Molecular Pharmacology of the Vesicular Monoamine Transporter

Henry, Jean‐Pierre; Sagné, Corinne; Botton, Damien; Isambert, M.F.; Gasnier, Bruno

doi:10.1016/s1054-3589(08)60736-x

Cited by 29 publications

(19 citation statements)

References 5 publications

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“…Acidification of the lumen of the secretory vesicle by VATPases is critical for the transport of small transmitter molecules and biogenic amines such as catecholamines (33)(34)(35). To access whether V-ATPase activity is effectively reduced at low concentrations of bafilomycin A1, we evaluated the effect of the inhibitor on vesicular norepinephrine uptake in PC12 cells.…”

Section: Effect Of Bafilomycin A1 On Trafficking Of Full-length Ormentioning

confidence: 99%

“…Alteration of the chromaffin granule matrix may also be achieved by interfering with the vesicular monoamine transporter vesicular monoamine transporter (34) and could also affect the granular sorting of CgA. Because bafilomycin disruption of the vesicular pH gradient may result in non-exocytotic catecholamine discharge (Fig.…”

Section: H ϩ -Atpase-mediated Acidification and Chromogranin A Sortingmentioning

confidence: 99%

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Role of H+-ATPase-mediated Acidification in Sorting and Release of the Regulated Secretory Protein Chromogranin A

Taupenot

Harper

O’Connor

2005

Journal of Biological Chemistry

121

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The constitutive and regulated secretory pathways represent the classical routes for secretion of proteins from neuroendocrine cells. Selective aggregation of secretory granule constituents in an acidic, bivalent cation-rich environment is considered to be a prerequisite for sorting to the regulated secretory pathway. The effect of selective vacuolar H ؉ -ATPase (V-ATPase) inhibitor bafilomycin A1 on the pH gradient along the secretory pathway was used here to study the role of acidification on the trafficking of the regulated secretory protein chromogranin A (CgA) in PC12 cells. Sorting of CgA was assessed by three-dimensional deconvolution microscopy, subcellular fractionation, and secretagogue-stimulated release, examining a series of full-length or truncated domains of human CgA (CgA-(1-115), CgA-(233-439)) fused to either green fluorescent protein or to a novel form of secreted embryonic alkaline phosphatase (EAP). We show that a full-length CgA/ EAP chimera is sorted to chromaffin granules for exocytosis. Inhibition of V-ATPase by bafilomycin A1 markedly reduced the secretagogue-stimulated release of CgA-EAP by perturbing sorting of the chimera (at the trans-Golgi network or immature secretory granule) rather than the late steps of exocytosis. The effect of bafilomycin A1 on CgA secretion depends on a sorting determinant located within the amino terminus (CgA-(1-115)) but not the C-terminal region of the granin. Moreover, examination of chromaffin granule abundance in PC12 cells exposed to bafilomycin A1 reveals a substantial decrease in the number of dense-core vesicles. We propose that a V-ATPase-mediated pH gradient in the secretory pathway is an important factor for the formation of dense-core granules by regulating the ability of CgA to form aggregates, a crucial step that may underlie the granulogenic function of the protein.The constitutive and regulated secretory pathways represent the classical routes for secretion of proteins from neuroendocrine cells (1). The constitutive pathway allows rapid transport of proteins in small vesicles originating from the outermost layer of the Golgi complex (the trans-Golgi network, or TGN 1 ) and destined for rapid fusion with the plasma membrane. The regulated secretory pathway is characterized by the concentration of a selected (segregated) pool of secretory proteins into granules with a typical electron-dense appearance on transmission electron microscopy. These granules may remain in the cell for an extended period of time after their formation until prompted to undergo exocytotic fusion with the plasma membrane by a secretagogue characteristic for a particular cell type.Selective aggregation or condensation of secretory granule constituents in a mildly acidic environment and in the presence of millimolar concentrations of bivalent cations like Ca 2ϩ is considered to be an important prerequisite for two proposed models of sorting within the regulated secretory pathway, namely sorting-for-entry and sorting-by-retention (2-4). In the sorting-for-entry model, th...

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Section: Effect Of Bafilomycin A1 On Trafficking Of Full-length Ormentioning

confidence: 99%

Section: H ϩ -Atpase-mediated Acidification and Chromogranin A Sortingmentioning

confidence: 99%

Role of H+-ATPase-mediated Acidification in Sorting and Release of the Regulated Secretory Protein Chromogranin A

Taupenot

Harper

O’Connor

2005

Journal of Biological Chemistry

121

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“…As mentioned, reserpine is a non-selective inhibitor of the vesicular monoamine transporter [1]. Thus, one could raise the possibility that the behavioral alterations induced by reserpine treatment are related exclusively to the dopamine depletion caused by this blockage.…”

Section: Discussionmentioning

confidence: 99%

“…Reserpine precludes the storage of monoamines through the blockage of the synaptic vesicles transporters [1]. Consequently, synaptic vesicles are still available but there is a reduction in the amount of dopamine in the synaptic cleft.…”

Section: Introductionmentioning

confidence: 99%

Alpha-Tocopherol Counteracts Cognitive and Motor Deficits Induced by Repeated Treatment with Reserpine

Sarmento-Silva¹,

Lima²,

Cabral³

et al. 2015

Biochem Pharmacol (Los Angel)

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“…It has been reported that ATP uptake is also inhibited by bafilomycin A1, a selective V-ATPase inhibitor, in bovine chromaffin granule ghosts [2]. In addition, reserpine which is a specific inhibitor of VMAT [10] decreases not only CA content but also ATP content in the vesicles of bovine chromaffin cells [6]. Therefore, using on-line assay method for CA and ATP, it is possible to examine the effects of various agents affecting the synthesis and storage of CA on the amount of ATP released from PC12 cells.…”

mentioning

confidence: 99%

Release of Dopamine and ATP from PC12 Cells Treated with Dexamethasone, Reserpine and Bafilomycin A1.

Kasai

Ohta

Nakazato

et al. 2001

The Journal of Veterinary Medical Science

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ABSTRACT. The amounts and time courses of dopamine and ATP released from perfused PC12 cells were examined using a simultaneous on-line recording system. High KCl (60 mM) caused dopamine and ATP release with similar time courses. The relative amount of dopamine to ATP in the effluent was 9.5. In PC12 cells cultured with dexamethasone, reserpine or bafilomycin A1 for 2 days, these drugs did not affect increases of intracellular Ca 2+ in response to high KCl. Dexamethasone doubled the amount of dopamine release induced by high KCl without changing the amount of ATP release. High KCl failed to cause dopamine release in reserpine-treated cells but evoked ATP release. Bafilomycin A1 decreased both high KCl-induced dopamine and ATP release. The ratio of released ATP to total adenine nucleotides and adenosine in response to high KCl was not changed by treatment with the drugs. These results suggest that dopamine and ATP are simultaneously released from secretory vesicles of PC12 cells, in which they are stored via different pathways. Similar to dopamine uptake into secretory vesicles, the H + -gradient across the vesicular membrane developed by vacuolar ATPase may play an important role in the vesicular uptake of ATP. KEY WORDS: ATP, dopamine, on-line, PC12 cell, V-ATPase.J. Vet. Med. Sci. 63(4): 367-372, 2001 It is well known that catecholamine (CA) is stored together with adenosine 5'-triphosphate (ATP) in secretory vesicles of the adrenal medulla [32] and pheochromocytoma (PC12) cells [31]. In adrenal chromaffin cells, it has been reported that CA is present in secretory vesicles but not in the cytosol [24] and that 75% of ATP in the cells is in secretory vesicles [7]. ATP stored in secretory visicles has been shown to be released on exocytosis [5]. ATP has been reported to evoke CA release from adrenal chromaffin cells [1,15] and PC12 cells [13] and to inhibit Ca 2+ currents in adrenal chromaffin cells [3,23].Continuous and on-line assay methods for CA released from cultured adrenal chromaffin cells [11,17] and perfused adrenal glands [4,18] have been developed using an electrochemical detector. We previously reported a simultaneous on-line assay method for CA and ATP released from cultured porcine adrenal chromaffin cells using an electrochemical detector and luciferin-luciferase, respectively [14]. Using this system, we found that CA and ATP appeared in the effluent with similar time courses in response to various secretagogues including high KCl. In the sympathetic nerves of the guinea-pig vas deferens, however, it has been reported that the ratios of CA and ATP appearing in the effluent greatly change during stimulation, suggesting the presence of heterogeneous secretory vesicles with respect to the concentrations of CA and/or ATP [28] and post-release degradation of ATP by soluble ectonucleotidases [29]. Furthermore, the vesicles isolated from PC12 cells have been reported to contain CA and ATP at various concentration ratios (CA/ATP) ranging from 13 to 29 [31].It is well known that ATP and CA are taken up ...

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Molecular Pharmacology of the Vesicular Monoamine Transporter

Cited by 29 publications

References 5 publications

Role of H+-ATPase-mediated Acidification in Sorting and Release of the Regulated Secretory Protein Chromogranin A

Role of H+-ATPase-mediated Acidification in Sorting and Release of the Regulated Secretory Protein Chromogranin A

Alpha-Tocopherol Counteracts Cognitive and Motor Deficits Induced by Repeated Treatment with Reserpine

Release of Dopamine and ATP from PC12 Cells Treated with Dexamethasone, Reserpine and Bafilomycin A1.

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