Species Human Entrez 6571 | Human Mouse Ensembl ENSG00000165646 | |
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Aliases SLC18A2, SVAT, SVMT, VAT2, VMAT2, solute carrier family 18 member A2 External IDs OMIM: 193001 MGI: 106677 HomoloGene: 2298 GeneCards: SLC18A2 | ||
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. VMAT2 is an integral membrane protein that transports monoamines—particularly neurotransmitters such as dopamine, norepinephrine, serotonin, and histamine—from cellular cytosol into synaptic vesicles. In nigrostriatal pathway and mesolimbic pathway dopamine-releasing neurons, VMAT2 function is also necessary for the vesicular release of the neurotransmitter GABA.
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Binding sites and ligands
VMAT2 is believed to possess at least two distinct binding sites, which are characterized by tetrabenazine (TBZ) and reserpine binding to the transporter. Amphetamine (TBZ site) and methamphetamine (reserpine site) bind at distinct sites on VMAT2 to inhibit its function. VMAT2 inhibitors like tetrabenazine and reserpine reduce the concentration of monoamine neurotransmitters in the synaptic cleft by inhibiting uptake through VMAT2; the inhibition of VMAT2 uptake by these drugs prevents the storage of neurotransmitters in synaptic vesicles and reduces the quantity of neurotransmitters that are released through exocytosis. Although many substituted amphetamines induce the release of neurotransmitters from vesicles through VMAT2 while inhibiting uptake through VMAT2, they facilitate the release of monoamine neurotransmitters into the synaptic cleft by simultaneously reversing the direction of transport through the primary plasma membrane transport proteins for monoamines (i.e., the dopamine transporter, norepinephrine transporter, and serotonin transporter) in monoamine neurons. Other VMAT2 inhibitors such as GZ-793A inhibit the reinforcing effects of methamphetamine, but without producing stimulant or reinforcing effects themselves.
Inhibition of VMAT2
VMAT2 is essential for enabling the release of neurotransmitters from the axon terminals of monoamine neurons into the synaptic cleft. If VMAT2 function is inhibited or compromised, monoamine neurotransmitters such as dopamine cannot be released into the synapse via typical release mechanisms (i.e., exocytosis resulting from action potentials).
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.
In popular culture
Geneticist Dean Hamer has suggested that a particular allele of 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. Hamer himself notes that VMAT2 plays at most a minor role in influencing spirituality. Furthermore, Hamer's claim that the VMAT2 gene contributes to spirituality is controversial. Hamer's study has not been published in a peer reviewed journal and a reanalysis of the correlation demonstrates that it is not statistically significant.