Impact of the F508del mutation on ovine CFTR, a Cl- channel with enhanced conductance and ATP-dependent gating

The Journal of Physiology
Z CaiDavid N Sheppard

Abstract

Malfunction of the cystic fibrosis transmembrane conductance regulator (CFTR), a gated pathway for chloride movement, causes the common life-shortening genetic disease cystic fibrosis (CF). Towards the development of a sheep model of CF, we have investigated the function of sheep CFTR. We found that sheep CFTR was noticeably more active than human CFTR, while the most common CF mutation, F508del, had reduced impact on sheep CFTR function. Our results demonstrate that subtle changes in protein structure have marked effects on CFTR function and the consequences of the CF mutation F508del. Cross-species comparative studies are a powerful approach to understanding the epithelial Cl(-) 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(-) channel regulated by PKA-dependent phosphorylation, inhibited by the open-channel blocker glibenclamide. However, for three reasons, ovine CFTR was ...Continue Reading

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Citations

Sep 29, 2015·The Journal of Pathology·C Bruce A WhitelawBhanu P Telugu
May 5, 2016·Theriogenology·David K Meyerholz
Oct 4, 2016·Cellular and Molecular Life Sciences : CMLS·Oscar Moran
Apr 11, 2019·American Journal of Physiology. Lung Cellular and Molecular Physiology·Samuel J BoseDavid N Sheppard
Nov 1, 2015·Biochemical Society Transactions·Samuel J BoseDavid N Sheppard
Mar 28, 2018·The Journal of General Physiology·Tzyh-Chang HwangSamantha Destefano
Oct 26, 2016·The Journal of Physiology·Jeng-Haur ChenDavid N Sheppard
May 17, 2017·PLoS Biology·Sebastian KirchnerZoya Ignatova
Jan 22, 2019·Frontiers in Pharmacology·Anna SemaniakouValerie Chappe

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