The vesicular monoamine transporter 2: An underexplored pharmacological target

doi:10.1016/j.neuint.2013.12.003

Neurochemistry International

Volume 73, July 2014, Pages 89-97

https://doi.org/10.1016/j.neuint.2013.12.003 Get rights and content

Highlights

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VMAT1 and VMAT2 transport cytosolic monoamines into synaptic vesicles.
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Reduced VMAT function has been linked to neurodegenerative conditions.
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Modulation of vesicular function may be beneficial in treating a variety of diseases.
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Fluorescent ligands can assess vesicular function in a high throughput format.

Abstract

Active transport of neurotransmitters into synaptic vesicles is required for their subsequent exocytotic release. In the monoamine system, this process is carried out by the vesicular monoamine transporters (VMAT1 and VMAT2). These proteins are responsible for vesicular packaging of dopamine, norepinephrine, serotonin, and histamine. These proteins are essential for proper neuronal function; however, compared to their plasma membrane counterparts, there are few drugs available that target these vesicular proteins. This is partly due to the added complexity of crossing the plasma membrane, but also to the technical difficulty of assaying for vesicular uptake in high throughput. Until recently, reagents to enable high throughput screening for function of these vesicular neurotransmitter transporters have not been available. Fortunately, novel compounds and methods are now making such screening possible; thus, a renewed focus on these transporters as potential targets is timely and necessary.

Section snippets

Vesicular monoamine transporters: overview

The vesicular monoamine transporters (VMATs) are part of the Major Facilitator Superfamily (MFS) and the solute carrier family of transporters (SLC) subfamily. Like other MFS family members, VMATs contain 12 transmembrane spanning domains, with cytosolic C- and N-terminals and large glycosylated intravesicular loops. Members of the SLC18 subfamily are Drug:H⁺ antiporters; these transporters exchange intravesicular protons for extravesicular neurotransmitter.

The vesicular monoamine transporters

Vesicular monoamine transporters in disease

Many neurological and psychiatric disorders can be linked to dysfunction of monoaminergic systems, including Parkinson’s disease (PD), Huntington’s disease, ADHD, dystonia, schizophrenia, addiction, and depression (Howell and Kimmel, 2008, Picconi et al., 2003, Russell, 2002, Schwartz et al., 2003, Song et al., 2012, Taylor et al., 2000). Although the origin of monoaminergic dysfunction varies, manipulation of vesicular function could be a useful target for modulating monoamine homeostasis.

Current therapeutics targeting VMAT2

Despite the recognized importance of the vesicle in dopaminergic disease, few FDA approved drugs directly and specifically target the vesicle. Two VMAT2 inhibitors, reserpine and tetrabenazine (TBZ), have demonstrated efficacy in the treatment of disease. Although other drugs, such as amphetamine and methylphenidate, are known to affect VMAT2 function, these drugs have a complicated pharmacology due to their interaction with plasmalemmal transporters and inhibition of neurotransmitter

Vesicular transporters as targets for drug development

The majority of drugs used to treat PD and other monoamine disorders target receptors or plasma membrane transporters. While current treatments for PD, such as l-DOPA and dopamine agonists, may compensate temporarily for reduced endogenous dopamine signaling, they do not promote normal neurotransmission, maintain neuronal integrity, or prevent the progression of degeneration. In addition, long-term modulation of these targets often alters receptor sensitivity resulting in loss of effectiveness

Current methods to measure uptake by vesicular neurotransmitter transporters

Until very recently, methods for measuring the activity of vesicular neurotransmitter transporters were not amenable to the high throughput analysis that enables drug development. Vesicular transport is typically measured by radioactive neurotransmitter uptake into vesicles isolated from rat or mouse brain tissue. Vesicles can be prepared from animals treated with various drugs or toxicants to determine the systemic effect on uptake (Hatcher et al., 2008, Chu et al., 2010, Guillot et al., 2008,

A fluorescent assay for VMAT2 transport

Our lab and others have been working to develop high throughput screening techniques for transport function in VMAT2 containing vesicles. We recently reported the development of a fluorescent assay for measuring VMAT2 function (Bernstein et al., 2012). The assay utilizes the Neurotransmitter Uptake Assay from Molecular Devices, which consists of a proprietary fluorescent dye that is transported by monoamine transporters and an impermeable masking dye that blocks extracellular fluorescence.

Conclusions

Radioactive neurotransmitter uptake in isolated synaptic vesicles has unquestionably enhanced the understanding of VMAT2-mediated transport. However, these assays are not amenable to high throughput screening due to the required high animal expenditure and safety restrictions of radiation usage. Development of the fluorescent high throughput assay overcomes these limitations. Cell lines are a practically unlimited resource, enabling easy replication, generation of dose response curves, and

Acknowledgements

This work was supported by P30ES019776, P01ES016175, T32ES012870.

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ReviewThe vesicular monoamine transporter 2: An underexplored pharmacological target

Highlights

Abstract

Section snippets

Vesicular monoamine transporters: overview

Vesicular monoamine transporters in disease

Current therapeutics targeting VMAT2

Vesicular transporters as targets for drug development

Current methods to measure uptake by vesicular neurotransmitter transporters

A fluorescent assay for VMAT2 transport

Conclusions

Acknowledgements

J. Neurosci. Methods

Exp. Neurol.

J. Biol. Chem.

Neurotoxicology

Neurotoxicology

Neurotoxicology

Clin. Ther.

J. Biol. Chem.

Neuron

Am. J. Geriatr. Pharmacother.

Neuropeptides

Neurotoxicology

J. Biol. Chem.

Biochem. Pharmacol.

J. Biol. Chem.

J. Biol. Chem.

Neuroscience

Neurotoxicology

Cell

Toxicology

Neurochem. Int.

Trends Pharmacol. Sci.

Neuron

Bioorg. Med. Chem. Lett.

J. Biol. Chem.

Environ. Res.

Neuroscience

Toxicol. Lett.

Behav. Brain Res.

Exp. Neurol.

Vesicular integrity in Parkinson’s disease

Curr. Neurol. Neurosci. Rep.

Dopamine- or L-DOPA-induced neurotoxicity: the role of dopamine quinone formation and tyrosinase in a model of Parkinson’s disease

Neurotox. Res.

Pesticide exposure and risk for Parkinson’s disease

Ann. Neurol.

Uptake of glutamate into synaptic vesicles by an inorganic phosphate transporter

Science

PCB-induced inhibition of the vesicular monoamine transporter predicts reductions in synaptosomal dopamine content

Toxicol. Sci.

Dopamine neurotoxicity – inhibition of mitochondrial respiration

J. Neurochem.

The use of an irreversible beta-adrenoreceptor antagonist to examine reserpine- and hypothermia-induced supersensitivity of guinea-pig atria

J. Auton. Pharmacol.

Potentiating action of chlorpromazine and reserpine

Nature

Deletion of Go2alpha abolishes cocaine-induced behavioral sensitization by disturbing the striatal dopamine system

FASEB J.

Polychlorinated biphenyl-induced reduction of dopamine transporter expression as a precursor to Parkinson’s disease-associated dopamine toxicity

Toxicol. Sci.

Reduced vesicular storage of dopamine causes progressive nigrostriatal neurodegeneration

J. Neurosci.

Double-knockout mice for alpha- and beta-synucleins: effect on synaptic functions

Proc. Natl. Acad. Sci. USA

Overexpression of the Drosophila vesicular monoamine transporter increases motor activity and courtship but decreases the behavioral response to cocaine

Mol. Psychiatry

Vesicular neurotransmitter transporters as targets for endogenous and exogenous toxic substances

Annu. Rev. Pharmacol. Toxicol.

Unregulated cytosolic dopamine causes neurodegeneration associated with oxidative stress in mice

J. Neurosci.

Effect of antihypertensive therapy on sympathetic nervous system activity in patients with essential hypertension

Fed. Proc.

Methamphetamine alters vesicular monoamine transporter-2 function and potassium-stimulated dopamine release

J. Neurochem.

Age-related decline in striatal dopamine content and motor performance occurs in the absence of nigral cell loss in a genetic mouse model of Parkinson’s disease

Eur. J. Neurosci.

Leaky catecholamine stores: undue waste or a stress response coping mechanism?

Ann. N.Y. Acad. Sci.

Review
The vesicular monoamine transporter 2: An underexplored pharmacological target