Disease relevance of Slc18a2

• 4. The results are consistent with a role for VMAT2 in the transport of histamine into enterochromaffin-like cell secretory vesicles, and with upregulation of the transporter to accommodate the increased histamine biosynthesis and secretion that accompanies achlorhydria [1].
• VAChT was progressively restricted to a small population of VMAT2-negative post-ganglionic neurons in the adult sympathetic chain, while VMAT2 expression persisted in sympathetic principal ganglion and SIF cells but was eventually extinguished in cranial parasympathetic ganglia [2].
• The classical diabetic autonomic neuropathy (DAN) that eventually occurs in the heart was not present in BB diabetic rats at this early stage as evidenced by normal cardiac VMAT2 immunostaining and normal cardiac norepinephrine content [3].
• Coexpression of tyrosine hydroxylase, GTP cyclohydrolase I, aromatic amino acid decarboxylase, and vesicular monoamine transporter 2 from a helper virus-free herpes simplex virus type 1 vector supports high-level, long-term biochemical and behavioral correction of a rat model of Parkinson's disease [4].
• Our work indicates that both the expression level of VMAT2 and capacity of vesicular packaging of DA are important in protecting DAergic cells from MPP+ toxicity [5].

High impact information on Slc18a2

• Because the location of vesicular monoamine transporter 2 (VMAT2) defines the secretory vesicles capable of monoamine release, we have studied its trafficking to assess the potential for monoamine release by exocytosis [6].
• In neuroendocrine PC12 cells, VMAT2 localizes exclusively to large dense-core vesicles (LDCVs), and we now show that cytoplasmic signals target VMAT2 directly to LDCVs within the biosynthetic pathway [6].
• In neurons, VMAT2 localizes to a population of vesicles that we now find undergo regulated exocytosis in dendrites [6].
• Sorting of vesicular monoamine transporter 2 to the regulated secretory pathway confers the somatodendritic exocytosis of monoamines [6].
• Although hippocampal neurons do not express typical LDCV proteins, transfected chromogranins A, B, and brain-derived neurotrophic factor (BDNF) colocalize with VMAT2 [6].

Chemical compound and disease context of Slc18a2

• Two other structures rich in choline acetyltransferase, the electric organ of Torpedo and the ciliary ganglion of the chick embryo did not contain measurable amounts of [3H]TBZOH binding sites, suggesting that the monoamine transporter is not an ubiquitous component of cholinergic synaptic vesicles [7].
• Prevention of METH-induced hyperthermia attenuated the decrease in VMAT-2 as well as dopamine and 5-HT content [8].
• Although bupropion attenuated the METH-induced reduction in VMAT-2 activity acutely, it did not prevent the long-term dopaminergic toxicity or the METH-induced redistribution of VMAT-2 protein [9].
• Hence, the VMAT-2 may be an important target for developing strategies to treat not only cocaine addiction but also other disorders involving alterations in neuronal DA disposition, including Parkinson's disease [10].
• The maintenance of hyperthermia during lobeline + METH exposure restored the effects of METH on decreases in VMAT-2 as well as dopamine and 5-HT content [8].

Biological context of Slc18a2

• Phosphorylation of a vesicular monoamine transporter by casein kinase II [11].
• 2. Polymerase chain reaction (PCR) cloning using oligonucleotide primers to DNA sequences conserved within the VMAT family provided evidence for VMAT2, but not VMAT1 in rat gastric corpus [1].
• The down-regulation of VMAT2 in this dopaminergic regions may serve as an adaptatory mechanism in the response to prolonged stress, and may be relevant to chronic stress-induced depression [12].
• The reduced levels of VMAT2 protein binding capacity were not accompanied by a parallel alteration in VMAT2 mRNA levels in the VTA, the SNC and the DR [13].
• In addition, the brains of VMAT2 heterozygotes contain substantially lower monoamine levels than those of wild-type littermates, and depolarization induces less dopamine release from heterozygous than from wild-type cultures, suggesting that VMAT2 expression regulates monoamine storage and release [14].

Anatomical context of Slc18a2

• VMAT2 thus defines a population of secretory vesicles that mediate the activity-dependent somatodendritic release of multiple retrograde signals involved in synaptic function, growth, and plasticity [6].
• Preferential localization of a vesicular monoamine transporter to dense core vesicles in PC12 cells [15].
• A cDNA for a rat vesicular monoamine transporter, designated MAT, was isolated by expression cloning in a mammalian cell line (CV-1) [16].
• One isoform occurs in the adrenal gland (VMAT1) and another in the brain (VMAT2) [11].
• Using heterologous expression in Chinese hamster ovary, PC12, and COS cells, we find that rat VMAT2, but not VMAT1, is constitutively phosphorylated [11].

Associations of Slc18a2 with chemical compounds

• Purified CKI and CKII phosphorylate the wild-type carboxyl terminus of VMAT2, but not a double mutant with both serines 512 and 514 replaced by alanine [11].
• Phosphoamino acid analysis indicates that this phosphorylation occurs on serine residues, and the analysis of VMAT1-VMAT2 chimeras and site-directed mutagenesis localize the phosphorylation sites to serines 512 and 514 at the carboxyl terminus of VMAT2 [11].
• Expression and regulation of a vesicular monoamine transporter in rat stomach: a putative histamine transporter [1].
• A series of cyclo-3beta-(4-aminophenyl)-2beta-tropanemethanol analogues (5a-m) possessing varying linker groups between the 2- and 3-position on the tropane ring were synthesized and evaluated for their monoamine transporter binding properties [17].
• Omeprazole also elevated VMAT2 expression in rats fasted for 48 h, but fasting alone, or refeeding fasted animals had no effect [1].

Physical interactions of Slc18a2

• However, SDCVs also contain membrane proteins characteristic of certain secretory granules like the vesicular monoamine transporter and the membrane-bound form of dopamine beta-hydroxylase [18].

Regulatory relationships of Slc18a2

• Gastrin induces expression and promoter activity of the vesicular monoamine transporter subtype 2 [19].

Other interactions of Slc18a2

• Our results provide further evidence that VMAT2 is the vesicular amine transporter responsible for accumulation of monoamines into secretory vesicles of monoaminergic neurons and ECL cells [20].
• VMAT2 and the vesicular acetylcholine transporter VAChT were co-expressed in early development of the primary sympathetic chain as well as in the cranial parasympathetic ganglia [2].
• Synaptophysin and VMAT-2 could be detected not only in the ECL cells, but also in a population of HDC-negative cells [21].
• It was unexpected that quantification of immunoautoradiograms showed a partial recovery of all three dopaminergic markers (TH, DAT, and VMAT2) in the denervated territories of the striatum of moderately lesioned rats receiving levodopa [22].
• Deletion analysis of the rat vesicular monoamine transporter subtype 2 promoter defined the minimal promoter sequence necessary for full basal activity as a -121 bp segment upstream of exon 1 containing two Sp1 sites (-97 to -88 bp and -68 to -59 bp) and a cAMP-responsive element (-44 to -35 bp) [19].

Analytical, diagnostic and therapeutic context of Slc18a2

• The VMAT2 mRNA level was analyzed by in situ hybridization, in the VTA, SNC and the dorsal raphe (DR) nucleus [13].
• VMAT2 expression at the protein level was assessed by autoradiography using [(3)H]dihydrotetrabenazine ([(3)H]TBZOH) binding, in the prefrontal cortex, the striatum and its subregions, nucleus accumbens (NAC), ventral tegmental area (VTA) and the substantia nigra pars compacta (SNC) [13].
• The cellular localization of the vesicular monoamine transporter 2 (VMAT2) in the rat digestive tract was investigated with immunohistochemistry [20].
• We studied the expression of the brain-type vesicular monoamine transporter (VMAT2) in the Flinders sensitive line (FSL) rats, which represent a genetic animal model for clinical depression in humans [13].
• Recent molecular cloning techniques have identified the vesicular monoamine transporter (VMAT2) that is expressed in brain [23].

References