Disease relevance of SLC18A1

• A second isoform of the human vesicular monoamine transporter (hVMAT) has been cloned from a pheochromocytoma cDNA library [1].
• The expression of VMAT1 and VMAT2 was also examined in infants with hyperinsulinemic hypoglycemia and in adults with pancreatic endocrine tumors (PETs) [2].
• In contrast, there was greater expression of VMAT 1 in VHL than MEN 2 tumours, while expression of VMAT 2 did not differ significantly [3].
• This human transplantable carcinoid tumor, designated GOT1, grafted to nude mice, will give unique possibilities for studies of somatostatin receptor- and VMAT-mediated radionuclide uptake as well as for studies of secretory mechanisms [4].
• CONCLUSIONS: VMAT2 and VMAT1 are reliable markers for differentiation of gastric endocrine hyperplasia and neoplasia from ECL and EC cells, respectively [5].

Psychiatry related information on SLC18A1

• The vesicular monoamine transporter 1 gene (VMAT1/SLC18A1) maps to the shared bipolar disorder (BPD)/schizophrenia (SZ) susceptibility locus on chromosome 8p21 [6].

High impact information on SLC18A1

• Our result show that PC12 cells lack small dense core vesicles, i.e., the catecholamine-storing, but secretory protein-lacking, vesicles found in sympathetic neurons and imply that the biogenesis of these vesicles requires the expression of a distinct type of vesicular amine transporter and/or a change in endosomal protein sorting [7].
• Surprisingly, however, despite the presence of a reserpine-sensitive vesicular amine transporter in early endosomes, SLMVs lacked detectable uptake and storage of catecholamines [7].
• Expression screening was used to isolate cDNA clones encoding a synaptic vesicle membrane protein, VAT-1, which is specifically expressed in the electric lobe of marine rays [8].
• The VAT-1 RNA is localized to the electromotor nucleus, and the fusion protein antibody stains the electric organ, demonstrating that the protein is transported to nerve terminals [8].
• Reserpine and ketanserin are slightly more potent inhibitors of VMAT2-mediated transport than of VMAT1-mediated transport, whereas tetrabenazine binds to and inhibits only VMAT2 [1].

Chemical compound and disease context of SLC18A1

• Serotonin-producing endocrine tumours (ileal and appendiceal carcinoids) expressed predominantly VMAT1, while histamine-producing endocrine tumours (gastric carcinoids) expressed VMAT2 almost exclusively [9].
• One carcinoid was copositive for VMAT1 and serotonin but negative for VMAT2 [5].
• Mammalian protein homologous to VAT-1 of Torpedo californica: isolation from Ehrlich ascites tumor cells, biochemical characterization, and organization of its gene [10].

Biological context of SLC18A1

• In view of this assessment of lymphocyte DAT and VMAT transporters can be considered for identifying pathologies characterized by impaired dopaminergic neurotransmission [11].
• The full-length VMAT1 transcript is produced from 16 exons [12].
• As a consequence, there is a shift of reading frame, and exon 16 is translated in an alternative reading frame, yielding a novel protein with a shorter and unrelated C-terminus compared with the native VMAT1 protein [12].
• Stimulation of vesicular [3H]serotonin efflux is due to dissipation of the transmembrane pH difference generated by ATP hydrolysis and to direct interaction with the vesicular amine transporter [13].
• VAChT and VMAT exchange two protons per substrate molecule with very similar initial velocity kinetics and pH dependencies [14].

Anatomical context of SLC18A1

• The unique distributions of hVMAT1 and hVMAT2 provide new markers for multiple neuroendocrine lineages, and examination of their transport properties provides mechanistic insights into the pharmacology and physiology of amine storage in cardiovascular, endocrine, and central nervous system function [1].
• VMAT1 and VMAT2 are coexpressed in all chromaffin cells of the adrenal medulla [1].
• C. elegans VMAT is associated with synaptic vesicles in approximately 25 neurons, including all of the cells reported to contain dopamine and serotonin, plus a few others [15].
• Vesicular monoamine transporter 1 (VMAT1) is an integral protein in the membrane of secretory vesicles of neuroendocrine and endocrine cells that allows the transport of biogenic monoamines, such as serotonin, from the cytoplasm into the secretory vesicles [12].
• These findings indicate that human peripheral blood lymphocytes possess DAT plasma membrane and VMAT-1 and VMAT-2 transporters [11].

Associations of SLC18A1 with chemical compounds

• The vesicular amine transporter family (SLC18): amine/proton antiporters required for vesicular accumulation and regulated exocytotic secretion of monoamines and acetylcholine [16].
• When C. elegans VMAT is expressed in mammalian cells, it has serotonin and dopamine transport activity; norepinephrine, tyramine, octopamine, and histamine also have high affinity for the transporter [15].
• This study assessed whether these distinctions relate to differences in expression of the transporters responsible for uptake and storage of catecholamines - the noradrenaline transporter and the vesicular monoamine transporters (VMAT 1 and VMAT 2) [3].
• We also found that VMAT1 has a higher affinity for tryptamine than VMAT2 [17].
• Furthermore, methamphetamine preferentially inhibits transport by SVAT relative to CGAT, apparently by competing at the site of amine recognition rather than by disrupting the vesicular pH gradient [18].

Physical interactions of SLC18A1

• [3H]Dihydrotetrabenazine shows no detectable binding to CGAT but does bind to SVAT, accounting for the differential sensitivity [18].

Regulatory relationships of SLC18A1

• In rat, VMAT1 is expressed in the adrenal gland whereas VMAT2 is expressed in the brain [19].

Other interactions of SLC18A1

• The contribution of the two transporter isoforms to monoamine storage in human neuroendocrine tissues was examined with isoform-specific polyclonal antibodies against hVMAT1 and hVMAT2 [1].
• Tyrosine hydroxylase immunoreactivity was diffused to cytoplasm and to plasma membrane of lymphocytes, whereas DAT and VMAT-1 immunoreactivity were located almost exclusively in lymphocyte plasma membrane and cytoplasm, respectively [11].
• Can Quantification of VMAT and SSTR Expression Be Helpful for Planning Radionuclide Therapy of Malignant Pheochromocytomas [20]?
• However, when the intracellular compartments of VMAT-expressing CHO cells are preloaded with different monoamines, transport becomes susceptible to G-protein-dependent regulation, with differences between the two transporter isoforms [21].
• This study elucidates that TPH1, VMAT1, and Survivin should be further investigated as potential target antigens for T cell-mediated immunotherapy of midgut carcinoids [22].

Analytical, diagnostic and therapeutic context of SLC18A1

• Immunofluorescence revealed that anti-dopamine, anti-tyrosine hydroxylase, anti-DAT, anti-VMAT-1 and anti-VMAT-2 antibodies labeled the total population of cytospin-centrifuged lymphocytes mounted on microscope slides [11].
• By confocal laser scanning microscopy, VMAT1-positive cells were identified as enterochromaffin (EC) cells and VMAT2-positive cells as beta-cells [2].
• Using immunohistochemistry (IHC) and in situ hybridization (ISH), we demonstrated the mutually exclusive expression of VMAT1 in endocrine cells of the duct system and of VMAT2 in many cells of the islets of Langerhans [2].
• Molecular cloning has identified two vesicular monoamine transporters (VMATs), one expressed in non-neural cells of the periphery (VMAT1) and the other by multiple monoamine cell populations in the brain (VMAT2) [17].
• Using site-directed mutagenesis to replace residues in TMD5-8 of VMAT2 with the equivalent residues from VMAT1, we now show that the sensitivity of VMAT2 to tetrabenazine requires Ala-315, and this interaction occurs independently of the interaction with residues in TMD9-12 [23].

References