Vesicular monoamine transporter
VMATs utilize a proton gradient generated by V-ATPases in vesicle membranes to power monoamine import.
Monoamines transported by VMATs are mainly noradrenaline, adrenaline, dopamine, serotonin, histamine, and trace amines.
In the 1970s, scientists like Arvid Carlsson recognized the need to understand how transport systems and ion gradients work in different organisms in order to explore new treatment options such as reserpine (RES).
[4][12] The current model of VMAT function proposes that the efflux of two protons (H+) against the H+ gradient is coupled with influx of one monoamine.
[4] Studies indicate that the amino acid residue His419, located on the domain between TMDs X and XI of rat VMAT1, plays a role in energy coupling to the amine transport by assisting the first proton-dependent conformational change.
[4][14] Specifically, the residues Lys139 and Asp427 are thought to compose an ion pair that promotes high-affinity interaction with VMAT substrates and inhibitors.
[4][12][17] The imidazoleamine histamine has a thirtyfold higher affinity for VMAT2 compared to VMAT1,[4] and is thought to bind to a different site than other monoamines.
Heterozygous VMAT mutants display hypersensitivity to amphetamine, cocaine, and MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), the latter being a substance causally linked to Parkinson's disease (PD) in rodents.
[22] The current working model proposes that RES and the substrate bind to a single site in a pH-gradient modulated conformational structure of the transporter.
[4][25] The highest amount of genetic variance between VMAT1 and VMAT2 exists near the N- and C- terminals in the cytosolic phase, and in the glycosylated loop between TMDs I and II.
VMAT2 presence does not independently protect neurons from PD, but a decrease in VMAT2 expression has been shown to correlate with susceptibility to the disease,[32] which may be due to a ratio between the dopamine transporter and VMAT2.
[34] Reduced VMAT2 levels were identified in specific subregions of the striatum involved in clinical depression, including the nucleus accumbens shell but not the core, the ventral tegmental area, and the substantia nigra's pars compacta.
[4] Many psychostimulant drugs are known to interact with VMAT, including amphetamine analogs such as methamphetamine, cocaine, and ecstasy (MDMA).
Studies indicate that both amphetamines and cocaine act to increase non-exocytotic release of dopamine in specific regions of the brain by interacting directly with VMAT2 function.
[4][21] By acting as a negative allosteric modulator, methamphetamine blocks the presynaptic cell's ability to use VMAT for vesicular packaging.
[9] A study performed by Sonsalla et al. demonstrated that methamphetamine treatment decreases DHTBZ binding and vesicular dopamine uptake.
[4][21] Another study demonstrated that multiple high doses of methamphetamine removed DTBZ binding sites from the vesicles.
[21] This “Weak Base Hypothesis” proposes that amphetamine analogs enter the cell through transport and lipophilic diffusion, then diffuses through the vesicular membrane where they accumulate in synaptic vesicles and offset the proton electrochemical gradient in the vesicle that drives monoamine transport through VMAT.
[12] It has also mobilized a synapsin-dependent reserve pool of dopamine-containing synaptic vesicles, which interacts with the vesicular trafficking cycle to increase dopamine release.
This is theorized to be a defensive mechanism against the depletive effects cocaine has on cytosolic dopamine through increasing monoamine storage capacity.
Research suggests a decline in VMAT2 protein through prolonged cocaine use could play an important role in the development of cocaine-induced mood disorders.
[9] MDMA is known to affect serotonergic neurons, but has been shown to inhibit synaptosomal and vesicular uptake of serotonin and dopamine[4] to roughly the same extent in vitro.
[35] Much of the current research related to VMAT explores the genetic underpinnings of neuropsychiatric disorders as they may be affected by SLC18A family mutations.
A combination of imaging, neurochemical, biochemical, cell biological, genetic, and immunohistochemical evidence has been compiled to provide the most current comprehensive understanding of the role the VMAT2 plays in amphetamine and cocaine abuse and addiction through aminergic neurotransmission.
[4] Further studies are needed in order to confirm these findings and to gain a better understanding of the role of VMATs in the central nervous system.
[36] Further research is needed to clarify the extent to which these proteins modulate the trafficking of VMATs, and whether they may be exploited in order to gather more information about the exact mechanism of how disorders such as PD occurs, and how they may potentially be treated.
Studies have shown that at the synaptic membrane, enzymes responsible for the synthesis of dopamine, tyrosine hydroxylase and amino acid aromatic decarboxylase are physically and functionally coupled with VMAT2.
Current research related to VMAT uses VMAT2 knockout mice to explore the behavioral genetics of this transporter in an animal model.
[9][35] From knockout and knockdown mice, researchers have discovered that it is good to have over-expression or under-expression of the VMAT genes in some circumstances.
[35] Studies involving animals have prompted scientists to work on developing drugs that inhibit or enhance the function of VMATs.
