Vesicular Monoamine Transport Inhibitors

Mahata, Manjula; Mahata, Sushil K.; Parmer, Robert J.; O’Connor, Daniel T.

doi:10.1161/01.hyp.28.3.414

Cited by 32 publications

(8 citation statements)

References 28 publications

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“…Schwartz et al (35) reported that only a small fraction of dihydropyridine binding sites are functional calcium channels. The dihydropyridine and phenylalkylamine drugs have been reported to bind to ␣-adrenergic receptors (17), P-glycoprotein (32), 1 receptors (31), the vesicular monoamine transporter (27), and the nucleoside transporter (39). Interestingly, binding to the nucleoside transporter was inhibited by increasing concentrations of nucleosides in the binding medium (39).…”

Section: Resultsmentioning

confidence: 99%

Calcium-independent inhibition of glucose transport in PC-12 and L6 cells by calcium channel antagonists

Ardizzone¹,

Lu²,

Dwyer

2002

American Journal of Physiology-Cell Physiology

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The goal of these studies was to determine whether different calcium channel antagonists affect glucose transport in a neuronal cell line. Rat pheochromocytoma (PC-12) cells were treated with L-, T-, and N-type calcium channel antagonists before measurement of accumulation of 2-[(3)H]deoxyglucose (2-[(3)H]DG). The L-type channel antagonists nimodipine, nifedipine, verapamil, and diltiazem all inhibited glucose transport in a dose-dependent manner (2-150 microM) with nimodipine being the most potent and diltiazem only moderately inhibiting transport. T- and N-type channel antagonists had no effect on transport. The L-type channel agonist l-BAY K 8644 also inhibited uptake of 2-[(3)H]DG. The ability of these drugs to inhibit glucose transport was significantly diminished by the presence of unlabeled 2-DG in the uptake medium. Some experiments were performed in the presence of EDTA (4 mM) or in uptake buffer without calcium. The absence of calcium in the uptake medium had no effect on inhibition of glucose transport by nimodipine or verapamil. To examine the effects of these drugs on a cell model of a peripheral tissue, we studied rat L6 muscle cells. The drugs inhibited glucose transport in L6 myoblasts in a dose-dependent manner that was independent of calcium in the uptake medium. These studies suggest that the calcium channel antagonists inhibit glucose transport in cells through mechanisms other than the antagonism of calcium channels, perhaps by acting directly on glucose transporters.

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Section: Resultsmentioning

confidence: 99%

Calcium-independent inhibition of glucose transport in PC-12 and L6 cells by calcium channel antagonists

Ardizzone¹,

Lu²,

Dwyer

2002

American Journal of Physiology-Cell Physiology

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“…The later discovery that reserpine is an irreversible and non-specific VMAT1/2 inhibitor provided a mechanistic explanation for the effects of this compound (5, 6, 91). The anti-hypertensive effect results from VMAT2 inhibition in the sympathetic nervous system and chromaffin cells, reducing sympathetic tone and, in turn, reduced blood pressure (92, 93). Despite its effectiveness for treating hypertension, the inhibition of VMAT2 within the CNS causes the aforementioned deleterious symptoms, including severe depression (88, 94).…”

Section: Current Therapeutics Targeting Vmat2mentioning

confidence: 99%

The vesicular monoamine transporter 2: An underexplored pharmacological target

Bernstein

Stout

Miller

2014

Neurochemistry International

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Active transport of neurotransmitters into synaptic vesicles is required for their subsequent exocytotic release. In the monoamine system, this process is carried out by the vesicular monoamine transporters (VMAT1 and VMAT2). These proteins are responsible for vesicular packaging of dopamine, norepinephrine, serotonin, and histamine. These proteins are essential for proper neuronal function; however, compared to their plasma membrane counterparts, there are few drugs available that target these vesicular proteins. This is partly due to the added complexity of crossing the plasma membrane, but also to the technical difficulty of assaying for vesicular uptake in high throughput. Until recently, reagents to enable high throughput screening for function of these vesicular neurotransmitter transporters have not been available. Fortunately, novel compounds and methods are now making such screening possible; thus, a renewed focus on these transporters as potential targets is timely and necessary.

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“…Sequencing results were analyzed at each Edman cycle by the algorithm "Hydrosites" (for Macintosh) to deconvolute multiple amino-terminal sequences derived from the same parent molecule at a given cycle (22). Activity of Synthetic Catestatins-Peptides were subjected to a test of activity by inhibition of secretagogue-stimulated norepinephrine release from [ 3 H]norepinephrine-prelabeled PC12 pheochromocytoma cells, over a 30-min secretion period, as described previously (10,23). The stimuli to catecholamine release were either nicotinic cholinergic (60 M nicotine) or membrane depolarization (by 55 mM KCl).…”

Section: Preparation Of Tissuementioning

confidence: 99%

Formation of the Catecholamine Release-inhibitory Peptide Catestatin from Chromogranin A

Taylor¹,

Taupenot²,

Mahata³

et al. 2000

Journal of Biological Chemistry

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We conclude that catestatin is cleaved extensively in vivo, and the peptide is released by exocytosis. In chromaffin granules, the major form of catestatin is cleaved at dibasic sites, while smaller carboxyl-terminal forms also occur. Knowledge of cleavage sites of catestatin from chromogranin A may provide a useful starting point in analysis of the relationship between structure and function for this peptide.Chromogranin A, the major soluble protein in catecholamine storage vesicles, not only stabilizes the core of such vesicles (1) but also serves as a prohormone cleaved into several biologically active peptides, including the insulin release-inhibitory fragments pancreastatin (2) and ␤-granin (3-5), the vasodilator vasostatin (6, 7), and the parathyroid hormone release-inhibitory parastatin (8). Recently we described an additional chromogranin A fragment, catestatin (bovine chromogranin A 344 -364), which acts specifically as a potent (IC 50 ϳ200 -400 nM) nicotinic cholinergic antagonist to inhibit catecholamine release (9, 10), suggesting a novel autocrine feedback mechanism controlling sympathochromaffin exocytosis. Initial studies of catestatin relied on synthetic peptides (10); hence, the existence of the peptide in vivo remains unexplored, as do its precise cleavage sites from chromogranin A.In this study, we explored processing of the catestatin region of chromogranin A in secretory granules of chromaffin cells and sympathetic nerves, as well as in human pheochromocytomas. We documented catestatin cleavage from chromogranin A and determined the precise endogenous cleavage sites bounding catestatin in bovine and human chromaffin granules by chromatographic separations coupled with amino-terminal amino acid sequencing, immunoprecipitation, and matrix-assisted laser desorption ionization (MALDI) 1 mass spectrometry. We confirmed catestatin's regulated secretion by chromaffin cells. A major form of catestatin was processed at dibasic sites (bovine chromogranin A 332-364 or human chromogranin A 340 -372 ), while a smaller form was also identified (bovine chromogranin A 343-362 ). Both larger and smaller size forms were synthesized; each displayed specific antagonism of nicotinic cholinergicstimulated catecholamine release, while the smaller form had greater potency of inhibition. MATERIALS AND METHODS Preparation of TissueFractions-All preparative steps on tissues or protein fractions were conducted at 0 -4°C. Bovine adrenal medullary chromaffin granules were prepared by centrifugation on 0.3 M/1.6 M sucrose density step gradients, as described previously (10). After granule hypotonic lysis and centrifugal removal of granule membranes, the soluble proteins and peptides in the supernatant were size-fractionated on a 2.6 ϫ 80-cm Sephacryl S-300 column (Amersham Pharmacia Biotech), eluting with the volatile buffer 0.3 M ammonium acetate, pH 6.5, as described previously (11). The buffer was removed by lyophilization before further studies. In some experiments, bovine chromaffin granule proteins/peptides (200 l c...

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Vesicular Monoamine Transport Inhibitors

Cited by 32 publications

References 28 publications

Calcium-independent inhibition of glucose transport in PC-12 and L6 cells by calcium channel antagonists

Calcium-independent inhibition of glucose transport in PC-12 and L6 cells by calcium channel antagonists

The vesicular monoamine transporter 2: An underexplored pharmacological target

Formation of the Catecholamine Release-inhibitory Peptide Catestatin from Chromogranin A

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