Proton-Translocating ATPases

Al‐Awqati, Qais

doi:10.1146/annurev.cellbio.2.1.179

Cited by 26 publications

(34 citation statements)

References 52 publications

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“…This has been demonstrated in epithelial cells, such as the intercalated cells of the cortical collecting tubule, which amplify or diminish apical membrane H+-ATPases in response to changes in Pco2 and pH (45). These cells are also capable of reversing surface membrane polarity in response to environmental stimuli (46).…”

mentioning

confidence: 94%

Alterations in the establishment and maintenance of epithelial cell polarity as a basis for disease processes.

1990

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mentioning

confidence: 94%

Alterations in the establishment and maintenance of epithelial cell polarity as a basis for disease processes.

1990

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“…Because PC3 shows a strict pH dependence (Orci et al, 1994;Smeekens et al, 1992), the acidification inside the secretory vesicles has fundamental importance for maintenance of whole-body homeostasis. It has been suggested for decades that the proton gradients might be involved in the fusion of secretory vesicles to the target membrane (Al-Awqati, 1986;Burgess and Kelly, 1987). Barg et al showed that the acidic pH might regulate priming of the granules for secretion, a process involving pairing of SNARE proteins on the vesicles and target membranes to establish fusion competence (Barg et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Thea3 isoform of V-ATPase regulates insulin secretion from pancreatic β-cells

Sun‐Wada

Toyomura

Murata

et al. 2006

Journal of Cell Science

200

175

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Vacuolar-type H+-ATPase (V-ATPase) is a multi-subunit enzyme that has important roles in the acidification of a variety of intracellular compartments and some extracellular milieus. Four isoforms for the membrane-intrinsic subunit (subunit a) of the V-ATPase have been identified in mammals, and they confer distinct cellular localizations and activities on the proton pump. We found that V-ATPase with the a3 isoform is highly expressed in pancreatic islets, and is localized to membranes of insulin-containing secretory granules in β-cells. oc/oc mice, which have a null mutation at the a3 locus, exhibited a reduced level of insulin in the blood, even with high glucose administration. However, islet lysates contained mature insulin, and the ratio of the amount of insulin to proinsulin in oc/oc islets was similar to that of wild-type islets, indicating that processing of insulin was normal even in the absence of the a3 function. The insulin contents of oc/oc islets were reduced slightly, but this was not significant enough to explain the reduced levels of the blood insulin. The secretion of insulin from isolated islets in response to glucose or depolarizing stimulation was impaired. These results suggest that the a3 isoform of V-ATPase has a regulatory function in the exocytosis of insulin secretion.

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“…In one experiment the addition of TFP inhibited the rate of Ca2+ uptake in mutant and wild-type (1,14). Precisely which ions are transported or exchanged is not known.…”

Section: Discussionmentioning

confidence: 98%

“…There are several classes of membrane-bound ATPases that have been described in the biochemical literature (1,3,9,14,34). These ion pumps contribute to the plasma membrane electrochemical gradient, control cell volume, and can participate in the active transport of amino acids and sugars.…”

Section: Discussionmentioning

confidence: 99%

A dominant trifluoperazine resistance gene from Saccharomyces cerevisiae has homology with F0F1 ATP synthase and confers calcium-sensitive growth.

Shih¹,

Wagner²,

Feinstein³

et al. 1988

Mol. Cell. Biol.

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The antipsychotic drug trifluoperazine has been long considered a calmodulin inhibitor from in vitro studies but may function in vivo as a more general inhibitor by disturbing ion fluxes and altering the membrane potential. Resistance to trifluoperazine can arise in Saccharomyces cerevisiae cells by alterations in at least three distinct genetic loci. One locus, defined by a spontaneous dominant trifluoperazine resistance mutation (TFP1 408), was isolated and sequenced. The mechanism of action of the phenothiazine tranquilizers has been the subject of numerous studies (42). Studies reported in the pharmacological literature suggest that the phenothiazines inhibit one of the two types of dopamine receptors (24, 48), a hypothesis consistent with the antipsychotic and Parkinson's disease-like effects. Reports in the biochemical literature suggest that the phenothiazines may function as inhibitors of calcium-binding proteins, especially calmodulin (50) and protein kinase C (25), and may affect calcium-or calmodulin-regulated processes in cells (47). This alternative model is consistent with the effect of these drugs in vivo, since neurons and muscle cells are two types of cells in the body that are dependent on calcium gradients or currents for function.The medical effectiveness of the phenothiazines is directly related to the hydrophobicity of the molecule and varies with the side-chain modifications to the planar ring (50). Trifluoperazine (TFP) is the most hydrophobic of the medically effective phenothiazines. The hydrophobic character of the phenothiazine tranquilizers confers two properties to the drugs: lipid solubility and membrane association. Therefore these drugs can cross the blood-brain barrier readily, can get into any cell type, and can associate with or intercalate into any membranous structure.Since TFP is a medically important drug that affects cells that are dependent upon calcium gradients for function in vivo and inhibits calcium-binding proteins with hydrophobic domains in vitro, we isolated spontaneous TFP-resistant mutants of the simple eucaryote Saccharomyces cerevisiae in an attempt to find mutations in genes coding for proteins involved in calcium transport or regulated pathways. Calcium-sensitive or -dependent mutants of S. cerevisiae have been isolated before (30)(31)(32), and calcium-related biochemical activities have been documented in S. cerevisiae (8, 10-* Corresponding author.12, 29, 38). TFP-resistant pseudorevertants of a calciumdependent mutation have been isolated and are recessive to the wild type for TFP resistance and show TFP-dependent growth at 37°C (30). In this report we describe the isolation and characterization of a spontaneous mutation to dominant TFP resistance and the sequence of the gene encoding it.MATERIALS AND METHODS Strains and plasmids. S. cerevisiae strains were of the S288c background. The wild-type haploids used in this work were NF134 (Mata his4-539 lys2-801 ura3-52) and NF147 (MATTa ade2-101 ura3-52) (43). NF408 was a spontaneous mutation of NF147 to dom...

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Proton-Translocating ATPases

Cited by 26 publications

References 52 publications

Alterations in the establishment and maintenance of epithelial cell polarity as a basis for disease processes.

Alterations in the establishment and maintenance of epithelial cell polarity as a basis for disease processes.

Thea3 isoform of V-ATPase regulates insulin secretion from pancreatic β-cells

A dominant trifluoperazine resistance gene from Saccharomyces cerevisiae has homology with F0F1 ATP synthase and confers calcium-sensitive growth.

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