Dopamine transporter

Source: Wikipedia, the free encyclopedia.

SLC6A3
Gene ontology
Molecular function
Cellular component
Biological process
Sources:Amigo / QuickGO
Ensembl

ENSG00000142319
ENSG00000276996

ENSMUSG00000021609

UniProt

Q01959

Q61327

RefSeq (mRNA)

NM_001044

NM_010020

RefSeq (protein)

NP_001035

NP_034150

Location (UCSC)Chr 5: 1.39 – 1.45 MbChr 13: 73.68 – 73.73 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

The dopamine transporter (DAT, also sodium-dependent dopamine transporter) is a membrane-spanning protein coded for in the human by the SLC6A3

synaptic cleft back into cytosol. In the cytosol, other transporters sequester the dopamine into vesicles for storage and later release. Dopamine reuptake via DAT provides the primary mechanism through which dopamine is cleared from synapses, although there may be an exception in the prefrontal cortex, where evidence points to a possibly larger role of the norepinephrine transporter.[5]

DAT is implicated in a number of dopamine-related disorders, including

genetic polymorphism, known as a variable number tandem repeat, in the SLC6A3 gene, which influences the amount of protein expressed.[6]

Function

DAT is an

synaptic cleft and deposits it into surrounding cells, thus terminating the signal of the neurotransmitter. Dopamine underlies several aspects of cognition, including reward, and DAT facilitates regulation of that signal.[7]

Mechanism

DAT is a

Na+/K+ ATPase.[8]

In the most widely accepted model for monoamine transporter function, sodium ions must bind to the extracellular domain of the transporter before dopamine can bind. Once dopamine binds, the protein undergoes a conformational change, which allows both sodium and dopamine to unbind on the intracellular side of the membrane.[9]

Studies using electrophysiology and radioactive-labeled dopamine have confirmed that the dopamine transporter is similar to other monoamine transporters in that one molecule of neurotransmitter can be transported across the membrane with one or two sodium ions. Chloride ions are also needed to prevent a buildup of positive charge. These studies have also shown that transport rate and direction is totally dependent on the sodium gradient.[10]

Because of the tight coupling of the membrane potential and the sodium gradient, activity-induced changes in membrane polarity can dramatically influence transport rates. In addition, the transporter may contribute to dopamine release when the neuron depolarizes.[10]

DAT–Cav coupling

Preliminary evidence suggests that the dopamine transporter couples to L-type

CAMKII-mediated phosphorylation of the dopamine transporter as a downstream effect;[11] since DAT phosphorylation by CAMKII results in dopamine efflux in vivo, activation of transporter-coupled calcium channels is a potential mechanism by which certain drugs (e.g., amphetamine) trigger neurotransmitter release.[11]

Protein structure

The initial determination of the membrane topology of DAT was based upon

proteases, which digest proteins into smaller fragments, and glycosylation, which occurs only on extracellular loops, and largely verified the initial predictions of membrane topology.[13] The exact structure of the Drosophila melanogaster dopamine transporter (dDAT) was elucidated in 2013 by X-ray crystallography.[14]

Location and distribution

Pharmacodynamics of amphetamine in a dopamine neuron
A pharmacodynamic model of amphetamine and TAAR1
via AADC
The image above contains clickable links
Amphetamine enters the presynaptic neuron across the neuronal membrane or through DAT.
CAMKIIα-dependent pathway, in turn producing dopamine efflux.[20][21]

Regional distribution of DAT has been found in areas of the brain with established dopaminergic circuitry, including the nigrostriatal, mesolimbic, and mesocortical pathways.[22] The nuclei that make up these pathways have distinct patterns of expression. Gene expression patterns in the adult mouse show high expression in the substantia nigra pars compacta.[23]

DAT in the mesocortical pathway, labeled with radioactive antibodies, was found to be enriched in dendrites and cell bodies of neurons in the substantia nigra pars compacta and ventral tegmental area. This pattern makes sense for a protein that regulates dopamine levels in the synapse.

Staining in the

D2 dopamine receptors. The latter was thus demonstrated to be an autoreceptor on cells that release dopamine. TAAR1 is a presynaptic intracellular receptor that is also colocalized with DAT and which has the opposite effect of the D2 autoreceptor when activated;[15][24] i.e., it internalizes dopamine transporters and induces efflux through reversed transporter function via PKA and PKC
signaling.

Surprisingly, DAT was not identified within any synaptic active zones. These results suggest that striatal dopamine reuptake may occur outside of synaptic specializations once dopamine diffuses from the synaptic cleft.

In the

plasma membranes.[25]

Within the

Golgi complex, and multivesicular bodies, identifying probable sites of synthesis, modification, transport, and degradation.[26]

Genetics and regulation

The

DAT1, is located on chromosome 5p15.[6]
The protein encoding region of the gene is over 64 kb long and comprises 15 coding segments or
exons.[27]
This gene has a variable number tandem repeat (VNTR) at the 3’ end (rs28363170) and another in the intron 8 region.[28] Differences in the VNTR have been shown to affect the basal level of expression of the transporter; consequently, researchers have looked for associations with dopamine-related disorders.[29]

Sp-1
.

While transcription factors control which cells express DAT, functional regulation of this protein is largely accomplished by

Dopamine autoreceptors also regulate DAT by directly opposing the effect of TAAR1 activation.[15]

The human dopamine transporter (hDAT) contains a

Zinc supplementation may reduce the minimum effective dose of amphetamine when it is used for the treatment of attention deficit hyperactivity disorder.[38]

Biological role and disorders

The rate at which DAT removes dopamine from the synapse can have a profound effect on the amount of dopamine in the cell. This is best evidenced by the severe cognitive deficits, motor abnormalities, and hyperactivity of mice with no dopamine transporters.

ADHD
.

Differences in the functional

withdrawal symptoms from alcoholism, although this is a point of controversy.[43][44] An allele of the DAT gene with normal protein levels is associated with non-smoking behavior and ease of quitting.[45] Additionally, male adolescents particularly those in high-risk families (ones marked by a disengaged mother and absence of maternal affection) who carry the 10-allele VNTR repeat show a statistically significant affinity for antisocial peers.[46][47]

Increased activity of DAT is associated with several different disorders, including

clinical depression.[48]

Mutations in DAT have been shown to cause

movement disorder characterized by progressively worsening dystonia and parkinsonism.[49]

Pharmacology

The dopamine transporter is the target of substrates, dopamine releasers, transport inhibitors and allosteric modulators.[50][51]

Cocaine blocks DAT by binding directly to the transporter and reducing the rate of transport.

CAMKIIα-mediated phosphorylation of the transporter, which putatively arises from the activation of DAT-coupled L-type calcium channels by amphetamine.[11]

The dopaminergic mechanisms of each drug are believed to underlie the pleasurable feelings elicited by these substances.[7]

Interactions

Dopamine transporter has been shown to

interact
with:

Apart from these innate protein-protein interactions, recent studies demonstrated that viral proteins such as HIV-1 Tat protein interacts with the DAT[56][57] and this binding may alter the dopamine homeostasis in HIV positive individuals which is a contributing factor for the HIV-associated neurocognitive disorders.[58]

See also

References

  1. ^ a b c ENSG00000276996 GRCh38: Ensembl release 89: ENSG00000142319, ENSG00000276996 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000021609 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. S2CID 23682303
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  6. ^
    PMID 1478653
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  7. ^
    S2CID 52857162
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  8. S2CID 21545649
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  9. PMID 8994051
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  10. ^
    S2CID 42196576
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  11. ^
    PMID 26162812
    . One example of interest is CaMKII, which has been well characterized as an effector of Ca2+ currents downstream of L-type Ca2+ channels [21,22]. Interestingly, DAT is a CaMKII substrate and phosphorylated DAT favors the reverse transport of dopamine [48,49], constituting a possible mechanism by which electrical activity and L-type Ca2+ channels may modulate DAT states and dopamine release. ... In summary, our results suggest that pharmacologically, S(+)AMPH is more potent than DA at activating hDAT-mediated depolarizing currents, leading to L-type Ca2+ channel activation, and the S(+)AMPH-induced current is more tightly coupled than DA to open L-type Ca2+ channels.
  12. ^
    PMID 1948035
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  13. PMID 8702957
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  14. PMID 24037379
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  15. ^
    PMID 21073468
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  16. ^
    PMID 21272013
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  17. PMID 27141430
    . Despite the challenges in determining synaptic vesicle pH, the proton gradient across the vesicle membrane is of fundamental importance for its function. Exposure of isolated catecholamine vesicles to protonophores collapses the pH gradient and rapidly redistributes transmitter from inside to outside the vesicle. ... Amphetamine and its derivatives like methamphetamine are weak base compounds that are the only widely used class of drugs known to elicit transmitter release by a non-exocytic mechanism. As substrates for both DAT and VMAT, amphetamines can be taken up to the cytosol and then sequestered in vesicles, where they act to collapse the vesicular pH gradient.
  18. PMID 21772817
    . Three important new aspects of TAs action have recently emerged: (a) inhibition of firing due to increased release of dopamine; (b) reduction of D2 and GABAB receptor-mediated inhibitory responses (excitatory effects due to disinhibition); and (c) a direct TA1 receptor-mediated activation of GIRK channels which produce cell membrane hyperpolarization.
  19. ^ "TAAR1". GenAtlas. University of Paris. 28 January 2012. Retrieved 29 May 2014.  • tonically activates inwardly rectifying K(+) channels, which reduces the basal firing frequency of dopamine (DA) neurons of the ventral tegmental area (VTA)
  20. ^
    PMID 25033183
    . AMPH also increases intracellular calcium (Gnegy et al., 2004) that is associated with calmodulin/CamKII activation (Wei et al., 2007) and modulation and trafficking of the DAT (Fog et al., 2006; Sakrikar et al., 2012).
  21. ^
    PMID 23968642
    . AMPH and METH also stimulate DA efflux, which is thought to be a crucial element in their addictive properties [80], although the mechanisms do not appear to be identical for each drug [81]. These processes are PKCβ– and CaMK–dependent [72, 82], and PKCβ knock-out mice display decreased AMPH-induced efflux that correlates with reduced AMPH-induced locomotion [72].
  22. S2CID 46295607
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  23. PMID 17437647
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  24. ^ Maguire JJ, Davenport AP (19 July 2016). "Trace amine receptor: TA1 receptor". IUPHAR/BPS Guide to PHARMACOLOGY. International Union of Basic and Clinical Pharmacology. Retrieved 22 September 2016.
  25. PMID 8551328
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  26. S2CID 21202901
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  27. PMID 9300814
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  28. S2CID 39416578
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  29. PMID 11803445
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  30. S2CID 19410051
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  31. PMID 13679416
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  32. S2CID 20618165
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  33. PMID 15718104
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  34. PMID 19325074
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  35. S2CID 24589993
    . Zinc binds at ... extracellular sites of the DAT [103], serving as a DAT inhibitor. In this context, controlled double-blind studies in children are of interest, which showed positive effects of zinc [supplementation] on symptoms of ADHD [105,106]. It should be stated that at this time [supplementation] with zinc is not integrated in any ADHD treatment algorithm.
  36. PMID 21338876
    . They did not confirm the predicted straightforward relationship between uptake and release, but rather that some compounds including AMPH were better releasers than substrates for uptake. Zinc, moreover, stimulates efflux of intracellular [3H]DA despite its concomitant inhibition of uptake (Scholze et al., 2002).
  37. ^
    PMID 11940571
    . The human dopamine transporter (hDAT) contains an endogenous high affinity Zn2+ binding site with three coordinating residues on its extracellular face (His193, His375, and Glu396). ... Although Zn2+ inhibited uptake, Zn2+ facilitated [3H]MPP+ release induced by amphetamine, MPP+, or K+-induced depolarization specifically at hDAT but not at the human serotonin and the norepinephrine transporter (hNET).
  38. PMID 23021477
    . With regard to zinc supplementation, a placebo controlled trial reported that doses up to 30 mg/day of zinc were safe for at least 8 weeks, but the clinical effect was equivocal except for the finding of a 37% reduction in amphetamine optimal dose with 30 mg per day of zinc.110
  39. S2CID 9629915
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  40. PMID 11304827
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  41. S2CID 22881996
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  42. PMID 38420272
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  44. PMID 10578237
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  45. PMID 12630565
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  46. S2CID 46592146
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  47. ^ Florida State University (2 October 2008). "Specific Gene Found In Adolescent Men With Delinquent Peers". ScienceDaily. Retrieved 8 October 2008.
  48. S2CID 32882588
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  49. PMID 24613933
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  50. PMID 25788711
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  51. PMID 31184115
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  52. S2CID 54381509
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  54. S2CID 17318937
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  55. PMID 12177201
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  56. PMID 25604666
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  57. PMID 23645138
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  58. S2CID 13319355
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External links
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