Disease relevance of SLC18A2

• Because VMAT2 influences a form of toxicity similar to Parkinson's disease, we extended the analysis to two SNPs identified in a population with Parkinson's disease [1].
• In contrast, VMAT2 expression was lost in many insulinomas, independent of their biological behavior [2].
• The expression of VMAT1 and VMAT2 was also examined in infants with hyperinsulinemic hypoglycemia and in adults with pancreatic endocrine tumors (PETs) [2].
• The detailed three-dimensional molecular structure of any monoamine transporter is not known, but the three-dimensional electron density projection map of Escherichia coli Na+/H+ antiporter (NhaA) has provided structural basis for constructing models of such transporters using molecular modelling techniques [3].
• Serotonin-producing endocrine tumours (ileal and appendiceal carcinoids) expressed predominantly VMAT1, while histamine-producing endocrine tumours (gastric carcinoids) expressed VMAT2 almost exclusively [4].
• Methylation and histone deacetylase inhibitory agents rescued SLC18A2 expression in three prostate cancer cell lines [5].

Psychiatry related information on SLC18A2

• Vesicular monoamine transporter type 2 and benzodiazepine binding site expressions were each preserved in Alzheimer's disease striatum [6].
• We conclude that dementia with Lewy bodies may be distinguished from Alzheimer's disease by postmortem examination or by future in vivo measurements of the striatal vesicular monoamine transporter type 2 [6].
• We conclude that DNA polymorphisms located in SLC18A2 might contribute to the development of substance dependence [7].
• The vesicular monoamine transporter 1 gene (VMAT1/SLC18A1) maps to the shared bipolar disorder (BPD)/schizophrenia (SZ) susceptibility locus on chromosome 8p21 [8].
• Subjects suffering from cocaine-induced mood disorders displayed a greater loss of VMAT2 immunoreactivity that approached significance [9].

High impact information on SLC18A2

• Recent work indicates physiological regulation of the expression of genes encoding cytosolic enzymes such as histidine decarboxylase, which converts histidine to histamine, and of secretory granule transporters such as vesicular monoamine transporter type 2, which concentrates amines in secretory vesicles [10].
• We screened for variants in the complete coding sequence and intron-exon junctions of two candidate genes for neuropsychiatric phenotypes: SLC6A4, encoding the serotonin transporter; and SLC18A2, encoding the vesicular monoamine transporter [11].
• However, levels of DOPA decarboxylase and the vesicular monoamine transporter, known to be reduced in Parkinson's disease, were normal [12].
• The vesicular monoamine transporter 2 (VMAT2) is present in all monoaminergic neurons including epinephrine- and histamine-synthesizing cells [13].
• Interestingly, the presence of VMAT2 in vesicles underlying dendrites, axons, and soma suggests that monoamines may be released at these cellular domains [13].

Chemical compound and disease context of SLC18A2

• One carcinoid was copositive for VMAT1 and serotonin but negative for VMAT2 [14].
• Most notable is the selective degeneration of DAT- and VMAT2-expressing dopamine nerve terminals in the striatum thought to underlie Parkinson's disease [15].
• Tetrabenazine (TBZ), a high affinity and specific inhibitor of the vesicular monoamine transporter, has been labeled with carbon-11 as a potential probe for in vivo positron emission tomographic imaging of monoaminergic neuronal losses in neurodegenerative diseases [16].

Biological context of SLC18A2

• SLC18A2 promoter haplotypes and identification of a novel protective factor against alcoholism [17].
• We have re-sequenced a 17.4 kb DNA in the SLC18A2 promoter region for Caucasians and revealed 47 polymorphisms that confer 13 haplotypes [17].
• The vesicular monoamine transporter 2 (VMAT2, SLC18A2) takes up cytosolic monoamines into intracellular secretory vesicles, preventing their neurotoxicity in the cytosol and discharging them into extracellular space by exocytosis [17].
• In addition, association was tested using single nucleotide polymorphisms (SNPs) within the KCNMA1, HTR7 and SLC18A2 genes that may relate to a finding on chromosome 10 [18].
• Exon/intron boundaries, novel polymorphisms, and association analysis with schizophrenia of the human synaptic vesicle monoamine transporter (SVMT) gene [19].

Anatomical context of SLC18A2

• VMAT2 alone is expressed in histamine-storing enterochromaffin-like cells of the oxyntic mucosa of the stomach [20].
• 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 [20].
• VMAT1 and VMAT2 are coexpressed in all chromaffin cells of the adrenal medulla [20].
• The results of uptake experiments with glandular epithelial cells confirmed not only the presence of functional VMAT-2 transporter protein in the secretory phase but also the absence of a histamine-specific plasma membrane transporter throughout the cycle [21].
• VMAT-2 mRNA was localized in the stroma during the proliferative phase and in the epithelium during the secretory phase [21].

Associations of SLC18A2 with chemical compounds

• Catecholamines exhibit a 3-fold higher affinity, and histamine exhibits a 30-fold higher affinity, for VMAT2 [20].
• 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 [20].
• Cultures were pretreated with either corticosterone, a specific inhibitor of EMT, or reserpine, a specific inhibitor of VMAT-2 [21].
• It has been shown that one-copy deletion of the VMAT2 gene increases locomotion activity significantly in response to drug treatments and dopamine neuron death rate in response to neurotoxin treatments in knockout mice [17].
• We conclude that human VMAT2 Cys 126 in loop 1/2 and Cys 333 in loop 7/8 form a disulfide bond which contributes to efficient monoamine transport [22].

Physical interactions of SLC18A2

• VMAT2 binding is elevated in dopa-responsive dystonia: visualizing empty vesicles by PET [23].
• [3H]Dihydrotetrabenazine shows no detectable binding to CGAT but does bind to SVAT, accounting for the differential sensitivity [24].
• CONCLUSIONS: Reduced striatal VMAT2 binding suggests nigrostriatal pathology in HD, most severely in the HDr phenotype [25].

Regulatory relationships of SLC18A2

• In rat, VMAT1 is expressed in the adrenal gland whereas VMAT2 is expressed in the brain [26].
• Accordingly, 5-hydroxytryptamine 1B receptor antagonists prevent G-proteinmediated inhibition of uptake in partially filled platelets and synaptic vesicles expressing VMAT2 [27].
• 4. Using a pulse-chase labelling protocol, cleavage of 34-residue gastrin (G34) was found to be inhibited by co-expression with VMAT2, and this was reversed by reserpine [28].
• In somata and dendrites of the midbrain dopaminergic neurons, D2R labeling is expressed in most dendrites that contain VMAT2 storage vesicles, as well as in both excitatory and inhibitory afferents [29].

Other interactions of SLC18A2

• 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 [20].
• Three Types of Tyrosine Hydroxylase-Positive CNS Neurons Distinguished by Dopa Decarboxylase and VMAT2 Co-Expression [30].
• After 4 weeks of differentiation in vitro, cortical and striatal NSCs gave rise to similar numbers of GABAergic and VMAT2- and parvalbumin-containing neurons [31].
• Statistical analysis with the KCNMA1, HTR7 and SLC18A2 genes, which lie in the support region of interest revealed no evidence for association after correction for multiple comparisons [18].
• Neurons containing VMAT2 constituted 14-20% of all intrinsic neurons in the upper GI tract, and there was an equal number of TH-positive neurons [32].

Analytical, diagnostic and therapeutic context of SLC18A2

• Functional identification and molecular cloning of a human brain vesicle monoamine transporter [33].
• Confocal laser microscopy demonstrated that dopamine and VMAT-2 immunoreactivity was developed mainly in cytoplasmic punctiform areas likely corresponding to vesicles and to a lower extent was associated to plasma membrane [34].
• Western blot analysis using antibodies raised against amino or carboxy terminus of DAT or against VMAT-1 or VMAT-2 revealed labeling of single bands of approximately 76, 55 or 68 KDa, respectively, displaying similar migration characteristics in lymphocytes and test tissues used for comparison [34].
• 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 [34].
• 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].

References