 4673.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacology, Institute of Medical Biology, University of Tromsø, N-9037, Tromsø, Norway

    Aina Westrheim Ravna, Ingebrigt Sylte & Svein G. Dahl

Authors
  1. Aina Westrheim Ravna
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ingebrigt Sylte
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Svein G. Dahl
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ravna, A.W., Sylte, I. & Dahl, S.G. Molecular model of the neural dopamine transporter. J Comput Aided Mol Des 17, 367–382 (2003). https://doi.org/10.1023/A:1026116017725

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1026116017725

Search

Navigation