scholarly journals Regulation of the Dopamine and Vesicular Monoamine Transporters: Pharmacological Targets and Implications for Disease

2015 ◽  
Vol 67 (4) ◽  
pp. 1005-1024 ◽  
Author(s):  
Christopher L. German ◽  
Michelle G. Baladi ◽  
Lisa M. McFadden ◽  
Glen R. Hanson ◽  
Annette E. Fleckenstein
Keyword(s):  
Monoamine Transporters ◽  
Pharmacological Targets ◽  
Vesicular Monoamine Transporters

The mechanism of the releasing action of amphetamine. Uptake, superfusion, and electrophysiological studies on transporter-transfected cells

2000 ◽  
Vol 72 (6) ◽  
pp. 1045-1050 ◽  
Author(s):  
C. Pifl ◽  
H. H Sitte ◽  
H. Reither ◽  
E. A. Singer
Keyword(s):  
Patch Clamp ◽  
Molecular Targets ◽  
Monoamine Transporters ◽  
Transfected Cells ◽  
Whole Cell Patch Clamp ◽  
Sodium Dependent ◽  
Electrophysiological Studies ◽  
Inward Currents ◽  
Vesicular Monoamine Transporters ◽  
The Brain

Amphetamine analogues are able to induce signs of neurotoxicity in the brain. In order to understand this type of neurotoxicity, the interaction of amphetamine with its molecular targets must be elucidated. These molecular targets are plasmalemmal and vesicular monoamine transporters. We investigated the interaction of amphetamine with these transporters in cells transfected with the respective cDNA. Superfusion and whole-cell, patch-clamp experiments were performed, and the toxicity of substrates of the transporters was studied. Amphetamine was taken up by dopamine transporter-expressing cells in a sodium-dependent and cocaine-blockable manner. Furthermore, it elicited inward currents in these cells concentration-dependently. Correlation of uptake, release, and patch-clamp experiments suggest that ion fluxes induced by substrate-gating on transporters may significantly contribute to the releasing action of amphetamine and of other transporter substrates. Dopamine accumulation into serotoninergic terminals depleted of serotonin by 3,4-methylenedioxymethamphetamine was discussed as a mechanism of Ecstasy-toxicity. This is in agreement with a toxic effect of intracellular dopamine which could be demonstrated on our transporter-overexpressing cells. These results, apart from their relevance for the toxicity by amphetamine analogues, may also have bearings on the mechanisms in neurodegenerative diseases affecting monoamine transmitters.

scholarly journals Uptake of meta-iodobenzylguanidine in neuroendocrine tumours is mediated by vesicular monoamine transporters

2003 ◽  
Vol 89 (7) ◽  
pp. 1383-1388 ◽  
Author(s):  
L Kölby ◽  
P Bernhardt ◽  
A-M Levin-Jakobsen ◽  
V Johanson ◽  
B Wängberg ◽  
...  
Keyword(s):  
Neuroendocrine Tumours ◽  
Monoamine Transporters ◽  
Vesicular Monoamine Transporters

scholarly journals Syrosingopine sensitizes cancer cells to killing by metformin

2016 ◽  
Vol 2 (12) ◽  
pp. e1601756 ◽  
Author(s):  
Don Benjamin ◽  
Marco Colombi ◽  
Sravanth K. Hindupur ◽  
Charles Betz ◽  
Heidi A. Lane ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Drug Combination ◽  
Therapeutic Strategy ◽  
Synthetic Lethality ◽  
Glycolytic Enzyme ◽  
Transformed Cells ◽  
Monoamine Transporters ◽  
Vesicular Monoamine Transporters ◽  
The Individual

We report that the anticancer activity of the widely used diabetic drug metformin is strongly potentiated by syrosingopine. Synthetic lethality elicited by combining the two drugs is synergistic and specific to transformed cells. This effect is unrelated to syrosingopine’s known role as an inhibitor of the vesicular monoamine transporters. Syrosingopine binds to the glycolytic enzyme α-enolase in vitro, and the expression of the γ-enolase isoform correlates with nonresponsiveness to the drug combination. Syrosingopine sensitized cancer cells to metformin and its more potent derivative phenformin far below the individual toxic threshold of each compound. Thus, combining syrosingopine and codrugs is a promising therapeutic strategy for clinical application for the treatment of cancer.

scholarly journals Biochemistry and molecular biology of the vesicular monoamine transporter from chromaffin granules.

1994 ◽  
Vol 196 (1) ◽  
pp. 251-262 ◽  
Author(s):  
J P Henry ◽  
D Botton ◽  
C Sagne ◽  
M F Isambert ◽  
C Desnos ◽  
...  
Keyword(s):  
Adrenal Gland ◽  
Synaptic Vesicles ◽  
Adrenal Glands ◽  
Secretory Granules ◽  
Monoamine Transporters ◽  
Chromaffin Granules ◽  
Cos Cells ◽  
Transmembrane Segments ◽  
Glycosylation Sites ◽  
Vesicular Monoamine Transporters

Prior to secretion, monoamines (catecholamines, serotonin, histamine) are concentrated from the cytoplasm into vesicles by vesicular monoamine transporters (VMAT). These transporters also carry non-physiological compounds, e.g. the neurotoxin methyl-4-phenylpyridinium. VMAT acts as an electrogenic antiporter (exchanger) of protons and monoamines, using a proton electrochemical gradient. Vesicular transport is inhibited by specific ligands, including tetrabenazine, ketanserin and reserpine. The mechanism of transport and the biochemistry of VMAT have been analyzed with the help of these tools, using mainly the chromaffin granules from bovine adrenal glands as a source of transporter. Although biochemical studies did not suggest a multiplicity of VMATs, two homologous but distinct VMAT genes have recently been cloned from rat, bovine and human adrenal glands. The VMAT proteins are predicted to possess 12 transmembrane segments, with both extremities lying on the cytoplasmic side. They possess N-glycosylation sites in a putative luminal loop and phosphorylation sites in cytoplasmic domains. In rat, VMAT1 is expressed in the adrenal gland whereas VMAT2 is expressed in the brain. In contrast, we found that the bovine adrenal gland expressed both VMAT1 and VMAT2. VMAT2 corresponds to the major transporter of chromaffin granules, as shown by partial peptidic sequences of the purified protein and by a pharmacological analysis of the transport obtained in transfected COS cells (COS cells are monkey kidney cells possessing the ability to replicate SV-40-origin-containing plasmids). We discuss the possibility that VMAT1 may be specifically addressed to large secretory granules vesicles, whereas VMAT2 may also be addressed to small synaptic vesicles; species differences would then reflect the distinct physiological roles of the small synaptic vesicles in the adrenal gland.

scholarly journals A Phosphorylation Site Regulates Sorting of the Vesicular Acetylcholine Transporter to Dense Core Vesicles

2000 ◽  
Vol 149 (2) ◽  
pp. 379-396 ◽  
Author(s):  
David E. Krantz ◽  
Clarissa Waites ◽  
Viola Oorschot ◽  
Yongjian Liu ◽  
Rachel I. Wilson ◽  
...  
Keyword(s):  
Phosphorylation Site ◽  
Dense Core ◽  
Vesicular Acetylcholine Transporter ◽  
Monoamine Transporters ◽  
Dense Core Vesicles ◽  
Kinase C ◽  
Large Dense Core Vesicles ◽  
Dileucine Motif ◽  
Phosphorylation Event ◽  
Vesicular Monoamine Transporters

Vesicular transport proteins package classical neurotransmitters for regulated exocytotic release, and localize to at least two distinct types of secretory vesicles. In PC12 cells, the vesicular acetylcholine transporter (VAChT) localizes preferentially to synaptic-like microvesicles (SLMVs), whereas the closely related vesicular monoamine transporters (VMATs) localize preferentially to large dense core vesicles (LDCVs). VAChT and the VMATs contain COOH-terminal, cytoplasmic dileucine motifs required for internalization from the plasma membrane. We now show that VAChT undergoes regulated phosphorylation by protein kinase C on a serine (Ser-480) five residues upstream of the dileucine motif. Replacement of Ser-480 by glutamate, to mimic the phosphorylation event, increases the localization of VAChT to LDCVs. Conversely, the VMATs contain two glutamates upstream of their dileucine-like motif, and replacement of these residues by alanine conversely reduces sorting to LDCVs. The results provide some of the first information about sequences involved in sorting to LDCVs. Since the location of the transporters determines which vesicles store classical neurotransmitters, a change in VAChT trafficking due to phosphorylation may also influence the mode of transmitter release.

Expression and function of the rat vesicular monoamine transporter 2

2008 ◽  
Vol 294 (4) ◽  
pp. C1004-C1011 ◽  
Author(s):  
Yoav Adam ◽  
Robert H. Edwards ◽  
Shimon Schuldiner
Keyword(s):  
Structural Data ◽  
Monoamine Transporters ◽  
Substrate Molecule ◽  
Electrogenic Transport ◽  
Multidrug Transporters ◽  
The Central Nervous System ◽  
Vesicular Monoamine Transporters ◽  
Vesicular Transporters ◽  
High Level ◽  
And Function

The vesicular monoamine transporters (VMATs) are essential proteins, involved in the storage of monoamines in the central nervous system and in endocrine cells, in a process that involves exchange of 2H+with one substrate molecule. The VMATs interact with various native substrates and clinically relevant drugs and display the pharmacological profile of multidrug transporters. Vesicular transporters suffer from a lack of biochemical and structural data due to the difficulties in their expression. In this work we present the high-level expression of rat VMAT2 (rVMAT2) in a stable a human embryonic kidney cell line (HEK293), generated using the resistance to the neurotoxin 1-methyl-4-phenylpyridinium (MPP+) conferred by the protein. In addition, we describe novel procedures for the solubilization and purification of active protein, and its reconstitution into proteoliposomes. The partially purified protein in detergent binds the inhibitor tetrabenazine and, after reconstitution, displays high levels of ΔμH+-driven electrogenic transport of serotonin. The reconstituted purified rVMAT2 has wild-type affinity for serotonin, and its turnover rate is ∼0.4 substrate molecule/s.

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