| SLC18A1 | |||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Identifiers | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Aliases | SLC18A1, CGAT, VAT1, VMAT1, Vesicular monoamine transporter 1, solute carrier family 18 member A1, VMAT2 | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM:193002;MGI:106684;HomoloGene:20664;GeneCards:SLC18A1;OMA:SLC18A1 - orthologs | ||||||||||||||||||||||||||||||||||||||||||||||||||
| |||||||||||||||||||||||||||||||||||||||||||||||||||
| |||||||||||||||||||||||||||||||||||||||||||||||||||
| |||||||||||||||||||||||||||||||||||||||||||||||||||
| |||||||||||||||||||||||||||||||||||||||||||||||||||
| |||||||||||||||||||||||||||||||||||||||||||||||||||
| Wikidata | |||||||||||||||||||||||||||||||||||||||||||||||||||
| |||||||||||||||||||||||||||||||||||||||||||||||||||
Vesicular monoamine transporter 1 (VMAT1), also known aschromaffin granule amine transporter (CGAT) orsolute carrier family 18 member 1 (SLC18A1), is aprotein that in humans is encoded by theSLC18A1gene. VMAT1 is anintegral membrane protein, which is embedded insynaptic vesicles and serves to transfermonoamines, such asnorepinephrine,epinephrine,dopamine, andserotonin, between thecytosol and synaptic vesicles.[5] SLC18A1 is anisoform of thevesicular monoamine transporter.
The idea that there must be specifictransport proteins associated with the uptake of monoamines andacetylcholine into vesicles developed due to the discovery of specific inhibitors which interfered with monoamineneurotransmission and also depleted monoamines inneuroendocrine tissues.[5] VMAT1 andVMAT2 were first identified in rats upon cloningcDNAs for proteins which gave non-amine accumulating recipient cells the ability to sequester monoamines.[6] Subsequently, human VMATs were cloned using human cDNA libraries with the rathomologs as probes, and heterologous-cell amine uptake assays were performed to verify transport properties.[7]
Acrossmammalian species, VMATs have been found to be structurally well conserved; VMAT1s have an overallsequence identity exceeding 80%. However, there exists only a 60% sequence identity between the human VMAT1 and VMAT2.[8]
VMAT1 is an acidicglycoprotein with an apparent weight of 40kDa.[9] Although thecrystallographic structure has not yet been fully resolved, VMAT1 is known to have either twelvetransmembrane domains (TMDs), based on Kyte-Doolittlehydrophobicity scale analysis[7] or ten TMDs, based on MAXHOM alignment. MAXHOM alignment was determined using the "profile-fed neural network systems from Heidelberg" (PHD) program.[5] The main difference between these two models arises from the placement of TMDs II and IV in the vesicle lumen or thecytoplasm.
VMATs are found in a variety of cell types throughout the body, however, VMAT1 is found exclusively inneuroendocrine cells, in contrast to VMAT2, which is also found in thePNS andCNS. Specifically, VMAT1 is found inchromaffin cells,enterochromaffin cells, andsmall intensely fluorescent cells (SIFs).[10] Chromaffin cells are responsible for releasing thecatecholamines (norepinephrine andepinephrine) intosystemic circulation. Enterochromaffin cells are responsible for storing serotonin in the gastrointestinal tract. SIFs areinterneurons associated with thesympathetic nervous system which are managed by dopamine.
VMAT1 is found in bothlarge dense-core vesicles (LDCVs) as well as in smallsynaptic vesicles (SSVs). This was discovered via studying rat adrenal medulla cells (PC12 cells).[11] LDCVs are 70-200 nm in size and exist throughout theneuron (soma,dendrites, etc.). SSVs are much smaller (usually about 40 nm) and typically exist as clusters in the presynaptic cleft.
Theactive transport of monoamines from the cytosol into storage vesicles operates against a large (>105) concentration gradient.Secondary active transport is the type of active transport used, meaning that VMAT1 is anantiporter. This transport is facilitated viaproton gradient generated by the protein protonATPase. The inward transport of the monoamine is coupled with the efflux of two protons per monoamine.[12] The first proton is thought to cause a change in VMAT1'sconformation, which pushes a high affinity aminebinding 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 thatHis419, located between TMDs X and XI, plays the key role in the first of these conformational changes, and thatAsp431, located on TMD XI, does likewise during the second change.[9]
Several reuptake inhibitors of VMATs are known to exist, includingreserpine (RES),tetrabenazine (TBZ),dihydrotetrabenazine (DTBZOH), andketanserin (KET). It is thought that RES exhibitscompetitive 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 exhibitnon-competitive inhibition, instead binding toallosteric sites and decreasing the activity of the VMAT rather than simply blocking its substrate binding site.[9] 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.[10]
The expression of VMAT1 in healthy endocrine cells was compared to VMAT1 expression in infants withhyperinsulinemic hypoglycemia and adults with pancreatic endocrine tumors.[13] Throughimmunohistochemistry (IHC) andin 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.
VMAT1 also has effects on the modulation ofgastrin processing inG 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).[14]
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 certainmechanosensors.[15] The regulation of serotonin in the gut is critically important, as it modulates appetite and controls intestinal contraction.
Presence of VMAT1 in cells has been shown to protect them from the damaging effects of cooling and rewarming associated withhypothermia.[16] Experiments were carried out onaortic andkidney cells andtissues. Evidence was found that an accumulation of serotonin using VMAT1 andTPH1 allowed for the subsequent release of serotonin when exposed to cold temperatures. This allowscystathionine beta synthase (CBS) mediated generation ofH2S. The protection against the damage caused by hypothermia is due to a reduction in the generation ofreactive oxygen species (ROS), which can induceapoptosis, due to the presence of H2S.[17]
VMAT1 (SLC18A1) maps to a sharedbipolar disorder(BPD)/schizophrenialocus, which is located onchromosome 8p21.[18][19] It is thought that disruption in transport of monoamine neurotransmitters due to variation in the VMAT1 gene may be relevant to theetiology 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 andmRNA 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.[18] 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.[20] 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.
