Cystic Fibrosis Transmembrane Conductance Regulator-associated ATP and Adenosine 3′-Phosphate 5′-Phosphosulfate Channels in Endoplasmic Reticulum and Plasma Membranes

Pasyk, Eva A.; Foskett, J. Kevin

doi:10.1074/jbc.272.12.7746

Cited by 87 publications

(67 citation statements)

References 58 publications

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“…The cystic fibrosis transmembrane conductance regulator (CFTR) has been associated recently with an adenosine 3 phosphate 5 phosphosulfate channel in the endoplasmic reticulum (104). Because the concentrations of PAPS in these studies were between 10 and 100 mM and the apparent Km for PAPS transport into Golgi vesicles is approximately 1 µM (31, 50), the physiological significance of these studies is not clear.…”

Section: Transport Of Atp and Nucleotide Sugars Into The Endoplasmic mentioning

confidence: 89%

Transporters of Nucleotide Sugars, Atp, and Nucleotide Sulfate in the Endoplasmic Reticulum and Golgi Apparatus

Hirschberg

Robbins²,

Abeijón³

1998

Annu. Rev. Biochem.

349

306

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The lumens of the endoplasmic reticulum and Golgi apparatus are the subcellular sites where glycosylation, sulfation, and phosphorylation of secretory and membrane-bound proteins, proteoglycans, and lipids occur. Nucleotide sugars, nucleotide sulfate, and ATP are substrates for these reactions. ATP is also used as an energy source in the lumen of the endoplasmic reticulum during protein folding and degradation. The above nucleotide derivatives and ATP must first be translocated across the membrane of the endoplasmic reticulum and/or Golgi apparatus before they can serve as substrates in the above lumenal reactions. Translocation of the above solutes is mediated for highly specific transporters, which are antiporters with the corresponding nucleoside monophosphates as shown by biochemical and genetic approaches. Mutants in mammals, yeast, and protozoa showed that a defect in a specific translocator activity results in selective impairments of the above posttranslational modifications, including loss of virulence of pathogenic protozoa. Several of these transporters have been purified and cloned. Experiments with yeast and mammalian cells demonstrate that these transporters play a regulatory role in the above reactions. Future studies will address the structure of the above proteins, how they are targeted to different organelles, 49 0066-4154/98/0701-0049$08.00 Annu. Rev. Biochem. 1998.67:49-69

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Section: Transport Of Atp and Nucleotide Sugars Into The Endoplasmic mentioning

confidence: 89%

Transporters of Nucleotide Sugars, Atp, and Nucleotide Sulfate in the Endoplasmic Reticulum and Golgi Apparatus

Hirschberg

Robbins²,

Abeijón³

1998

Annu. Rev. Biochem.

349

306

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“…37,61,62 An alternative hypothesis has recently been proposed by which CFTR functions as a transporter of the sulfate donor adenosine 3'-phosphate 5'-phosphosulfate (PAPS) in Golgi compartments. 57 This mechanism attempts to explain that the increased sulfation of glycoproteins arises from an increase in the concentration of intravesicular sulfate donors. Previous studies have evaluated the extent of sialylation and sulfation in purified secreted mucin from CF patients, 30,31 primary tissue explants, 35,36 and human bronchial xenografts.…”

Section: Cftr As An Intracellular Chloride Channelmentioning

confidence: 99%

“…Although this regulatory function of CFTR is currently highly debated, 54 several additional laboratories have also noted that CFTR can facilitate ATP transport in a number of cell lines. [55][56][57] The added complexity of CFTR as a regulator of ATP transport in the airway has tremendous implications on potential mechanisms of interaction with other channels important in fluid and electrolyte balance.…”

Section: Cftr Is An Apical Membrane Chloride Channel and Regulator Ofmentioning

confidence: 99%

Cellular heterogeneity of CFTR expression and function in the lung: implications for gene therapy of cystic fibrosis

Jiang

Engelhardt

1998

Eur J Hum Genet

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Cystic fibrosis (CF) has become a paradigm disorder for the clinical testing of gene therapies in the treatment of inherited disease. In recent years, efforts directed at gene therapy of CF have concentrated on improving gene delivery systems to the airway. Surrogate endpoints for complementation of CFTR dysfunction in the lung have been primarily dependent on correction of chloride transport abnormalities. However, it is now clear that the pathophysiology of CF airways disease is far more complex than can be solely attributed to altered chloride permeability. For example, in addition to functioning as a chloride channel, CFTR also has been implicated in the regulation of other apical membrane conductance pathways through interactions with the amiloride sensitive epithelial sodium channel (ENaC) and the outwardly rectifying chloride channel (ORCC). Superimposed on this functional diversity of CFTR is a highly regulated pattern of CFTR expression in the lung. This heterogeneity occurs at both the level of CFTR protein expression within different cell types in the airway and the anatomical location of these cells in the lung. Potential targets for gene therapy of CF include ciliated, non-ciliated, and goblet cells in the surface airway epithelium as well as submucosal glands within the interstitium of the airways. Each of these distinct cellular compartments may have functionally distinct roles in processes which affect the pathogenesis of CF airways disease, such as fluid and electrolyte balance. However, it is presently unclear which of these cellular targets are most pathophysiologic relevant with regard to gene therapy. Elucidation of the underlying mechanisms of CFTR function in the airway will allow for the rational design of gene therapy approaches for CF lung diseases. This review will provide a summary of the field's current knowledge regarding CFTR functional diversity in the airway and the implications of such diversity for gene therapies of CF lung disease.

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“…CFTR-∆F508 is a folding mutation that is trapped in the endoplasmic reticulum and does not traffic to the apical plasma membrane (8,9). However, CFTR-∆F508 retains function as a cAMP-activated Clchannel (10). Therefore, identification of strategies for increasing anterograde trafficking of CFTR-∆F508 through the secretory pathway to the apical plasma membrane, where it can function as a cAMP-activated Cl -channel, would have important therapeutic implications for the treatment of CF.…”

Section: Introductionmentioning

confidence: 99%

A PDZ-interacting domain in CFTR is an apical membrane polarization signal

Moyer¹,

Denton²,

Karlson³

et al. 1999

J. Clin. Invest.

268

232

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Polarization of the cystic fibrosis transmembrane conductance regulator (CFTR), a cAMP-activated chloride channel, to the apical plasma membrane of epithelial cells is critical for vectorial transport of chloride in a variety of epithelia, including the airway, pancreas, intestine, and kidney. However, the motifs that localize CFTR to the apical membrane are unknown. We report that the last 3 amino acids in the COOH-terminus of CFTR (T-R-L) comprise a PDZ-interacting domain that is required for the polarization of CFTR to the apical plasma membrane in human airway and kidney epithelial cells. In addition, the CFTR mutant, S1455X, which lacks the 26 COOH-terminal amino acids, including the PDZ-interacting domain, is mispolarized to the lateral membrane. We also demonstrate that CFTR binds to ezrin-radixin-moesin-binding phosphoprotein 50 (EBP50), an apical membrane PDZ domain-containing protein. We propose that COOH-terminal deletions of CFTR, which represent about 10% of CFTR mutations, result in defective vectorial chloride transport, partly by altering the polarized distribution of CFTR in epithelial cells. Moreover, our data demonstrate that PDZ-interacting domains and PDZ domain-containing proteins play a key role in the apical polarization of ion channels in epithelial cells.

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Cystic Fibrosis Transmembrane Conductance Regulator-associated ATP and Adenosine 3′-Phosphate 5′-Phosphosulfate Channels in Endoplasmic Reticulum and Plasma Membranes

Cited by 87 publications

References 58 publications

Transporters of Nucleotide Sugars, Atp, and Nucleotide Sulfate in the Endoplasmic Reticulum and Golgi Apparatus

Transporters of Nucleotide Sugars, Atp, and Nucleotide Sulfate in the Endoplasmic Reticulum and Golgi Apparatus

Cellular heterogeneity of CFTR expression and function in the lung: implications for gene therapy of cystic fibrosis

A PDZ-interacting domain in CFTR is an apical membrane polarization signal

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