Vesicular monoamine transporter 1

Vesicular monoamine transporter 1 (VMAT1) also known as chromaffin granule amine transporter (CGAT) or solute carrier family 18 member 1 (SLC18A1) is a is_associated_with::protein that in humans is encoded by the SLC18A1 is_associated_with::gene. VMAT1 is an is_associated_with::integral membrane protein, which is embedded in is_associated_with::synaptic vesicles and serves to transfer is_associated_with::monoamines, such as is_associated_with::norepinephrine, is_associated_with::dopamine, and is_associated_with::serotonin, between the is_associated_with::cytosol and synaptic vesicles. SLC18A1 is an is_associated_with::isoform of the is_associated_with::vesicular monoamine transporter.

Discovery
The idea that there must be specific is_associated_with::transport proteins associated with the uptake of monoamines and is_associated_with::acetylcholine into vesicles developed due to the discovery of specific inhibitors which interfered with monoamine is_associated_with::neurotransmission and also depleted monoamines in is_associated_with::neuroendocrine tissues. VMAT1 and is_associated_with::VMAT2 were first identified in rats upon cloning is_associated_with::CDNAs for proteins which gave non-amine accumulating recipient cells the ability to sequester monoamines. Subsequently, human VMATs were cloned using human cDNA libraries with the rat is_associated_with::homologs as probes, and heterologous-cell amine uptake assays were performed to verify transport properties.

Structure
Across is_associated_with::mammalian species, VMATs have been found to be structurally well conserved; VMAT1s have an overall is_associated_with::sequence identity exceeding 80%. However, there exists only a 60% sequence identity between the human VMAT1 and VMAT2.

VMAT1 is an acidic is_associated_with::glycoprotein with an apparent weight of 40 is_associated_with::kDa. Although the is_associated_with::crystallographic structure has not yet been fully resolved, VMAT1 is known to have either twelve is_associated_with::transmembrane domains (TMDs), based on Kyte-Doolittle is_associated_with::hydrophobicity scale analysis or ten TMDs, based on MAXHOM alignment. MAXHOM alignment was determined using the "profile-fed neural network systems from Heidelberg" (PHD) program. The main difference between these two models arises from the placement of TMDs II and IV in the vesicle lumen or the is_associated_with::cytoplasm.

Cell types
VMATs are found in a variety of cell types throughout the body, however, VMAT1 is found exclusively in is_associated_with::neuroendocrine cells, in contrast to VMAT2, which is also found in the PNS and CNS. Specifically, VMAT1 is found in is_associated_with::chromaffin cells, is_associated_with::enterochromaffin cells, and is_associated_with::small intensely fluorescent cells (SIFs). Chromaffin cells are responsible for releasing the is_associated_with::catecholamines (norepinephrine and is_associated_with::epinephrine) into is_associated_with::systemic circulation. Enterochromaffin cells are responsible for storing serotonin in the gastrointestinal tract. SIFs are is_associated_with::interneurons associated with the is_associated_with::sympathetic nervous system which are managed by dopamine.

Vesicles
VMAT1 is found in both is_associated_with::large dense-core vesicles (LDCVs) as well as in small is_associated_with::synaptic vesicles (SSVs). This was discovered via studying rat adrenal medulla cells (PC12 cells). LDCVs are 70-200 nm in size and exist throughout the is_associated_with::neuron (is_associated_with::soma, is_associated_with::dendrites, etc.). SSVs are much smaller (usually about 40 nm) and typically exist as clusters in the presynaptic cleft.

Driving force
The is_associated_with::active transport of monoamines from the cytosol into storage vesicles operates against a large (>105) concentration gradient. is_associated_with::Secondary active transport is the type of active transport used, meaning that VMAT1 is an is_associated_with::antiporter. This transport is facilitated via is_associated_with::proton gradient generated by the protein proton is_associated_with::ATPase. The inward transport of the monoamine is coupled with the efflux of two protons per monoamine. The first proton is thought to cause a change in VMAT1's conformation, which pushes a high affinity amine is_associated_with::binding site, to which the monoamine attaches. The second proton then causes a second change in the conformation which pulls the monoamine into the vesicle and greatly reduces the affinity of the binding site for amines. A series of tests suggest that His419, located between TMDs X and XI, plays the key role in the first of these conformational changes, and that Asp431, located on TMD XI, does likewise during the second change.

Inhibition
Several reuptake inhibitors of VMATs are known to exist, including is_associated_with::reserpine (RES), is_associated_with::tetrabenazine (TBZ), is_associated_with::dihydrotetrabenazine (DTBZOH), and is_associated_with::ketanserin (KET). It is thought that RES exhibits is_associated_with::competitive inhibition, binding to the same site as the monoamine substrate, as studies have shown that it can be displaced via introduction of norepinephrine. TBZ, DTBZOH, and KET are thought to exhibit is_associated_with::non-competitive inhibition, instead binding to allosteric sites and decreasing the activity of the VMAT rather than simply blocking its substrate binding site. It has been found that these inhibitors are less effective at inhibiting VMAT1 than VMAT2, and the inhibitory effects of the tetrabenazines on VMAT1 is negligible.

Pancreatic cancer
The expression of VMAT1 in healthy endocrine cells was compared to VMAT1 expression in infants with is_associated_with::hyperinsulinemic hypoglycemia and adults with pancreatic endocrine tumors. Through is_associated_with::immunohistochemistry (IHC) and is_associated_with::in situ hybridization (ISH), they found VMAT1 and VMAT2 were located in mutually exclusive cell types, and that in insulinomas VMAT2 activity disappeared, suggesting that if only VMAT1 activity is present in the endocrine system, this type of cancer is likely.

Digestive system
VMAT1 also has effects on the modulation of is_associated_with::gastrin processing in is_associated_with::G cells. These intestinal endocrine cells process amine precursors, and VMAT1 pulls them into vesicles for storage. The activity of VMAT1 in these cells has a seemingly inhibitory effect on the processing of gastrin. Essentially, this means that certain compounds in the gut can be taken into these G cells and either amplify or inhibit the function of VMAT1, which will impact gastrin processing (conversion from G34 to G17).

Additionally, VMAT1 is known to play a role in the uptake and secretion of serotonin in the gut. Enterochromaffin cells in the intestines will secrete serotonin in response to the activation of certain is_associated_with::mechanosensors. The regulation of serotonin in the gut is critically important, as it modulates appetite and controls intestinal contraction.

Protection against hypothermia
Presence of VMAT1 in cells has been shown to protect them from the damaging effects of cooling and rewarming associated with is_associated_with::hypothermia. Experiments were carried out on aortic and is_associated_with::kidney cells and tissues. Evidence was found that an accumulation of serotonin using VMAT1 and is_associated_with::TPH1 allowed for the subsequent release of serotonin when exposed to cold temperatures. This allows is_associated_with::cystathionine beta synthase (CBS) mediated generation of H2S. The protection against the damage caused by hypothermia is due to a reduction in the generation of is_associated_with::reactive oxygen species (ROS), which can induce is_associated_with::apoptosis, due to the presence of H2S.

Mental disorders
VMAT1 (SLC18A1) maps to a shared is_associated_with::bipolar disorder(BPD)/is_associated_with::schizophrenia locus, which is located on is_associated_with::chromosome 8p21. It is thought that disruption in transport of monoamine neurotransmitters due to variation in the VMAT1 gene may be relevant to the is_associated_with::etiology of these mental disorders. One study looked at a population of European descent, examining the genotypes of a bipolar group and a control group. The study confirmed expression of VMAT1 in the brain at a protein and is_associated_with::mRNA level, and found a significant difference between the two groups, suggesting that, at least for people of European descent, variation in the VMAT1 gene may confer susceptibility. A second study examined a population of Japanese individuals, one group healthy and the other schizophrenic. This study resulted in mostly inconclusive findings, but some indications that variation in the VMAT1 gene would confer susceptibility to schizophrenia in Japanese women. While these studies provide some promising insight into the cause of some of the most prevalent mental disorders, it is clear that additional research will be necessary in order to gain a full understanding.