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Gene Review

Slc6a3  -  solute carrier family 6 (neurotransmitter...

Rattus norvegicus

Synonyms: DA transporter, DAT, Sodium-dependent dopamine transporter, Solute carrier family 6 member 3
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Disease relevance of Slc6a3

  • Here, we demonstrate that DAT constitutively internalizes and recycles in rat pheochromocytoma (PC12) cells [1].
  • DAT also can transport dopamine neurotoxins and has been implicated in the selective vulnerability of nigrostriatal dopaminergic neurons in major models of Parkinson's disease [2].
  • MSG treatment (4mg/g of body weight, administered on postnatal days 1, 3, 5, and 7) resulted in a reduction of D1 and D2 receptor expression from 30 days of age and persisted to adulthood (120 days of age), while DA transporter expression was significantly reduced from 14 days of age to adulthood [3].
  • Lordosis in response to solicitous males was observed in females after intercerebral ventricular administration of DAT antagonists WIN35,428 (80 ng) and cocaine (0.016-1.6 micrograms) [4].
  • These results indicate that anoxia enhances DA release by a mechanism involving both the reversed DA transporter and endogenous glutamate [5].

Psychiatry related information on Slc6a3

  • With limited models of bipolar disorder, the DAT KD mice might provide a vehicle to screen for new psychiatric therapies to treat mania and its related symptoms [6].
  • Our present demonstration that these piperidine structures do, in fact, possess significant DAT activity, taken together with their reported lack of locomotor activity, provides a compelling argument for exploring this class of molecules further in animal behavioral experiments [7].
  • Haloperidol administration, but not clozapine, increased stereotyped behavior (p<0.01) in association with a decrease in striatal DAT expression (p<0.05) [8].
  • Our findings suggest that sigma2 receptors are coupled to the DAT via a Ca2+/calmodulin-dependent protein kinase II transduction system in PC12 cells, and that sigma2 receptor antagonists might be useful in the treatment of drug abuse by blocking elevation of DA levels via reversal of the DAT [9].
  • Bupropion, an efficacious antidepressant and smoking cessation agent, inhibits dopamine and norepinephrine transporters (DAT and NET, respectively) [10].

High impact information on Slc6a3

  • The DA transporter is a 619-amino acid protein with 12 hydrophobic putative membrane-spanning domains and homology to the norepinephrine and gamma-aminobutyric acid transporters [11].
  • Here, whole-cell patch clamp and perforated-patch recordings show that substrates of the dopamine transporter (DAT), such as dopamine (DA) and amphetamine, increase the firing activity of rat DA neurons in culture [12].
  • Thus, in addition to clearing extracellular DA, our results suggest that the currents associated with DAT modulate excitability and may regulate release of neurotransmitter from midbrain DA neurons [12].
  • These results demonstrate that aspartate and serine residues lying within the first and seventh hydrophobic putative transmembrane regions are crucial for DAT function and provide identification of residues differentially important for cocaine binding and for dopamine uptake [13].
  • In addition, for rats of the sham-lesioned and severely lesioned groups, immunoradiolabeling for TH, the dopamine transporter (DAT), and the vesicular monoamine transporter (VMAT2) at the striatal level was not significantly different between rats treated with levodopa or vehicle [14].

Chemical compound and disease context of Slc6a3


Biological context of Slc6a3


Anatomical context of Slc6a3

  • Kinetic analyses reveal robust constitutive DAT cycling to and from the plasma membrane, independent of transporter expression levels [1].
  • In primary cultures of rat embryonic midbrain neurons, DAT G585A, K590A, and D600A mutants were restricted to the cell soma and did not traffic to the dendrites or axonal processes [19].
  • The effect of these three mutations on ER export of DAT was demonstrated in porcine aortic endothelial cells and the immortalized neuronal cell line 1RB3AN27 [19].
  • It was found that alanine substitutions of Lys-590 and Asp-600 significantly delayed the delivery of DAT to the plasma membrane because of retention of DAT in the endoplasmic reticulum (ER) [19].
  • In mPFC, nucleus accumbens and striatum, total DAT immunoreactivity was not different between EC and IC groups [23].

Associations of Slc6a3 with chemical compounds

  • The dopamine transporter (DAT) removes dopamine from the extracellular milieu and is potently inhibited by number of psychoactive drugs, including cocaine, amphetamines, and methylphenidate (Ritalin) [1].
  • The plasma membrane dopamine transporter (DAT) has an essential role in terminating dopaminergic neurotransmission by reuptake of dopamine into the presynaptic neurons [19].
  • Most surprising, mutation of Gly-585 to alanine completely blocked the exit of DAT from the ER and surface expression of the transporter [19].
  • In vitro dephosphorylation assays showed substantial removal of (32)PO(4) from DATs by PP1 but not by protein phosphatase 2A, protein phosphatase 2B, or protein tyrosine phosphatase, and this effect was blocked by OA, verifying that the (32)PO(4) loss from DAT was due to dephosphorylation [20].
  • Alanine substitutions for six proline residues located in or near DAT transmembrane domains increase apparent affinity and decrease V(max) values for dopamine efflux mediated by these mutant transporters [24].

Physical interactions of Slc6a3

  • In the SN, treatment with TIQ alone did not change TH level although it enhanced DA content and decreased [(3)H]GBR 12,935 binding to DAT in the substantia nigra pars compacta (SNc) [25].

Regulatory relationships of Slc6a3

  • Our findings suggest that TNF-alpha plays a neuroprotective role in METH-induced drug dependence and neurotoxicity by activating plasmalemmal and vesicular DA transporter as well as inhibiting METH-induced increase in extracellular DA levels [26].

Other interactions of Slc6a3

  • In comparison with TH, the mean area density of DAT-labeled axons was low throughout the VP [27].
  • The addition of mesencephalic membrane fragments and striatal culture-conditioned media along with the cytokine mixture induced the expression of morphologically mature TH-ir cells that were also immunoreactive for dopa-decarboxylase, the DA transporter, and DA itself [28].
  • DAT mRNA is not abundant in the hypothalamus and the olfactory bulb at any stage of development [29].
  • Zitter mutant rats exhibiting a heterogeneous loss of striatal DA innervation were examined for DA transporter (DAT) binding and DA D3 receptor number by autoradiography and compared with Sprague-Dawley rats [30].
  • We confirmed this possibility by observing that both tryptophan hydroxylase (the synthesizing enzyme for serotonin) and the DA transporter, proteins particularly susceptible to oxidative modification, were rapidly (within 30 min), but reversibly (returned to control levels by 36 hr) inactivated by a single administration of METH [31].

Analytical, diagnostic and therapeutic context of Slc6a3

  • Using biotinylation and immunoblotting techniques, the present study examined whether the brain region-specific decrease in DA transporter (DAT) function is the result of a reduction in DAT cell surface expression [23].
  • To further investigate the cellular mechanisms of these alterations, the present study used quantitative autoradiography and in situ hybridization to assess dopamine membrane transporter (DAT) protein density and mRNA expression in restricted-fed and free-fed adult male rats [21].
  • The immunolabeled cells were subsequently assayed for their ability to express catecholamine transporter mRNAs by in situ hybridization using either a rat DAT or NET cRNA probe [32].
  • We have used electron microscopic immunocytochemistry with an N-terminal domain anti-peptide antibody to examine the subcellular distribution of DAT in the rat SN and dorsolateral striatum [2].
  • Antibodies specific for the dopamine transporter (DAT) was developed and characterized by immunoblot analysis, immunoprecipitation, and immunocytochemistry, and used for immunolocalization of transporter protein in rat brain at the light microscopic level [33].


  1. The dopamine transporter constitutively internalizes and recycles in a protein kinase C-regulated manner in stably transfected PC12 cell lines. Loder, M.K., Melikian, H.E. J. Biol. Chem. (2003) [Pubmed]
  2. The dopamine transporter is localized to dendritic and axonal plasma membranes of nigrostriatal dopaminergic neurons. Nirenberg, M.J., Vaughan, R.A., Uhl, G.R., Kuhar, M.J., Pickel, V.M. J. Neurosci. (1996) [Pubmed]
  3. Modification of dopaminergic markers expression in the striatum by neonatal exposure to glutamate during development. López-Pérez, S.J., Vergara, P., Ventura-Valenzuela, J.P., Ureña-Guerrero, M.E., Segovia, J., Beas-Zárate, C. Int. J. Dev. Neurosci. (2005) [Pubmed]
  4. In vivo regulation of central nervous system progesterone receptors: cocaine induces steroid-dependent behavior through dopamine transporter modulation of D5 receptors in rats. Apostolakis, E.M., Garai, J., Clark, J.H., O'Malley, B.W. Mol. Endocrinol. (1996) [Pubmed]
  5. Anoxia-induced dopamine release from rat striatal slices: involvement of reverse transport mechanism. Büyükuysal, R.L., Mete, B. J. Neurochem. (1999) [Pubmed]
  6. Valproate attenuates hyperactive and perseverative behaviors in mutant mice with a dysregulated dopamine system. Ralph-Williams, R.J., Paulus, M.P., Zhuang, X., Hen, R., Geyer, M.A. Biol. Psychiatry (2003) [Pubmed]
  7. Chemistry and pharmacology of the piperidine-based analogues of cocaine. Identification of potent DAT inhibitors lacking the tropane skeleton. Kozikowski, A.P., Araldi, G.L., Boja, J., Meil, W.M., Johnson, K.M., Flippen-Anderson, J.L., George, C., Saiah, E. J. Med. Chem. (1998) [Pubmed]
  8. Differential nigral expression of Bcl-2 protein family in chronically haloperidol and clozapine-treated rats: Role in neurotoxicity and stereotyped behavior. Saldaña, M., Bonastre, M., Aguilar, E., Marin, C. Exp. Neurol. (2007) [Pubmed]
  9. Modulation of amphetamine-stimulated [3H]dopamine release from rat pheochromocytoma (PC12) cells by sigma type 2 receptors. Weatherspoon, J.K., Werling, L.L. J. Pharmacol. Exp. Ther. (1999) [Pubmed]
  10. Bupropion inhibits nicotine-evoked [(3)H]overflow from rat striatal slices preloaded with [(3)H]dopamine and from rat hippocampal slices preloaded with [(3)H]norepinephrine. Miller, D.K., Sumithran, S.P., Dwoskin, L.P. J. Pharmacol. Exp. Ther. (2002) [Pubmed]
  11. Cloning and expression of a cocaine-sensitive dopamine transporter complementary DNA. Shimada, S., Kitayama, S., Lin, C.L., Patel, A., Nanthakumar, E., Gregor, P., Kuhar, M., Uhl, G. Science (1991) [Pubmed]
  12. Dopamine transporter-mediated conductances increase excitability of midbrain dopamine neurons. Ingram, S.L., Prasad, B.M., Amara, S.G. Nat. Neurosci. (2002) [Pubmed]
  13. Dopamine transporter site-directed mutations differentially alter substrate transport and cocaine binding. Kitayama, S., Shimada, S., Xu, H., Markham, L., Donovan, D.M., Uhl, G.R. Proc. Natl. Acad. Sci. U.S.A. (1992) [Pubmed]
  14. Chronic levodopa is not toxic for remaining dopamine neurons, but instead promotes their recovery, in rats with moderate nigrostriatal lesions. Murer, M.G., Dziewczapolski, G., Menalled, L.B., García, M.C., Agid, Y., Gershanik, O., Raisman-Vozari, R. Ann. Neurol. (1998) [Pubmed]
  15. Phosphatidylinositol 3-kinase, protein kinase C, and MEK1/2 kinase regulation of dopamine transporters (DAT) require N-terminal DAT phosphoacceptor sites. Lin, Z., Zhang, P.W., Zhu, X., Melgari, J.M., Huff, R., Spieldoch, R.L., Uhl, G.R. J. Biol. Chem. (2003) [Pubmed]
  16. Heteroaromatic analogs of 1-[2-(diphenylmethoxy)ethyl]- and 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazines (GBR 12935 and GBR 12909) as high-affinity dopamine reuptake inhibitors. Matecka, D., Lewis, D., Rothman, R.B., Dersch, C.M., Wojnicki, F.H., Glowa, J.R., DeVries, A.C., Pert, A., Rice, K.C. J. Med. Chem. (1997) [Pubmed]
  17. Methylenedioxymethamphetamine decreases plasmalemmal and vesicular dopamine transport: mechanisms and implications for neurotoxicity. Hansen, J.P., Riddle, E.L., Sandoval, V., Brown, J.M., Gibb, J.W., Hanson, G.R., Fleckenstein, A.E. J. Pharmacol. Exp. Ther. (2002) [Pubmed]
  18. Psychostimulants and vesicle trafficking: a novel mechanism and therapeutic implications. Hanson, G.R., Sandoval, V., Riddle, E., Fleckenstein, A.E. Ann. N. Y. Acad. Sci. (2004) [Pubmed]
  19. Multiple molecular determinants in the carboxyl terminus regulate dopamine transporter export from endoplasmic reticulum. Miranda, M., Sorkina, T., Grammatopoulos, T.N., Zawada, W.M., Sorkin, A. J. Biol. Chem. (2004) [Pubmed]
  20. Dopamine transporters are dephosphorylated in striatal homogenates and in vitro by protein phosphatase 1. Foster, J.D., Pananusorn, B., Cervinski, M.A., Holden, H.E., Vaughan, R.A. Brain Res. Mol. Brain Res. (2003) [Pubmed]
  21. Restricted feeding with scheduled sucrose access results in an upregulation of the rat dopamine transporter. Bello, N.T., Sweigart, K.L., Lakoski, J.M., Norgren, R., Hajnal, A. Am. J. Physiol. Regul. Integr. Comp. Physiol. (2003) [Pubmed]
  22. Strain differences in the distribution of dopamine transporter sites in rat brain. Jiao, X., Paré, W.P., Tejani-Butt, S. Prog. Neuropsychopharmacol. Biol. Psychiatry (2003) [Pubmed]
  23. Environmental enrichment decreases cell surface expression of the dopamine transporter in rat medial prefrontal cortex. Zhu, J., Apparsundaram, S., Bardo, M.T., Dwoskin, L.P. J. Neurochem. (2005) [Pubmed]
  24. Dopamine efflux via wild-type and mutant dopamine transporters: alanine substitution for proline-572 enhances efflux and reduces dependence on extracellular dopamine, sodium and chloride concentrations. Itokawa, M., Lin, Z., Uhl, G.R. Brain Res. Mol. Brain Res. (2002) [Pubmed]
  25. Effect of 1,2,3,4,-tetrahydroisoquinoline administration under conditions of CYP2D inhibition on dopamine metabolism, level of tyrosine hydroxylase protein and the binding of [3H]GBR 12,935 to dopamine transporter in the rat nigrostriatal, dopaminergic system. Lorenc-Koci, E., Antkiewicz-Michaluk, L., Wardas, J., Zapała, M., Wierońska, J. Brain Res. (2004) [Pubmed]
  26. Role of tumor necrosis factor-alpha in methamphetamine-induced drug dependence and neurotoxicity. Nakajima, A., Yamada, K., Nagai, T., Uchiyama, T., Miyamoto, Y., Mamiya, T., He, J., Nitta, A., Mizuno, M., Tran, M.H., Seto, A., Yoshimura, M., Kitaichi, K., Hasegawa, T., Saito, K., Yamada, Y., Seishima, M., Sekikawa, K., Kim, H.C., Nabeshima, T. J. Neurosci. (2004) [Pubmed]
  27. Regional and subcellular compartmentation of the dopamine transporter and tyrosine hydroxylase in the rat ventral pallidum. Mengual, E., Pickel, V.M. J. Comp. Neurol. (2004) [Pubmed]
  28. Differentiation of mesencephalic progenitor cells into dopaminergic neurons by cytokines. Ling, Z.D., Potter, E.D., Lipton, J.W., Carvey, P.M. Exp. Neurol. (1998) [Pubmed]
  29. Ontogeny of dopamine transporter mRNA expression in the rat brain. Fujita, M., Shimada, S., Nishimura, T., Uhl, G.R., Tohyama, M. Brain Res. Mol. Brain Res. (1993) [Pubmed]
  30. The zitter mutant rat exhibits loss of D3 receptors with degeneration of the dopamine system. Joyce, J.N., Yoshimoto, K., Ueda, S. Neuroreport (2000) [Pubmed]
  31. Methamphetamine-induced rapid and reversible reduction in the activities of tryptophan hydroxylase and dopamine transporters: oxidative consequences? Hanson, G.R., Gibb, J.W., Metzger, R.R., Kokoshka, J.M., Fleckenstein, A.E. Ann. N. Y. Acad. Sci. (1998) [Pubmed]
  32. Cell-type-specific expression of catecholamine transporters in the rat brain. Lorang, D., Amara, S.G., Simerly, R.B. J. Neurosci. (1994) [Pubmed]
  33. The dopamine transporter: immunochemical characterization and localization in brain. Ciliax, B.J., Heilman, C., Demchyshyn, L.L., Pristupa, Z.B., Ince, E., Hersch, S.M., Niznik, H.B., Levey, A.I. J. Neurosci. (1995) [Pubmed]
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