Vesicular monoamine transporter 1

Last updated
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
Orthologs
SpeciesHumanMouse
Entrez

6570

110877

Ensembl

ENSG00000036565

ENSMUSG00000036330

UniProt

P54219

Q8R090

RefSeq (mRNA)

NM_001135691
NM_001142324
NM_001142325
NM_003053

NM_153054

RefSeq (protein)

NP_001129163
NP_001135796
NP_001135797
NP_003044

NP_694694

Location (UCSC) Chr 8: 20.14 – 20.18 Mb Chr 8: 69.49 – 69.54 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Vesicular monoamine transporter 1 (VMAT1) also known as chromaffin granule amine transporter (CGAT) or solute carrier family 18 member 1 (SLC18A1) is a protein that in humans is encoded by the SLC18A1 gene. VMAT1 is an integral membrane protein, which is embedded in synaptic vesicles and serves to transfer monoamines, such as norepinephrine, epinephrine, dopamine, and serotonin, between the cytosol and synaptic vesicles. [5] SLC18A1 is an isoform of the vesicular monoamine transporter.

Contents

Discovery

The idea that there must be specific transport proteins associated with the uptake of monoamines and acetylcholine into vesicles developed due to the discovery of specific inhibitors which interfered with monoamine neurotransmission and also depleted monoamines in neuroendocrine tissues. [5] VMAT1 and VMAT2 were first identified in rats upon cloning cDNAs 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 rat homologs as probes, and heterologous-cell amine uptake assays were performed to verify transport properties. [7]

Structure

Across mammalian species, VMATs have been found to be structurally well conserved; VMAT1s have an overall sequence identity exceeding 80%. However, there exists only a 60% sequence identity between the human VMAT1 and VMAT2. [8]

VMAT1 is an acidic glycoprotein with an apparent weight of 40 kDa. [9] Although the crystallographic structure has not yet been fully resolved, VMAT1 is known to have either twelve transmembrane domains (TMDs), based on Kyte-Doolittle hydrophobicity 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 the cytoplasm.

Localization

Cell types

VMATs are found in a variety of cell types throughout the body, however, VMAT1 is found exclusively in neuroendocrine cells, in contrast to VMAT2, which is also found in the PNS and CNS. Specifically, VMAT1 is found in chromaffin cells, enterochromaffin cells, and small intensely fluorescent cells (SIFs). [10] Chromaffin cells are responsible for releasing the catecholamines (norepinephrine and epinephrine) into systemic circulation. Enterochromaffin cells are responsible for storing serotonin in the gastrointestinal tract. SIFs are interneurons associated with the sympathetic nervous system which are managed by dopamine.

Vesicles

VMAT1 is found in both large dense-core vesicles (LDCVs) as well as in small synaptic vesicles (SSVs). This was discovered via studying rat adrenal medulla cells (PC12 cells). [11] LDCVs are 70-200 nm in size and exist throughout the neuron (soma, dendrites, etc.). SSVs are much smaller (usually about 40 nm) and typically exist as clusters in the presynaptic cleft.

Function

Active transport of monoamines

Driving force

An example of secondary active transport Scheme secundary active transport-en.svg
An example of secondary active transport

The active 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 an antiporter. This transport is facilitated via proton gradient generated by the protein proton ATPase. 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's conformation, which pushes a high affinity amine 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. [9]

Inhibition

Several reuptake inhibitors of VMATs are known to exist, including reserpine (RES), tetrabenazine (TBZ), dihydrotetrabenazine (DTBZOH), and ketanserin (KET). It is thought that RES exhibits 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 non-competitive inhibition, instead binding to allosteric 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]

Clinical significance

Pancreatic cancer

The expression of VMAT1 in healthy endocrine cells was compared to VMAT1 expression in infants with hyperinsulinemic hypoglycemia and adults with pancreatic endocrine tumors. [13] Through immunohistochemistry (IHC) and 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 gastrin processing in 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). [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 certain mechanosensors. [15] 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 hypothermia. [16] Experiments were carried out on aortic and kidney cells and tissues. Evidence was found that an accumulation of serotonin using VMAT1 and TPH1 allowed for the subsequent release of serotonin when exposed to cold temperatures. This allows 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 reactive oxygen species (ROS), which can induce apoptosis, due to the presence of H2S. [17]

Mental disorders

VMAT1 (SLC18A1) maps to a shared bipolar disorder(BPD)/schizophrenia locus, which is located on chromosome 8p21. [18] [19] It is thought that disruption in transport of monoamine neurotransmitters due to variation in the VMAT1 gene may be relevant to the 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 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. [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.

Related Research Articles

<span class="mw-page-title-main">Monoamine neurotransmitter</span> Monoamine that acts as a neurotransmitter or neuromodulator

Monoamine neurotransmitters are neurotransmitters and neuromodulators that contain one amino group connected to an aromatic ring by a two-carbon chain (such as -CH2-CH2-). Examples are dopamine, norepinephrine and serotonin.

<span class="mw-page-title-main">Monoamine transporter</span> Proteins that function as integral plasma-membrane transporters

Monoamine transporters (MATs) are proteins that function as integral plasma-membrane transporters to regulate concentrations of extracellular monoamine neurotransmitters. The three major classes are serotonin transporters (SERTs), dopamine transporters (DATs), and norepinephrine transporters (NETs) and are responsible for the reuptake of their associated amine neurotransmitters. MATs are located just outside the synaptic cleft (peri-synaptically), transporting monoamine transmitter overflow from the synaptic cleft back to the cytoplasm of the pre-synaptic neuron. MAT regulation generally occurs through protein phosphorylation and post-translational modification. Due to their significance in neuronal signaling, MATs are commonly associated with drugs used to treat mental disorders as well as recreational drugs. Compounds targeting MATs range from medications such as the wide variety of tricyclic antidepressants, selective serotonin reuptake inhibitors such as fluoxetine (Prozac) to stimulant medications such as methylphenidate (Ritalin) and amphetamine in its many forms and derivatives methamphetamine (Desoxyn) and lisdexamfetamine (Vyvanse). Furthermore, drugs such as MDMA and natural alkaloids such as cocaine exert their effects in part by their interaction with MATs, by blocking the transporters from mopping up dopamine, serotonin, and other neurotransmitters from the synapse.

The God gene hypothesis proposes that human spirituality is influenced by heredity and that a specific gene, called vesicular monoamine transporter 2 (VMAT2), predisposes humans towards spiritual or mystic experiences. The idea has been proposed by geneticist Dean Hamer in the 2004 book called The God Gene: How Faith is Hardwired into our Genes.

The vesicular monoamine transporter (VMAT) is a transport protein integrated into the membranes of synaptic vesicles of presynaptic neurons. It transports monoamine neurotransmitters – such as dopamine, serotonin, norepinephrine, epinephrine, and histamine – into the vesicles, which release the neurotransmitters into synapses, as chemical messages to postsynaptic neurons. VMATs utilize a proton gradient generated by V-ATPases in vesicle membranes to power monoamine import.

<span class="mw-page-title-main">Reserpine</span> Drug used to treat high blood pressure

Reserpine is a drug that is used for the treatment of high blood pressure, usually in combination with a thiazide diuretic or vasodilator. Large clinical trials have shown that combined treatment with reserpine plus a thiazide diuretic reduces mortality of people with hypertension. Although the use of reserpine as a solo drug has declined since it was first approved by the FDA in 1955, the combined use of reserpine and a thiazide diuretic or vasodilator is still recommended in patients who do not achieve adequate lowering of blood pressure with first-line drug treatment alone. The reserpine-hydrochlorothiazide combo pill was the 17th most commonly prescribed of the 43 combination antihypertensive pills available In 2012.

<span class="mw-page-title-main">Dopamine transporter</span> Mammalian protein found in Homo sapiens

The dopamine transporter (DAT) also is a membrane-spanning protein coded for in the human by the SLC6A3 gene,, that pumps the neurotransmitter dopamine out of the synaptic cleft back into cytosol. In the cytosol, other transporters sequester the dopamine into vesicles for storage and later release. Dopamine reuptake via DAT provides the primary mechanism through which dopamine is cleared from synapses, although there may be an exception in the prefrontal cortex, where evidence points to a possibly larger role of the norepinephrine transporter.

<span class="mw-page-title-main">Enterochromaffin cell</span> Cell type

Enterochromaffin (EC) cells are a type of enteroendocrine cell, and neuroendocrine cell. They reside alongside the epithelium lining the lumen of the digestive tract and play a crucial role in gastrointestinal regulation, particularly intestinal motility and secretion. They were discovered by Nikolai Kulchitsky.

<span class="mw-page-title-main">Vesicular monoamine transporter 2</span> Mammalian protein found in Homo sapiens

The solute carrier family 18 member 2 (SLC18A2) also known as vesicular monoamine transporter 2 (VMAT2) is a protein that in humans is encoded by the SLC18A2 gene. SLC18A2 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, SLC18A2 function is also necessary for the vesicular release of the neurotransmitter GABA.

<span class="mw-page-title-main">Trace amine</span> Amine receptors in the mammalian brain

Trace amines are an endogenous group of trace amine-associated receptor 1 (TAAR1) agonists – and hence, monoaminergic neuromodulators – that are structurally and metabolically related to classical monoamine neurotransmitters. Compared to the classical monoamines, they are present in trace concentrations. They are distributed heterogeneously throughout the mammalian brain and peripheral nervous tissues and exhibit high rates of metabolism. Although they can be synthesized within parent monoamine neurotransmitter systems, there is evidence that suggests that some of them may comprise their own independent neurotransmitter systems.

Neurotransmitter transporters are a class of membrane transport proteins that span the cellular membranes of neurons. Their primary function is to carry neurotransmitters across these membranes and to direct their further transport to specific intracellular locations. There are more than twenty types of neurotransmitter transporters.

<span class="mw-page-title-main">Vesicular acetylcholine transporter</span> Protein-coding gene in the species Homo sapiens

The Vesicular acetylcholine transporter (VAChT) is a neurotransmitter transporter which is responsible for loading acetylcholine (ACh) into secretory organelles in neurons making acetylcholine available for secretion. It is encoded by Solute carrier family 18, member 3 (SLC18A3) gene, located within the first intron of the choline acetyltransferase gene. VAChT is able to transport ACh into vesicles by relying on an exchange between protons (H+) that were previously pumped into the vesicle diffusing out, thus acting as an antiporter. ACh molecules are then carried into the vesicle by the action of exiting protons. Acetylcholine transport utilizes a proton gradient established by a vacuolar ATPase.

<span class="mw-page-title-main">Lobeline</span> Chemical compound

Lobeline is a piperidine alkaloid found in a variety of plants, particularly those in the genus Lobelia, including Indian tobacco, Devil's tobacco, great lobelia, Lobelia chinensis, and Hippobroma longiflora. In its pure form, it is a white amorphous powder which is freely soluble in water.

<span class="mw-page-title-main">TAAR1</span> Protein-coding gene in the species Homo sapiens

Trace amine-associated receptor 1 (TAAR1) is a trace amine-associated receptor (TAAR) protein that in humans is encoded by the TAAR1 gene. TAAR1 is an intracellular amine-activated Gs-coupled and Gq-coupled G protein-coupled receptor (GPCR) that is primarily expressed in several peripheral organs and cells, astrocytes, and in the intracellular milieu within the presynaptic plasma membrane of monoamine neurons in the central nervous system (CNS). TAAR1 was discovered in 2001 by two independent groups of investigators, Borowski et al. and Bunzow et al. TAAR1 is one of six functional human trace amine-associated receptors, which are so named for their ability to bind endogenous amines that occur in tissues at trace concentrations. TAAR1 plays a significant role in regulating neurotransmission in dopamine, norepinephrine, and serotonin neurons in the CNS; it also affects immune system and neuroimmune system function through different mechanisms.

<span class="mw-page-title-main">SLC22A2</span> Protein-coding gene

Solute carrier family 22 member 2 is a protein that in humans is encoded by the SLC22A2 gene.

<span class="mw-page-title-main">SLC22A3</span> Protein-coding gene in the species Homo sapiens

Solute carrier family 22 member 3 (SLC22A3) also known as the organic cation transporter 3 (OCT3) or extraneuronal monoamine transporter (EMT) is a protein that in humans is encoded by the SLC22A3 gene.

An amino acid transporter is a membrane transport protein that transports amino acids. They are mainly of the solute carrier family.

<span class="mw-page-title-main">Reuptake inhibitor</span> Type of drug

Reuptake inhibitors (RIs) are a type of reuptake modulators. It is a drug that inhibits the plasmalemmal transporter-mediated reuptake of a neurotransmitter from the synapse into the pre-synaptic neuron. This leads to an increase in extracellular concentrations of the neurotransmitter and an increase in neurotransmission. Various drugs exert their psychological and physiological effects through reuptake inhibition, including many antidepressants and psychostimulants.

<span class="mw-page-title-main">Monoamine releasing agent</span> Class of compounds

A monoamine releasing agent (MRA), or simply monoamine releaser, is a drug that induces the release of a monoamine neurotransmitter from the presynaptic neuron into the synapse, leading to an increase in the extracellular concentrations of the neurotransmitter. Many drugs induce their effects in the body and/or brain via the release of monoamine neurotransmitters, e.g., trace amines, many substituted amphetamines, and related compounds.

Reverse transport, or transporter reversal, is a phenomenon in which the substrates of a membrane transport protein are moved in the opposite direction to that of their typical movement by the transporter. Transporter reversal typically occurs when a membrane transport protein is phosphorylated by a particular protein kinase, which is an enzyme that adds a phosphate group to proteins.

Catecholamines up (Catsup) is a dopamine regulatory membrane protein that functions as a zinc ion transmembrane transporter (orthologous to ZIP7), and a negative regulator of rate-limiting enzymes involved in dopamine synthesis and transport: Tyrosine hydroxylase (TH), GTP Cyclohydrolase I (GTPCH), and Vesicular Monoamine Transporter (VMAT) in Drosophila melanogaster.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000036565 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000036330 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. 1 2 3 Eiden LE, Schäfer MK, Weihe E, Schütz B (February 2004). "The vesicular amine transporter family (SLC18): amine/proton antiporters required for vesicular accumulation and regulated exocytotic secretion of monoamines and acetylcholine". Pflügers Arch. 447 (5): 636–40. doi:10.1007/s00424-003-1100-5. PMID   12827358. S2CID   20764857.
  6. ↑ Erickson JD, Eiden LE, Hoffman BJ (November 1992). "Expression cloning of a reserpine-sensitive vesicular monoamine transporter". Proc. Natl. Acad. Sci. U.S.A. 89 (22): 10993–7. Bibcode:1992PNAS...8910993E. doi: 10.1073/pnas.89.22.10993 . PMC   50469 . PMID   1438304.
  7. 1 2 Erickson JD, Eiden LE (December 1993). "Functional identification and molecular cloning of a human brain vesicle monoamine transporter". J. Neurochem. 61 (6): 2314–7. doi:10.1111/j.1471-4159.1993.tb07476.x. PMID   8245983. S2CID   7544757.
  8. ↑ Eiden LE, Schäfer MK, Weihe E, Schütz B (February 2004). "The vesicular amine transporter family (SLC18): amine/proton antiporters required for vesicular accumulation and regulated exocytotic secretion of monoamines and acetylcholine". Pflügers Arch. 447 (5): 636–40. doi:10.1007/s00424-003-1100-5. PMID   12827358. S2CID   20764857.
  9. 1 2 3 Wimalasena K (July 2011). "Vesicular monoamine transporters: structure-function, pharmacology, and medicinal chemistry". Med Res Rev. 31 (4): 483–519. doi:10.1002/med.20187. PMC   3019297 . PMID   20135628.
  10. 1 2 Erickson JD, Schafer MK, Bonner TI, Eiden LE, Weihe E (May 1996). "Distinct pharmacological properties and distribution in neurons and endocrine cells of two isoforms of the human vesicular monoamine transporter". Proc. Natl. Acad. Sci. U.S.A. 93 (10): 5166–71. Bibcode:1996PNAS...93.5166E. doi: 10.1073/pnas.93.10.5166 . PMC   39426 . PMID   8643547.
  11. ↑ Liu Y, Schweitzer ES, Nirenberg MJ, Pickel VM, Evans CJ, Edwards RH (December 1994). "Preferential localization of a vesicular monoamine transporter to dense core vesicles in PC12 cells". J. Cell Biol. 127 (5): 1419–33. doi:10.1083/jcb.127.5.1419. PMC   2120259 . PMID   7962100.
  12. ↑ Parsons SM (December 2000). "Transport mechanisms in acetylcholine and monoamine storage". The FASEB Journal. 14 (15): 2423–2434. doi: 10.1096/fj.00-0203rev . PMID   11099460. S2CID   693587.
  13. ↑ Anlauf M, Eissele R, Schäfer MK, Eiden LE, Arnold R, Pauser U, Klöppel G, Weihe E (August 2003). "Expression of the two isoforms of the vesicular monoamine transporter (VMAT1 and VMAT2) in the endocrine pancreas and pancreatic endocrine tumors" (PDF). J. Histochem. Cytochem. 51 (8): 1027–40. doi: 10.1177/002215540305100806 . PMID   12871984. S2CID   24334855.
  14. ↑ Hussain I, Bate GW, Henry J, Djali P, Dimaline R, Dockray GJ, Varro A (June 1999). "Modulation of gastrin processing by vesicular monoamine transporter type 1 (VMAT1) in rat gastrin cells". J. Physiol. 517 (2): 495–505. doi:10.1111/j.1469-7793.1999.00495.x. PMC   2269351 . PMID   10332097.
  15. ↑ Chin A, Svejda B, Gustafsson BI, Granlund AB, Sandvik AK, Timberlake A, Sumpio B, Pfragner R, Modlin IM, Kidd M (February 2012). "The role of mechanical forces and adenosine in the regulation of intestinal enterochromaffin cell serotonin secretion". Am. J. Physiol. Gastrointest. Liver Physiol. 302 (3): G397–405. doi:10.1152/ajpgi.00087.2011. PMC   3287403 . PMID   22038827.
  16. ↑ Talaei F, Schmidt M, Henning RH (2012). "Induction of VMAT-1 and TPH-1 expression induces vesicular accumulation of serotonin and protects cells and tissue from cooling/rewarming injury". PLOS ONE. 7 (1): e30400. Bibcode:2012PLoSO...730400T. doi: 10.1371/journal.pone.0030400 . PMC   3257274 . PMID   22253933.
  17. ↑ Talaei F, Bouma HR, Van der Graaf AC, Strijkstra AM, Schmidt M, Henning RH (2011). "Serotonin and dopamine protect from hypothermia/rewarming damage through the CBS/H2S pathway". PLOS ONE. 6 (7): e22568. Bibcode:2011PLoSO...622568T. doi: 10.1371/journal.pone.0022568 . PMC   3144905 . PMID   21829469.
  18. 1 2 Lohoff F, Dahl J, Ferraro T, Arnold S, Gallinat J, Sander T, Berrettini W (December 2006). "Variations in the vesicular monoamine transporter type 1 gene (VMAT1/SLC18A1) are associated with bipolar I disorder". Neuropsychopharmacology. 31 (12): 2739–2747. doi:10.1038/sj.npp.1301196. PMC   2507868 . PMID   16936705.
  19. ↑ Lohoff FW, Weller AE, Bloch PJ, Buono RJ, Doyle GA, Ferraro TN, Berrettini WH (2008). "Association between polymorphisms in the vesicular monoamine transporter 1 gene (VMAT1/SLC18A1) on chromosome 8p and schizophrenia". Neuropsychobiology. 57 (1–2): 55–60. doi:10.1159/000129668. PMID   18451639. S2CID   39523023.
  20. ↑ Richards M, Iijima Y, Kondo H, Shizuno T, Hori H, Arima K, Saitoh O, Kunugi H (2006). "Association study of the vesicular monoamine transporter 1 (VMAT1) gene with schizophrenia in a Japanese population". Behav Brain Funct. 2: 39. doi: 10.1186/1744-9081-2-39 . PMC   1697819 . PMID   17134514.
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