Abstract
The development of effective therapeutic interventions for neurodegeneration requires a better understanding of the early events that precede neuronal loss. Recent work in various disease models has begun to emphasize the significance of presynaptic dysfunction as an early event that occurs before manifestation of neurological disorders. Dysregulation of dopamine (DA) homeostasis is implicated in neurodegenerative diseases, drug addiction, and neuropsychiatric disorders. The neuronal plasma membrane dopamine transporter (DAT) is essential for the maintenance of DA homeostasis in the brain. α-synuclein is a 140-amino acid protein that forms a stable complex with DAT and is linked to the pathogenesis of neurodegenerative disease. In this review we will examine the prevailing hypotheses for α-synuclein-regulation of DAT biology.
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Abramov, E., Dolev, I., Fogel, H., Ciccotosto, G. D., Ruff, E., and Slutsky, I. (2009) Amyloid-beta as a positive endogenous regulator of release probability at hippocampal synapses, Nat Neurosci 12, 1567–1576.
Gray, B. C., Siskova, Z., Perry, V. H., and O’Connor, V. (2009) Selective presynaptic degeneration in the synaptopathy associated with ME7-induced hippocampal pathology, Neurobiol Dis 35, 63–74.
Zhang, C., Wu, B., Beglopoulos, V., Wines-Samuelson, M., Zhang, D., Dragatsis, I., Sudhof, T. C., and Shen, J. (2009) Presenilins are essential for regulating neurotransmitter release, Nature 460, 632–636.
Nemani, V. M., Lu, W., Berge, V., Nakamura, K., Onoa, B., Lee, M. K., Chaudhry, F. A., Nicoll, R. A., and Edwards, R. H. (2010) Increased expression of alpha-synuclein reduces neurotransmitter release by inhibiting synaptic vesicle reclustering after endocytosis, Neuron 65, 66–79.
Chandra, S., Fornai, F., Kwon, H. B., Yazdani, U., Atasoy, D., Liu, X., Hammer, R. E., Battaglia, G., German, D. C., Castillo, P. E., and Sudhof, T. C. (2004) Double-knockout mice for alpha- and beta-synucleins: effect on synaptic functions, Proc Natl Acad Sci U S A 101, 14966–14971.
Fujiwara, H., Hasegawa, M., Dohmae, N., Kawashima, A., Masliah, E., Goldberg, M. S., Shen, J., Takio, K., and Iwatsubo, T. (2002) alpha-Synuclein is phosphorylated in synucleinopathy lesions, Nat Cell Biol 4, 160–164.
Iwai, A., Masliah, E., Yoshimoto, M., Ge, N., Flanagan, L., de Silva, H. A., Kittel, A., and Saitoh, T. (1995) The precursor protein of non-A beta component of Alzheimer’s disease amyloid is a presynaptic protein of the central nervous system, Neuron 14, 467–475.
Klivenyi, P., Siwek, D., Gardian, G., Yang, L., Starkov, A., Cleren, C., Ferrante, R. J., Kowall, N. W., Abeliovich, A., and Beal, M. F. (2006) Mice lacking alpha-synuclein are resistant to mitochondrial toxins, Neurobiol Dis 21, 541–548.
Pronin, A. N., Morris, A. J., Surguchov, A., and Benovic, J. L. (2000) Synucleins are a novel class of substrates for G protein-coupled receptor kinases, J Biol Chem 275, 26515–26522.
Amara, S. G., and Arriza, J. L. (1993) Neurotransmitter transporters: three distinct gene families, Curr Opin Neurobiol 3, 337–344.
Amara, S. G., and Kuhar, M. J. (1993) Neurotransmitter transporters: recent progress, Annu Rev Neurosci 16, 73–93.
Rocha, B. A., Fumagalli, F., Gainetdinov, R. R., Jones, S. R., Ator, R., Giros, B., Miller, G. W., and Caron, M. G. (1998) Cocaine self-administration in dopamine-transporter knockout mice, Nat Neurosci 1, 132–137.
Giros, B., Jaber, M., Jones, S. R., Wightman, R. M., and Caron, M. G. (1996) Hyperlocomotion and indifference to cocaine and amphetamine in mice lacking the dopamine transporter, Nature 379, 606–612.
Bernheimer, H., Birkmayer, W., Hornykiewicz, O., Jellinger, K., and Seitelberger, F. (1973) Brain dopamine and the syndromes of Parkinson and Huntington. Clinical, morphological and neurochemical correlations, J Neurol Sci 20, 415–455.
Hornykiewicz, O., Kish, S. J., Becker, L. E., Farley, I., and Shannak, K. (1986) Brain neurotransmitters in dystonia musculorum deformans, N Engl J Med 315, 347–353.
Dawson, T. M., and Dawson, V. L. (2002) Neuroprotective and neurorestorative strategies for Parkinson’s disease, Nat Neurosci 5Suppl, 1058–1061.
Wise, C. D., and Stein, L. (1973) Dopamine-beta-hydroxylase deficits in the brains of schizophrenic patients, Science 181, 344–347.
Snyder, S. H., and Meyerhoff, J. L. (1973) How amphetamine acts in minimal brain dysfunction, Ann N Y Acad Sci 205, 310–320.
Sonders, M. S., and Amara, S. G. (1996) Channels in transporters, Curr Opin Neurobiol 6, 294–302.
Sonders, M. S., Quick, M., and Javitch, J. A. (2005) How did the neurotransmitter cross the bilayer? A closer view, Curr Opin Neurobiol 15, 296–304.
Sonders, M. S., Zhu, S. J., Zahniser, N. R., Kavanaugh, M. P., and Amara, S. G. (1997) Multiple ionic conductances of the human dopamine transporter: the actions of dopamine and psychostimulants, J Neurosci 17, 960–974.
Amara, S. G. (1992) Neurotransmitter transporters. A tale of two families, Nature 360, 420–421.
Amara, S. G. (1996) Neurotransmitter transporters: new insights into structure, function and pharmacology, Rev Bras Biol 56 Su 1 Pt 1, 5–19.
Amara, S. G. (2007) Chloride finds its place in the transport cycle, Nat Struct Mol Biol 14, 792–794.
Sitte, H. H., and Freissmuth, M. (2003) Oligomer formation by Na+-Cl—coupled neurotransmitter transporters, Eur J Pharmacol 479, 229–236.
Sitte, H. H., Hiptmair, B., Zwach, J., Pifl, C., Singer, E. A., and Scholze, P. (2001) Quantitative analysis of inward and outward transport rates in cells stably expressing the cloned human serotonin transporter: inconsistencies with the hypothesis of facilitated exchange diffusion, Mol Pharmacol 59, 1129–1137.
Sitte, H. H., Huck, S., Reither, H., Boehm, S., Singer, E. A., and Pifl, C. (1998) Carrier-mediated release, transport rates, and charge transfer induced by amphetamine, tyramine, and dopamine in mammalian cells transfected with the human dopamine transporter, J Neurochem 71, 1289–1297.
Sitte, H. H., Scholze, P., Schloss, P., Pifl, C., and Singer, E. A. (2000) Characterization of carrier-mediated efflux in human embryonic kidney 293 cells stably expressing the rat serotonin transporter: a superfusion study, J Neurochem 74, 1317–1324.
Sitte, H. H., Singer, E. A., and Scholze, P. (2002) Bi-directional transport of GABA in human embryonic kidney (HEK-293) cells stably expressing the rat GABA transporter GAT-1, Br J Pharmacol 135, 93–102.
Chen, N., and Reith, M. E. (2000) Structure and function of the dopamine transporter, Eur J Pharmacol 405, 329–339.
Chen, N., and Reith, M. E. (2003) Na+ and the substrate permeation pathway in dopamine transporters, Eur J Pharmacol 479, 213–221.
Ingram, S. L., and Amara, S. G. (2000) Arachidonic acid stimulates a novel cocaine-sensitive cation conductance associated with the human dopamine transporter, J Neurosci 20, 550–557.
Ingram, S. L., Prasad, B. M., and Amara, S. G. (2002) Dopamine transportermediated conductances increase excitability of midbrain dopamine neurons, Nat Neurosci 5, 971–978.
Khoshbouei, H., Sen, N., Guptaroy, B., Johnson, L., Lund, D., Gnegy, M. E., Galli, A., and Javitch, J. A. (2004) N-terminal phosphorylation of the dopamine transporter is required for amphetamine-induced efflux, PLoS Biol 2, E78.
Khoshbouei, H., Wang, H., Lechleiter, J. D., Javitch, J. A., and Galli, A. (2003) Amphetamine-induced dopamine efflux. A voltage-sensitive and intracellular Na+-dependent mechanism, J Biol Chem 278, 12070–12077.
Binda, F., Dipace, C., Bowton, E., Robertson, S. D., Lute, B. J., Fog, J. U., Zhang, M., Sen, N., Colbran, R. J., Gnegy, M. E., Gether, U., Javitch, J. A., Erreger, K., and Galli, A. (2008) Syntaxin 1A interaction with the dopamine transporter promotes amphetamine-induced dopamine efflux, Mol Pharmacol 74, 1101–1108.
Carvelli, L., Blakely, R. D., and Defelice, L. J. (2008) Dopamine transporter/syntaxin 1A interactions regulate transporter channel activity and dopaminergic synaptic transmission, Proc Natl Acad Sci U S A.
Dipace, C., Sung, U., Binda, F., Blakely, R. D., and Galli, A. (2007) Amphetamine induces a calcium/calmodulin-dependent protein kinase II-dependent reduction in norepinephrine transporter surface expression linked to changes in syntaxin 1A/transporter complexes, Mol Pharmacol 71, 230–239.
Lee, K. H., Kim, M. Y., Kim, D. H., and Lee, Y. S. (2004) Syntaxin 1A and receptor for activated C kinase interact with the N-terminal region of human dopamine transporter, Neurochem Res 29, 1405–1409.
Sulzer, D., Chen, T. K., Lau, Y. Y., Kristensen, H., Rayport, S., and Ewing, A. (1995) Amphetamine redistributes dopamine from synaptic vesicles to the cytosol and promotes reverse transport, J Neurosci 15, 4102–4108.
Sulzer, D., and Edwards, R. (2000) Vesicles: equal in neurotransmitter concentration but not in volume, Neuron 28, 5–7.
Sulzer, D., and Edwards, R. H. (2005) Antidepressants and the monoamine masquerade, Neuron 46, 1–2.
Sulzer, D., Maidment, N. T., and Rayport, S. (1993) Amphetamine and other weak bases act to promote reverse transport of dopamine in ventral midbrain neurons, J Neurochem 60, 527–535.
Sulzer, D., Pothos, E., Sung, H. M., Maidment, N. T., Hoebel, B. G., and Rayport, S. (1992) Weak base model of amphetamine action, Ann N Y Acad Sci 654, 525–528.
Abeliovich, A., Schmitz, Y., Farinas, I., Choi-Lundberg, D., Ho, W. H., Castillo, P. E., Shinsky, N., Verdugo, J. M., Armanini, M., Ryan, A., Hynes, M., Phillips, H., Sulzer, D., and Rosenthal, A. (2000) Mice lacking alpha-synuclein display functional deficits in the nigrostriatal dopamine system, Neuron 25, 239–252.
Sulzer, D., and Rayport, S. (1990) Amphetamine and other psychostimulants reduce pH gradients in midbrain dopaminergic neurons and chromaffin granules: a mechanism of action, Neuron 5, 797–808.
Sulzer, D., St Remy, C., and Rayport, S. (1996) Reserpine inhibits amphetamine action in ventral midbrain culture, Mol Pharmacol 49, 338–342.
Sulzer, D., Ungar, F., and Holtzman, E. (1990) Further studies on the cationic staining of retinal photoreceptors, J Histochem Cytochem 38, 743–745.
Salahpour, A., Medvedev, I. O., Beaulieu, J. M., Gainetdinov, R. R., and Caron, M. G. (2007) Local knockdown of genes in the brain using small interfering RNA: a phenotypic comparison with knockout animals, Biol Psychiatry 61, 65–69.
Salahpour, A., Ramsey, A. J., Medvedev, I. O., Kile, B., Sotnikova, T. D., Holmstrand, E., Ghisi, V., Nicholls, P. J., Wong, L., Murphy, K., Sesack, S. R., Wightman, R. M., Gainetdinov, R. R., and Caron, M. G. (2008) Increased amphetamine-induced hyperactivity and reward in mice overexpressing the dopamine transporter, Proc Natl Acad Sci U S A 105, 4405–4410.
Falkenburger, B. H., Barstow, K. L., and Mintz, I. M. (2001) Dendrodendritic inhibition through reversal of dopamine transport, Science 293, 2465–2470.
Giros, B., el Mestikawy, S., Bertrand, L., and Caron, M. G. (1991) Cloning and functional characterization of a cocaine-sensitive dopamine transporter, FEBS Lett 295, 149–154.
Gingrich, J. A., Andersen, P. H., Tiberi, M., el Mestikawy, S., Jorgensen, P. N., Fremeau, R. T., Jr., and Caron, M. G. (1992) Identification, characterization, and molecular cloning of a novel transporter-like protein localized to the central nervous system, FEBS Lett 312, 115–122.
Girgis, R. R., Javitch, J. A., and Lieberman, J. A. (2008) Antipsychotic drug mechanisms: links between therapeutic effects, metabolic side effects and the insulin signaling pathway, Mol Psychiatry 13, 918–929.
Amara, S. G., and Pacholczyk, T. (1991) Sodium-dependent neurotransmitter reuptake systems, Curr Opin Neurobiol 1, 84–90.
Amara, S. G., and Sonders, M. S. (1998) Neurotransmitter transporters as molecular targets for addictive drugs, Drug Alcohol Depend 51, 87–96.
Cass, W. A., and Gerhardt, G. A. (1994) Direct in vivo evidence that D2 dopamine receptors can modulate dopamine uptake, Neurosci Lett 176, 259–263.
Mayfield, R. D., and Zahniser, N. R. (2001) Dopamine D2 receptor regulation of the dopamine transporter expressed in Xenopus laevis oocytes is voltage-independent, Mol Pharmacol 59, 113–121.
Meiergerd, S. M., Patterson, T. A., and Schenk, J. O. (1993) D2 receptors may modulate the function of the striatal transporter for dopamine: kinetic evidence from studies in vitro and in vivo, J Neurochem 61, 764–767.
Dickinson, S. D., Sabeti, J., Larson, G. A., Giardina, K., Rubinstein, M., Kelly, M. A., Grandy, D. K., Low, M. J., Gerhardt, G. A., and Zahniser, N. R. (1999) Dopamine D2 receptor-deficient mice exhibit decreased dopamine transporter function but no changes in dopamine release in dorsal striatum, J Neurochem 72, 148–156.
Blakely, R. D., and Defelice, L. (2007) All Aglow About Presynaptic Receptor Regulation of Neurotransmitter Transporters (Relates to article by Bolan, et al., Fast Forward 31 January 2007), Mol Pharmacol.
Schwartz, J. W., Blakely, R. D., and DeFelice, L. J. (2003) Binding and transport in norepinephrine transporters. Real-time, spatially resolved analysis in single cells using a fluorescent substrate, J Biol Chem 278, 9768–9777.
Schwartz, J. W., Novarino, G., Piston, D. W., and DeFelice, L. J. (2005) Substrate binding stoichiometry and kinetics of the norepinephrine transporter, J Biol Chem 280, 19177–19184.
Schwartz, J. W., Piston, D., and DeFelice, L. J. (2006) Molecular microfluorometry: converting arbitrary fluorescence units into absolute molecular concentrations to study binding kinetics and stoichiometry in transporters, Handb Exp Pharmacol, 23–57.
Swant, J., Goodwin, J. S., North, A., Ali, A. A., Gamble-George, J., Chirwa, S., and Khoshbouei, H. (2011) alpha-Synuclein stimulates a dopamine transporter-dependent chloride current and modulates the activity of the transporter, J Biol Chem 286, 43933–43943.
Bolan, E. A., Kivell, B., Jaligam, V., Oz, M., Jayanthi, L. D., Han, Y., Sen, N., Urizar, E., Gomes, I., Devi, L. A., Ramamoorthy, S., Javitch, J. A., Zapata, A., and Shippenberg, T. S. (2007) D2 receptors regulate dopamine transporter function via an extracellular signal-regulated kinases 1 and 2-dependent and phosphoinositide 3 kinase-independent mechanism, Mol Pharmacol 71, 1222–1232.
Torres, G. E., Yao, W. D., Mohn, A. R., Quan, H., Kim, K. M., Levey, A. I., Staudinger, J., and Caron, M. G. (2001) Functional interaction between monoamine plasma membrane transporters and the synaptic PDZ domain-containing protein PICK1, Neuron 30, 121–134.
Carneiro, A. M., Ingram, S. L., Beaulieu, J. M., Sweeney, A., Amara, S. G., Thomas, S. M., Caron, M. G., and Torres, G. E. (2002) The multiple LIM domain-containing adaptor protein Hic-5 synaptically colocalizes and interacts with the dopamine transporter, J Neurosci 22, 7045–7054.
Arteaga-Vizcaino, M., Espinoza Holguin, M., Torres Guerra, E., Diez-Ewald, M., Quintero, J., Vizcaino, G., Estevez, J., and Fernandez, N. (2001) [Effect of oral and intramuscular vitamin K on the factors II, VII, IX, X, and PIVKA II in the infant newborn under 60 days of age], Rev Med Chil 129, 1121–1129.
Giambalvo, C. T. (1992) Protein kinase C and dopamine transport—2. Effects of amphetamine in vitro, Neuropharmacology 31, 1211–1222.
Kantor, L., and Gnegy, M. E. (1998) Protein kinase C inhibitors block amphetamine-mediated dopamine release in rat striatal slices, J Pharmacol Exp Ther 284, 592–598.
Doolen, S., and Zahniser, N. R. (2001) Protein tyrosine kinase inhibitors alter human dopamine transporter activity in Xenopus oocytes, J Pharmacol Exp Ther 296, 931–938.
Doolen, S., and Zahniser, N. R. (2002) Conventional protein kinase C isoforms regulate human dopamine transporter activity in Xenopus oocytes, FEBS Lett 516, 187–190.
Foster, J. D., Pananusorn, B., and Vaughan, R. A. (2002) Dopamine transporters are phosphorylated on N-terminal serines in rat striatum, J Biol Chem 277, 25178–25186.
Mortensen, O. V., and Amara, S. G. (2003) Dynamic regulation of the dopamine transporter, Eur J Pharmacol 479, 159–170.
Melikian, H. E. (2004) Neurotransmitter transporter trafficking: endocytosis, recycling, and regulation, Pharmacol Ther 104, 17–27.
Johnson, L. A., Guptaroy, B., Lund, D., Shamban, S., and Gnegy, M. E. (2005) Regulation of amphetamine-stimulated dopamine efflux by protein kinase C beta, J Biol Chem 280, 10914–10919.
Cervinski, M. A., Foster, J. D., and Vaughan, R. A. (2005) Psychoactive substrates stimulate dopamine transporter phosphorylation and down-regulation by cocaine-sensitive and protein kinase C-dependent mechanisms, J Biol Chem 280, 40442–40449.
Fog, J. U., Khoshbouei, H., Holy, M., Owens, W. A., Vaegter, C. B., Sen, N., Nikandrova, Y., Bowton, E., McMahon, D. G., Colbran, R. J., Daws, L. C., Sitte, H. H., Javitch, J. A., Galli, A., and Gether, U. (2006) Calmodulin kinase II interacts with the dopamine transporter C terminus to regulate amphetamine-induced reverse transport, Neuron 51, 417–429.
Navaroli, D. M., Stevens, Z. H., Uzelac, Z., Gabriel, L., King, M. J., Lifshitz, L. M., Sitte, H. H., and Melikian, H. E. (2011) The plasma membrane-associated GTPase Rin interacts with the dopamine transporter and is required for protein kinase C-regulated dopamine transporter trafficking, J Neurosci 31, 13758–13770.
Cremona, M. L., Matthies, H. J., Pau, K., Bowton, E., Speed, N., Lute, B. J., Anderson, M., Sen, N., Robertson, S. D., Vaughan, R. A., Rothman, J. E., Galli, A., Javitch, J. A., and Yamamoto, A. (2011) Flotillin-1 is essential for PKC-triggered endocytosis and membrane microdomain localization of DAT, Nat Neurosci 14, 469–477.
Zapata, A., Kivell, B., Han, Y., Javitch, J. A., Bolan, E. A., Kuraguntla, D., Jaligam, V., Oz, M., Jayanthi, L. D., Samuvel, D. J., Ramamoorthy, S., and Shippenberg, T. S. (2007) Regulation of dopamine transporter function and cell surface expression by D3 dopamine receptors, J Biol Chem 282, 35842–35854.
Clayton, D. F., and George, J. M. (1998) The synucleins: a family of proteins involved in synaptic function, plasticity, neurodegeneration and disease, Trends Neurosci 21, 249–254.
Lavedan, C. (1998) The synuclein family, Genome Res 8, 871–880.
Lavedan, C., Buchholtz, S., Auburger, G., Albin, R. L., Athanassiadou, A., Blancato, J., Burguera, J. A., Ferrell, R. E., Kostic, V., Leroy, E., Leube, B., Mota-Vieira, L., Papapetropoulos, T., Pericak-Vance, M. A., Pinkus, J., Scott, W. K., Ulm, G., Vasconcelos, J., Vilchez, J. J., Nussbaum, R. L., and Polymeropoulos, M. H. (1998) Absence of mutation in the beta- and gamma-synuclein genes in familial autosomal dominant Parkinson’s disease, DNA Res 5, 401–402.
Lavedan, C., Dehejia, A., Pike, B., Dutra, A., Leroy, E., Ide, S. E., Root, H., Rubenstein, J., Boyer, R. L., Chandrasekharappa, S., Makalowska, I., Nussbaum, R. L., and Polymeropoulos, M. H. (1998) Contig map of the Parkinson’s disease region on 4q21-q23, DNA Res 5, 19–23.
Polymeropoulos, M. H., Lavedan, C., Leroy, E., Ide, S. E., Dehejia, A., Dutra, A., Pike, B., Root, H., Rubenstein, J., Boyer, R., Stenroos, E. S., Chandrasekharappa, S., Athanassiadou, A., Papapetropoulos, T., Johnson, W. G., Lazzarini, A. M., Duvoisin, R. C., Di Iorio, G., Golbe, L. I., and Nussbaum, R. L. (1997) Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease, Science 276, 2045–2047.
Kruger, R., Kuhn, W., Muller, T., Woitalla, D., Graeber, M., Kosel, S., Przuntek, H., Epplen, J. T., Schols, L., and Riess, O. (1998) Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson’s disease, Nat Genet 18, 106–108.
Zarranz, J. (2004) [From empiricism to neuroscience in Alzheimer’s disease], Rev Neurol 39, 576–582.
Wersinger, C., Prou, D., Vernier, P., Niznik, H. B., and Sidhu, A. (2003) Mutations in the lipid-binding domain of alpha-synuclein confer overlapping, yet distinct, functional properties in the regulation of dopamine transporter activity, Mol Cell Neurosci 24, 91–105.
Wersinger, C., Prou, D., Vernier, P., and Sidhu, A. (2003) Modulation of dopamine transporter function by alpha-synuclein is altered by impairment of cell adhesion and by induction of oxidative stress, FASEB J 17, 2151–2153.
Lee, F. J., Liu, F., Pristupa, Z. B., and Niznik, H. B. (2001) Direct binding and functional coupling of alpha-synuclein to the dopamine transporters accelerate dopamine-induced apoptosis, Faseb J 15, 916–926.
Davidson, W. S., Jonas, A., Clayton, D. F., and George, J. M. (1998) Stabilization of alpha-synuclein secondary structure upon binding to synthetic membranes, J Biol Chem 273, 9443–9449.
Weinreb, P. H., Zhen, W., Poon, A. W., Conway, K. A., and Lansbury, P. T., Jr. (1996) NACP, a protein implicated in Alzheimer’s disease and learning, is natively unfolded, Biochemistry 35, 13709–13715.
Eliezer, D., Kutluay, E., Bussell, R., Jr., and Browne, G. (2001) Conformational properties of alpha-synuclein in its free and lipid-associated states, J Mol Biol 307, 1061–1073.
Fortin, D. L., Troyer, M. D., Nakamura, K., Kubo, S., Anthony, M. D., and Edwards, R. H. (2004) Lipid rafts mediate the synaptic localization of alpha-synuclein, J Neurosci 24, 6715–6723.
Martinez, Z., Zhu, M., Han, S., and Fink, A. L. (2007) GM1 specifically interacts with alpha-synuclein and inhibits fibrillation, Biochemistry 46, 1868–1877.
Hong, W. C., and Amara, S. G. (2010) Membrane cholesterol modulates the outward facing conformation of the dopamine transporter and alters cocaine binding, J Biol Chem 285, 32616–32626.
Foster, J. D., Adkins, S. D., Lever, J. R., and Vaughan, R. A. (2008) Phorbol ester induced trafficking-independent regulation and enhanced phosphorylation of the dopamine transporter associated with membrane rafts and cholesterol, J Neurochem 105, 1683–1699.
Gnegy, M. E. (2003) The effect of phosphorylation on amphetaminemediated outward transport, Eur J Pharmacol 479, 83–91.
Granas, C., Ferrer, J., Loland, C. J., Javitch, J. A., and Gether, U. (2003) N-terminal truncation of the dopamine transporter abolishes phorbol ester- and substance P receptor-stimulated phosphorylation without impairing transporter internalization, J Biol Chem 278, 4990–5000.
Holton, K. L., Loder, M. K., and Melikian, H. E. (2005) Nonclassical, distinct endocytic signals dictate constitutive and PKC-regulated neurotransmitter transporter internalization, Nat Neurosci 8, 881–888.
Okochi, M., Eimer, S., Bottcher, A., Baumeister, R., Romig, H., Walter, J., Capell, A., Steiner, H., and Haass, C. (2000) A loss of function mutant of the presenilin homologue SEL-12 undergoes aberrant endoproteolysis in Caenorhabditis elegans and increases abeta 42 generation in human cells, J Biol Chem 275, 40925–40932.
Okochi, M., Walter, J., Koyama, A., Nakajo, S., Baba, M., Iwatsubo, T., Meijer, L., Kahle, P. J., and Haass, C. (2000) Constitutive phosphorylation of the Parkinson’s disease associated alpha-synuclein, J Biol Chem 275, 390–397.
Gorbatyuk, O. S., Li, S., Sullivan, L. F., Chen, W., Kondrikova, G., Manfredsson, F. P., Mandel, R. J., and Muzyczka, N. (2008) The phosphorylation state of Ser-129 in human alpha-synuclein determines neurodegeneration in a rat model of Parkinson disease, Proc Natl Acad Sci U S A 105, 763–768.
Carvelli, L., McDonald, P. W., Blakely, R. D., and Defelice, L. J. (2004) Dopamine transporters depolarize neurons by a channel mechanism, Proc Natl Acad Sci U S A 101, 16046–16051.
Torres, G. E. (2006) The dopamine transporter proteome, J Neurochem 97 Suppl 1, 3–10.
Egana, L. A., Cuevas, R. A., Baust, T. B., Parra, L. A., Leak, R. K., Hochendoner, S., Pena, K., Quiroz, M., Hong, W. C., Dorostkar, M. M., Janz, R., Sitte, H. H., and Torres, G. E. (2009) Physical and functional interaction between the dopamine transporter and the synaptic vesicle protein synaptogyrin-3, J Neurosci 29, 4592–4604.
Cervinski, M. A., Foster, J. D., and Vaughan, R. A. (2010) Syntaxin 1A regulates dopamine transporter activity, phosphorylation and surface expression, Neuroscience 170, 408–416.
Hastrup, H., Karlin, A., and Javitch, J. A. (2001) 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 U S A 98, 10055–10060.
Hastrup, H., Sen, N., and Javitch, J. A. (2003) The human dopamine transporter forms a tetramer in the plasma membrane: cross-linking of a cysteine in the fourth transmembrane segment is sensitive to cocaine analogs, J Biol Chem 278, 45045–45048.
Sorkina, T., Doolen, S., Galperin, E., Zahniser, N. R., and Sorkin, A. (2003) Oligomerization of dopamine transporters visualized in living cells by fluorescence resonance energy transfer microscopy, J Biol Chem 278, 28274–28283.
Torres, G. E., Carneiro, A., Seamans, K., Fiorentini, C., Sweeney, A., Yao, W. D., and Caron, M. G. (2003) Oligomerization and trafficking of the human dopamine transporter. Mutational analysis identifies critical domains important for the functional expression of the transporter, J Biol Chem 278, 2731–2739.
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Butler, B., Saha, K. & Khoshbouei, H. α-synuclein regulation of dopamine transporter. Translat.Neurosci. 3, 249–257 (2012). https://doi.org/10.2478/s13380-012-0036-7
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DOI: https://doi.org/10.2478/s13380-012-0036-7