Vesicular monoamine transporter 1

Source: Wikipedia, the free encyclopedia.
SLC18A1
Identifiers
Gene ontology
Molecular function
Cellular component
Biological process
Sources:Amigo / QuickGO
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 MbChr 8: 69.49 – 69.54 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/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

isoform of the vesicular monoamine transporter
.

Discovery

The idea that there must be specific

homologs as probes, and heterologous-cell amine uptake assays were performed to verify transport properties.[7]

Structure

Across

sequence identity exceeding 80%. However, there exists only a 60% sequence identity between the human VMAT1 and VMAT2.[8]

VMAT1 is an acidic

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

interneurons associated with the sympathetic nervous system
which are managed by dopamine.

Vesicles

VMAT1 is found in both

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

The

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

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

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.

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000036565 – Ensembl, May 2017
  2. ^ a b c 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. ^
    S2CID 20764857
    .
  6. PMID 1438304
    .
  7. ^
    S2CID 7544757
    .
  8. S2CID 20764857
    .
  9. ^
    PMID 20135628
    .
  10. ^
    PMID 8643547
    .
  11. PMID 7962100
    .
  12. S2CID 693587
    .
  13. S2CID 24334855
    .
  14. PMID 10332097
    .
  15. PMID 22038827
    .
  16. PMID 22253933
    .
  17. PMID 21829469
    .
  18. ^
    PMID 16936705
    .
  19. S2CID 39523023
    .
  20. PMID 17134514
    .

External links
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