| pubmed-article:10790148 | rdf:type | pubmed:Citation | lld:pubmed |
| pubmed-article:10790148 | lifeskim:mentions | umls-concept:C0015127 | lld:lifeskim |
| pubmed-article:10790148 | lifeskim:mentions | umls-concept:C0031453 | lld:lifeskim |
| pubmed-article:10790148 | lifeskim:mentions | umls-concept:C0055363 | lld:lifeskim |
| pubmed-article:10790148 | lifeskim:mentions | umls-concept:C0332161 | lld:lifeskim |
| pubmed-article:10790148 | lifeskim:mentions | umls-concept:C1314792 | lld:lifeskim |
| pubmed-article:10790148 | lifeskim:mentions | umls-concept:C1413365 | lld:lifeskim |
| pubmed-article:10790148 | lifeskim:mentions | umls-concept:C1442161 | lld:lifeskim |
| pubmed-article:10790148 | lifeskim:mentions | umls-concept:C1879547 | lld:lifeskim |
| pubmed-article:10790148 | pubmed:dateCreated | 2000-7-3 | lld:pubmed |
| pubmed-article:10790148 | pubmed:abstractText | In cell-attached patches stimulated with cAMP agonists, the single-channel open probability (Po) of the phenylalanine 508-deleted cystic fibrosis transmembrane conductance regulator (DeltaF508-CFTR) channel, the most common disease-associated mutation in cystic fibrosis, was abnormally low (a functional defect). To investigate the mechanism for the poor response of DeltaF508-CFTR to cAMP stimulation, we examined, in excised inside-out patches, protein kinase A (PKA)-dependent phosphorylation activation and ATP-dependent gating of wild-type (WT) and DeltaF508-CFTR channels expressed in NIH3T3 mouse fibroblasts. For WT-CFTR, the activation time course of CFTR channel current upon addition of PKA and ATP followed a sigmoidal function with time constants that decreased as [PKA] was increased. The curvilinear relationship between [PKA] and the apparent activation rate suggests an incremental phosphorylation-dependent activation of CFTR at multiple phosphorylation sites. The time course of PKA-dependent activation of DeltaF508-CFTR channel current also followed a sigmoidal function, but the rate of activation was at least 7-fold slower than that with WT channels. This result suggests that deletion of phenylalanine 508 causes attenuated PKA-dependent phosphorylation of the CFTR chloride channel. Once DeltaF508-CFTR channels were maximally activated with PKA, the mutant channel and WT channel had indistinguishable steady-state Po values, ATP dose-response relationships and single-channel kinetics, indicating that DeltaF508-CFTR is not defective in ATP-dependent gating. By measuring whole-cell current density, we compared the number of functional channels in WT- and DeltaF508-CFTR cell membrane. Our data showed that the estimated channel density for DeltaF508-CFTR was approximately 10-fold lower than that for WT-CFTR, but the cAMP-dependent whole-cell current density differed by approximately 200-fold. We thus conclude that the functional defect (a decrease in Po) of DeltaF508-CFTR is as important as the trafficking defect (a decrease in the number of functional channels in the plasma membrane) in cystic fibrosis pathogenesis. | lld:pubmed |
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| pubmed-article:10790148 | pubmed:language | eng | lld:pubmed |
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| pubmed-article:10790148 | pubmed:citationSubset | IM | lld:pubmed |
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| pubmed-article:10790148 | pubmed:status | MEDLINE | lld:pubmed |
| pubmed-article:10790148 | pubmed:month | May | lld:pubmed |
| pubmed-article:10790148 | pubmed:issn | 0022-3751 | lld:pubmed |
| pubmed-article:10790148 | pubmed:author | pubmed-author:HoYY | lld:pubmed |
| pubmed-article:10790148 | pubmed:author | pubmed-author:WangFF | lld:pubmed |
| pubmed-article:10790148 | pubmed:author | pubmed-author:HwangT CTC | lld:pubmed |
| pubmed-article:10790148 | pubmed:author | pubmed-author:ZeltwangerSS | lld:pubmed |
| pubmed-article:10790148 | pubmed:issnType | Print | lld:pubmed |
| pubmed-article:10790148 | pubmed:day | 1 | lld:pubmed |
| pubmed-article:10790148 | pubmed:volume | 524 Pt 3 | lld:pubmed |
| pubmed-article:10790148 | pubmed:owner | NLM | lld:pubmed |
| pubmed-article:10790148 | pubmed:authorsComplete | Y | lld:pubmed |
| pubmed-article:10790148 | pubmed:pagination | 637-48 | lld:pubmed |
| pubmed-article:10790148 | pubmed:dateRevised | 2009-11-18 | lld:pubmed |
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| pubmed-article:10790148 | pubmed:year | 2000 | lld:pubmed |
| pubmed-article:10790148 | pubmed:articleTitle | Deletion of phenylalanine 508 causes attenuated phosphorylation-dependent activation of CFTR chloride channels. | lld:pubmed |
| pubmed-article:10790148 | pubmed:affiliation | Department of Physiology, Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO 65211, USA. | lld:pubmed |
| pubmed-article:10790148 | pubmed:publicationType | Journal Article | lld:pubmed |
| pubmed-article:10790148 | pubmed:publicationType | Research Support, U.S. Gov't, P.H.S. | lld:pubmed |
| pubmed-article:10790148 | pubmed:publicationType | Research Support, Non-U.S. Gov't | lld:pubmed |
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