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dc.contributor.authorZhiwei Caien_US
dc.contributor.authorTimea Palmai-Pallagen_US
dc.contributor.authorPissared Khuituanen_US
dc.contributor.authorMichael J. Mutoloen_US
dc.contributor.authorClément Boinoten_US
dc.contributor.authorBeihui Liuen_US
dc.contributor.authorToby S. Scott-Warden_US
dc.contributor.authorIsabelle Callebauten_US
dc.contributor.authorAnn Harrisen_US
dc.contributor.authorDavid N. Shepparden_US
dc.contributor.otherUniversity of Bristolen_US
dc.contributor.otherNorthwestern University Feinberg School of Medicineen_US
dc.contributor.otherMahidol Universityen_US
dc.contributor.otherUniversite de Poitiersen_US
dc.contributor.otherSorbonne Universiteen_US
dc.contributor.otherWeatherall Institute of Molecular Medicineen_US
dc.identifier.citationJournal of Physiology. Vol.593, No.11 (2015), 2427-2446en_US
dc.description.abstract© 2015 The Physiological Society. Cross-species comparative studies are a powerful approach to understanding the epithelial Cl<sup>-</sup> channel cystic fibrosis transmembrane conductance regulator (CFTR), which is defective in the genetic disease cystic fibrosis (CF). Here, we investigate the single-channel behaviour of ovine CFTR and the impact of the most common CF mutation, F508del-CFTR, using excised inside-out membrane patches from transiently transfected CHO cells. Like human CFTR, ovine CFTR formed a weakly inwardly rectifying Cl<sup>-</sup> channel regulated by PKA-dependent phosphorylation, inhibited by the open-channel blocker glibenclamide. However, for three reasons, ovine CFTR was noticeably more active than human CFTR. First, single-channel conductance was increased. Second, open probability was augmented because the frequency and duration of channel openings were increased. Third, with enhanced affinity and efficacy, ATP more strongly stimulated ovine CFTR channel gating. Consistent with these data, the CFTR modulator phloxine B failed to potentiate ovine CFTR Cl<sup>-</sup> currents. Similar to its impact on human CFTR, the F508del mutation caused a temperature-sensitive folding defect, which disrupted ovine CFTR protein processing and reduced membrane stability. However, the F508del mutation had reduced impact on ovine CFTR channel gating in contrast to its marked effects on human CFTR. We conclude that ovine CFTR forms a regulated Cl<sup>-</sup> channel with enhanced conductance and ATP-dependent channel gating. This phylogenetic analysis of CFTR structure and function demonstrates that subtle changes in structure have pronounced effects on channel function and the consequences of the CF mutation F508del.en_US
dc.rightsMahidol Universityen_US
dc.subjectBiochemistry, Genetics and Molecular Biologyen_US
dc.titleImpact of the F508del mutation on ovine CFTR, a Cl&lt;sup&gt;-&lt;/sup&gt; channel with enhanced conductance and ATP-dependent gatingen_US
Appears in Collections:Scopus 2011-2015

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