Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Comment
. 2009 Jun;119(6):1455-8.
doi: 10.1172/jci39632.

Infantile parkinsonism-dystonia: a dopamine "transportopathy"

Craig Blackstone  1
Affiliations
Comment

Infantile parkinsonism-dystonia: a dopamine "transportopathy"

Craig Blackstone. J Clin Invest. 2009 Jun.

Abstract

The dopamine transporter (DAT) retrieves the neurotransmitter dopamine from the synaptic cleft at dopaminergic synapses. Variations in solute carrier family 6A, member 3 (SLC6A3/DAT1), the human gene encoding DAT, have been implicated in attention deficit hyperactivity and bipolar disorders, and DAT is a prominent site of action for drugs such as amphetamines and cocaine. In this issue of the JCI, Kurian et al. report that an autosomal recessive infantile parkinsonism-dystonia is caused by loss-of-function mutations in DAT that impair dopamine reuptake (see the related article beginning on page 1595). Though this might be predicted to result in dopamine excess in the synaptic cleft, it likely also causes depletion of presynaptic dopamine stores and possibly downregulation of postsynaptic dopamine receptor function, resulting in impairments in dopaminergic neurotransmission consistent with the clinical presentation. This is the first report of a genetic alteration in DAT function underlying a parkinsonian disorder.

PubMed Disclaimer

Figures

Figure 1
Figure 1. Diagram of a dopaminergic synapse illustrating possible effects of the loss of DAT function.
(A) Presynaptic and postsynaptic neuron membranes and the synaptic cleft are indicated. D1-class and D2-class dopamine receptors are positively or negatively coupled to adenylate cyclase (AC) via G proteins (G). Coupling to other signaling pathways is not shown. Catechol O-methyltransferase (COMT) and monoamine oxidase B (MAO-B) are involved in the metabolism of dopamine (blue circles) to products such as homovanillic acid (HVA) and 3-methoxytyramine (3-MT). Dopamine in the cleft can bind presynaptically to D2 autoreceptors or the DAT, or postsynaptically to D1- and D2-class receptors. The DAT is predominately located perisynaptically. (B) In this issue of the JCI, Kurian et al. (14) show that SLC6A3/DAT1 loss-of-function mutations in individuals with infantile parkinsonism-dystonia result in inhibition of DAT-mediated dopamine reuptake activity. Increased time that dopamine is present in the synaptic cleft will result in dopamine degradation there, predominantly by COMT, as well as increased levels of the dopamine metabolite homovanillic acid in the cerebrospinal fluid. Overstimulation of D2 autoreceptors is predicted to inhibit the phosphorylation-dependent activation of tyrosine hydroxylase (TH), which is rate limiting for the production of dopamine. Mutations in the gene encoding TH have been implicated in other movement disorders such as L-dopa–responsive dystonia and infantile parkinsonism. Prolonged dopamine presence in the synaptic cleft may result in desensitization or downregulation of postsynaptic dopamine receptors, with alterations in downstream signaling.
See this image and copyright information in PMC

Comment on

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Carlsson A. Perspectives on the discovery of central monoaminergic neurotransmission. Annu. Rev. Neurosci. 1987;10:19–40. doi: 10.1146/annurev.ne.10.030187.000315. - DOI - PubMed
    1. Carlsson A. A paradigm shift in brain research. Science. 2001;294:1021–1024. doi: 10.1126/science.1066969. - DOI - PubMed
    1. Mehler-Wex C., Riederer P., Gerlach M. Dopaminergic dysbalance in distinct basal ganglia neurocircuits: implications for the pathophysiology of Parkinson’s disease, schizophrenia and attention deficit hyperactivity disorder. Neurotox. Res. 2006;10:167–179. - PubMed
    1. Yao W.-D., Spealman R.D., Zhang J. Dopaminergic signaling in dendritic spines. Biochem. Pharmacol. 2008;75:2055–2069. doi: 10.1016/j.bcp.2008.01.018. - DOI - PMC - PubMed
    1. He L., Vasiliou K., Nebert D.W. Analysis and update of the human solute carrier (SLC) gene superfamily. Hum. Genomics. 2009;3:195–206. - PMC - PubMed

Publication types

MeSH terms

Substances