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Wikipedia Article First Draft

Expression
Although both VMAT1 and VMAT2 are encoded by two different genes, the individual genetic sequences demonstrate high homology. However, identifying differences between the sequences may prove helpful in researching the function and mechanism of these transporters. For example, polymorphisms in VMAT2 which affect regulation and thus quantitative expression may identify as genetic risk factors for Parkinson's disease. Moreover, a specific VMAT1  genes (SLC18A2) has several associated polymorphisms which have a locus 8p21.3 that has been strongly connected to a susceptibility to Schizophrenia. Further research on the VMAT1 genes have suggested genetic susceptibilities to Bipolar Disorder and other anxiety-related disorders.

Regulation
Varying degrees of VMAT expression can modulate the amount of neurotransmitter that is packaged into secretory vesicles. Indeed, over expression of VMAT2 results in increased secretion of neurotransmitter upon cell stimulation (Brunt). Data suggests that deletion of the VMAT2 genes does not affect the size of small clear-core vesicles (Brunt); however, contrary preliminary data suggests this regulation may occur via altering the amount of VMATs that localise to each vesicle, directly affecting how much neurotransmitter is able to be packaged into the vesicle at any one time. This can influence the quanta that is released upon cell depolarization which can, in turn allow for regulation of many other cellular interactions in the CNS. Data suggests that deletion of the VMAT2 genes does not affect the overall size of small clear-core vesicles.

It is thought upstream activation of dopamine autoreceptors regulate trafficking and localization of VMAT2 receptors to secretory vesicles, however the exact mechanism by which this occurs is yet to be determined.

VMAT activity is heavily regulated by the H+ gradient that exists over the vesicular membrane. This is facilitated by vacuolar H+ATPase which enables an intravesicular pH of approximately 5.6 in addition to the maintenance of a somewhat less influential electrical gradient with the positive charge being orientated towards the cytosol (Brunt).

G-Proteins
VMATs may be also be regulated by changes in transcription, post-transcriptional modifications such as phosphorylation and mRNA splicing of exons, and vesicular transport inactivation facilitated by heterotrimeric G-proteins. It is thought that chromaffin granules possess these heterotrimeric G-proteins which have shown to be regulatory to small clear-core vesicles (Brunt).

Regulation by specific heterotrimeric G-proteins types is tissue-dependent for VMAT2; it is not known whether this is the case for VMAT1. Heterotrimeric G-proteins Gαo2 decreases VMAT1 activity in pancreatic and adrenal medulla cells, and activated heterotrimeric G-proteins inhibit VMAT2 activity in the brain, regardless of whether localised on small clear-core or large-dense-core vesicles. Activated heterotrimeric G-proteins Gαq downregulates VMAT2 mediated serotonin transport in blood platelets, but this is not the case in the brain where Gαq inhibits VMAT2 activity completely.

Location
VMAT1 is expressed mainly in large dense-core vesicles (LDCVs) of the periphery. It may be found in neuroendocrine cell, particularly chromaffin and enterochromaffin granules which are largely found in the medulla of the adrenal glands. It is also expressed in sympathetic neurons and blood platelets.

Co-expression of VMAT1 and VMAT2 subsets may also be found with VGLUT1 and VGLUT2 (vesicular glutamate transporters)  in complementary groups of glutamatergic neurons in the CNS. VMAT2 is also co-expressed in chromaffin cells.

VMAT2 favours expression in a variety of monoaminergic cells of the CNS such as the brain, sympathetic nervous system, mast cells and cells containing histamine in the gut. It is also prevalent in β-cells of the pancreas. Expression of the two transporters in internal organs seems to differ between species e.g. only VMAT1 is expressed in the rat adrenal medulla cells whereas VMAT2 is the major transporter in the bovine adrenal medulla cells.

Inhibition
It seems VMATs are of critical importance to mammalian functioning. Mutant homozygous VMAT(-/-) mice move little, feed poorly and die within a few days of birth. However, no physiological difference was discerned between wild type and mutant monoaminergic cells of mice, but there was a lesser degree of monoamines found in mutant mice CNS. This was also true for the CNS of VMAT (+/-) mutant mice compared to wild-type in addition to less dopamine release in response to cell depolarization.

In particular, inhibition of VMAT2 could potentially cause an increase in cytosolic catecholamine levels. This would result in an increase in efflux of said molecules through the plasma membrane, depleting the cell of catecholamines and causing increased oxidative stress and oxidative damage to catecholaminergic neurons.

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 in rodents. This suggests a protective role of VMATs against oxidative stress through removal of such substances from the cytosol (Brunt).

VMAT inhibitors include:
 * Reserpine(RES) and Ketanserin(KET) (potent inhibitors of VMAT2 mediated serotonin transport)
 * Tetrabenazine(TBZ) (specific to VMAT2)
 * Phenylethylamine
 * Amphetamine
 * MDMA (MDMA)
 * N-methyl-4-phenylpyridinium (MPP+)(very potent inhibitors of VMAT2 mediated serotonin transport)
 * Fenfluramine (specific to VMAT1 )
 * Non-hydrolysable GTP-analogue guanylyllimidodiphosphate GMP-P(NH)P (VMAT2 only) (Brent)

Pharmacology
It is thought the effects of cocaine and AMPH-related drugs are mediated through increasing non-exocytotic release of dopamine in specifically affected areas of the brain. This probably occurs through the direct manipulation of VMAT2 functioning.

Amphetamines
Studies suggest both METH and MDMA dramatically decrease striatal vesicular dopamine transport in mammals. Contrary to this, administration of DAT inhibitors such as cocaine or methylphenidate suddenly increases the Vmax of dopamine uptake and Bmax (maximum ligand binding) for the binding of DTBZOH (dihydrotetrabenazine) to VMAT2.

Decrease in VMAT function of striatal dopamine terminals due to METH is thought to be a consequence of neuronal nitric oxide synthase-dependent oxidation of VMAT2 in addition to a long-term decline in VMAT2 protein abundance and function. Also, any surviving dopamine terminals post-METH exposure potentially show a reduced buffering ability of cytosolic dopamine concentrations and a reduction in the capacity to cope with the consequential oxidative stress.

METH alters the subcellular location of VMAT2 which affects the distribution of dopamine in the cell. Treatment with METH relocates VMAT2 from a vesicle-enriched fraction to a location that is not continuous with synaptosomal preparations.

Repeated AMPH exposure may increase VMAT2 mRNA in certain brain regions with little or no decline upon withdrawal from the drug.

Cocaine
Like METH, cocaine alters the subcellular location of VMAT2, affecting cellular dopamine distribution. Administration of cocaine alters the VMAT2 protein from one of a synaptosomal membrane fraction to a vesicle-enriched fraction. Short-term exposure to cocaine increases VMAT2 density in the prefrontal cortex and striatum of mammalian brains. This is theorised to be a defensive mechanism against the depletive effects cocaine has on cytosolic dopamine through increasing monoamine storage capacity. Chronic cocaine use has been implicated with a reduction in VMAT2 immunoreactivity as well as a decrease in DTBZOH binding in humans. Reseach suggests a decline in VMAT2 protein through prolonged cocaine use could play an important role in the development of cocaine induced mood-disorders.