World Library  
Flag as Inappropriate
Email this Article

Vmat2

Article Id: WHEBN0025031632
Reproduction Date:

Title: Vmat2  
Author: World Heritage Encyclopedia
Language: English
Subject: Monoamine neurotransmitter, Benzphetamine, Neurotheology, Amphetamine mixed salts (medication), Lundbeck, Propylhexedrine, God gene, Vesicular monoamine transporter
Collection:
Publisher: World Heritage Encyclopedia
Publication
Date:
 

Vmat2

Solute carrier family 18 (vesicular monoamine), member 2
Identifiers
SLC18A2 Gene
Orthologs
SpeciesHumanMouse
File:Brain-Imaging-of-Vesicular-Monoamine-Transporter-Type-2-in-Healthy-Aging-Subjects-by-18F-FP-(+)-pone.0075952.s001.ogv

The vesicular monoamine transporter 2 (VMAT2) also known as solute carrier family 18 member 2 (SLC18A2) is a protein that in humans is encoded by the SLC18A2 gene.[1] VMAT2 is an integral membrane protein that transports monoamines—particularly neurotransmitters such as dopamine, norepinephrine, serotonin, and histamine—from cellular cytosol into synaptic vesicles.[2]

Binding sites and ligands

One binding site is that of dihydrotetrabenazine (DTBZ) and reserpine. Lobeline binds at this site. Dextroamphetamine and dextromethamphetamine bind at distinct sites to the VMAT2, inhibiting its function. Although the amphetamines inhibit VMAT2 presynaptically leading to diminished neurotransmitter, the primary mechanism for the enhancement of extracellular monoamines, like dopamine, is reversal of the dopamine transporter (DAT).[3] Other VMAT2 inhibitors such as GZ-793A inhibit the reinforcing effects of methamphetamine, but without producing stimulant or reinforcing effects themselves.[4]

Inhibition of VMAT2

VMAT2 is essential in the presynaptic neuron's ability to facilitate the release of neurotransmitters into the synaptic cleft. If VMAT2 function is inhibited or compromised, neurotransmitters, such as dopamine, cannot be released via normal transport (exocytosis, action potential) into the synapse. VMAT2 function inhibition can have many various effects on neurotransmitter function. Specifically of importance is its effect on the neurotransmitter dopamine.

Dopamine, specifically, is highly neurotoxic to most cellular structures, due to its ability to auto-oxidize in the presence of oxygen radicals. Dopamine, and other neurotransmitters, are metabolized via various processes into various substances, by enzymes such as monoamine oxidase (MAO), catechol-O-methyl transferase (COMT), and dopamine beta hydroxylase (DBH).

Vesicles normally protect dopamine from auto-oxidation and metabolism by monoamine oxidase and COMT. Impaired VMAT2 function/activity may contribute to symptoms of depression, anxiety, restless leg syndrome, akathisia, Parkinson's disease, social anxiety, and many other conditions, via inhibition of normal dopamine release into the synapse. Long-term use of amphetamine and methamphetamine causes long-lasting reductions in VMAT2 expression/activity, similar to chronic use of cocaine. This reduction of VMAT2 activity contributes significantly to the neurotoxic effects of amphetamine and methamphetamine.

Cocaine users display a marked reduction in VMAT2 immunoreactivity. Sufferers of cocaine-induced mood disorders displayed a significant loss of VMAT2 immunoreactivity; this might reflect damage to dopamine axon terminals in the striatum. These neuronal changes could play a role in causing disordered mood and motivational processes in more severely addicted users.[5]

VMAT2 function in mice

Mice bred without VMAT2 display marked depression and hypoactivity symptoms, and die within a few days of birth. Their brains exhibit a significant decrease of monoamine and catecholamine content, compared to wild-type mice. Depolarization does not normalize behavior in VMAT2-KO mice, compared to wild-type mice. Amphetamine, however, decreases the functional deficits caused by VMAT-deletion, indicating that monoamines/catecholamines, such as dopamine, are still present in the presynaptic cytoplasm, but not packaged into vesicles necessary for normal depolarization/exocytosis-induced release. In wild-type mice and humans, amphetamine inhibits VMAT2 function and reverses the dopamine transporter (DAT), causing the release of unprotected free cytoplasmic dopamine into the synaptic cleft. VMAT-2 deletion mimics the VMAT-2 inhibition caused by amphetamine, allowing amphetamine to simply reverse the DAT, releasing dopamine, and subsequently reducing functional deficits in VMAT2-KO mice. VMAT2-KO mice also display significantly increased neurotoxicity in response to amphetamine, due to the unprotected metabolism and auto-oxidation of dopamine in the presynaptic cytoplasm of dopamine neurons.[6][7]

Spirituality hypothesis

Main article: God gene

Geneticist Dean Hamer has suggested that the VMAT2 gene correlates with spirituality using data from a smoking survey, which included questions intended to measure "self-transcendence". Hamer performed the spirituality study on the side, independently of the National Cancer Institute smoking study. His findings were published in the mass-market book The God Gene: How Faith Is Hard-Wired Into Our Genes.[8][9] However Hamer's claim that the VMAT2 gene contributes to spirituality is controversial.[10] Hamer's study has not been published in the peer reviewed literature.[11]

References

Further reading

External links

  • Medical Subject Headings (MeSH)

This article was sourced from Creative Commons Attribution-ShareAlike License; additional terms may apply. World Heritage Encyclopedia content is assembled from numerous content providers, Open Access Publishing, and in compliance with The Fair Access to Science and Technology Research Act (FASTR), Wikimedia Foundation, Inc., Public Library of Science, The Encyclopedia of Life, Open Book Publishers (OBP), PubMed, U.S. National Library of Medicine, National Center for Biotechnology Information, U.S. National Library of Medicine, National Institutes of Health (NIH), U.S. Department of Health & Human Services, and USA.gov, which sources content from all federal, state, local, tribal, and territorial government publication portals (.gov, .mil, .edu). Funding for USA.gov and content contributors is made possible from the U.S. Congress, E-Government Act of 2002.
 
Crowd sourced content that is contributed to World Heritage Encyclopedia is peer reviewed and edited by our editorial staff to ensure quality scholarly research articles.
 
By using this site, you agree to the Terms of Use and Privacy Policy. World Heritage Encyclopedia™ is a registered trademark of the World Public Library Association, a non-profit organization.
 


Copyright © World Library Foundation. All rights reserved. eBooks from Project Gutenberg are sponsored by the World Library Foundation,
a 501c(4) Member's Support Non-Profit Organization, and is NOT affiliated with any governmental agency or department.