Dopamine transporters and neuronal injury

doi:10.1016/S0165-6147(99)01379-6

Trends in Pharmacological Sciences

Volume 20, Issue 10, 1 October 1999, Pages 424-429

https://doi.org/10.1016/S0165-6147(99)01379-6 Get rights and content

Abstract

The plasma membrane dopamine transporter (DAT) and the vesicular monoamine transporter (VMAT2) are essential for normal dopamine neurotransmission. DAT terminates the actions of dopamine by rapidly removing dopamine from the synapse, whereas VMAT2 loads cytoplasmic dopamine into vesicles for storage and subsequent release. Recent data suggest that perturbation of the tightly regulated balance between these two transporters predisposes the neurone to damage by a variety of insults. Most notable is the selective degeneration of DAT- and VMAT2-expressing dopamine nerve terminals in the striatum thought to underlie Parkinson’s disease. DAT and VMAT2 expression can predict the selective vulnerability of neuronal populations, which suggests that therapeutic strategies aimed at altering DAT and VMAT2 function could have significant benefits in a variety of disorders.

Section snippets

DAT is a molecular gateway for toxins

Although DAT expression is essential for normal dopamine neurotransmission, it also renders the dopamine neurone susceptible to damage by toxins that can be transported by DAT. Because many potentially toxic substances resemble dopamine and are thus substrates for DAT, they can be accumulated in the dopaminergic neurone by DAT. Inside the neurone, these compounds can disrupt mitochondrial function or react with other vulnerable targets (see Fig. 1a). A prime example is

Genetic knockout

One of the most valuable tools for understanding the function of a particular protein is the genetic deletion of the protein of interest, commonly known as a ‘knockout’. By inserting a specific sequence of DNA that disrupts normal transcription of the gene (typically encoding antibiotic resistance to aid in the selection of mutant gene), expression of the particular protein is effectively blocked. Because a particular protein is encoded by two copies of a gene it is necessary to have the gene

Acknowledgements

This work was supported by grants from the National Institutes of Health NS-37031 to AIL, ES-09248 to GWM, and HL-19576 to MGC. MGC is an Investigator of the Howard Hughes Medical Institute. RRG is a visiting scientist from the Institute of Pharmacology, Moscow, Russia.

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Citation Excerpt :
DA reuptake occurs via the dopamine transporter (DAT), a transmembrane Na+/K+ - dependent protein, member of the solute carrier 6 (SLC6) family. The pharmacological inhibition of the transporter can be studied as a solution to neurological and psychological disorders such as Attention Deficit Hyperactivity Disorder (ADHD), depression, addiction, schizophrenia and Tourette syndrome [43,69]. In humans, the DAT is coded by the SLC6A3 gene (or DAT1) present on chromosome 5p15.32, composed of 15 exons spanning 60 kb; it encodes 620 amino acids with many putative N-glycosylation sites that, for the transport of dopamine, need glycosylation [9].
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Trends in Pharmacological Sciences

ReviewDopamine transporters and neuronal injury

Abstract

Section snippets

DAT is a molecular gateway for toxins

Genetic knockout

Acknowledgements

Trends Pharmacol. Sci.

Cell

Biochem. Biophys. Res. Commun.

Brain Res. Mol. Brain Res.

J. Biol. Chem.

Arch. Biochem. Biophys.

Neuroscience

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Brain Res.

Methods Enzymol.

Exp. Neurol.

Neuron

Neuron

Eur. J. Pharmacol.

Neurosci. Lett.

Am. J. Hum. Genet.

Brain Res. Dev. Brain Res.

Pharmacol. Biochem. Behav.

Ecotoxicol. Environ. Saf.

Annu. Rev. Pharmacol. Toxicol.

Nature

J. Neurochem.

Science

Ciba Found. Symp.

Proc. Natl. Acad. Sci. U. S. A.

Physiol. Rev.

Proc. Natl. Acad. Sci. U. S. A.

J. Neurosci.

Proc. Natl. Acad. Sci. U. S. A.

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Ann. Neurol.

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Adv. Exp. Med. Biol.

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Review
Dopamine transporters and neuronal injury