Journal
CELLULAR PHYSIOLOGY AND BIOCHEMISTRY
Volume 29, Issue 5-6, Pages 775-790Publisher
KARGER
DOI: 10.1159/000265129
Keywords
CFTR; cGMP; Corrector; Cystic fibrosis; Potentiator; Xenopus laevis oocyte
Categories
Funding
- Mukoviszidose e.V. Giessen
- Deutsche Foerderungsgesellschaft zur Mukoviszidoseforschung e.V. Rhede
Ask authors/readers for more resources
The phosphodiesterase-5 inhibitor sildenafil is an established and approved drug to treat symptoms of a variety of human diseases. In the context of cystic fibrosis (CF), a genetic disease caused by a defective CFTR gene (e.g. Delta F508-CFTR), it was assumed that sildenafil could be a promising substance to correct impaired protein expression. This study focuses on the molecular mechanisms of sildenafil on CFTR recovery. We used Delta F508-CFTR/wt-CFTR expressing Xenopus laevis oocytes and human bronchial epithelial cell lines (CFBE41o(-)/16HBE14o(-)) to investigate the pathways of sildenafil action. Cells were treated with sildenafil and cAMP-mediated current (I-m), conductance (G(m)), and capacitance (C-m) were determined. Sildenafil increased I-m, G(m), and C-m of wt-CFTR and functionally restored Delta F508-CFTR in oocytes. These effects were also seen in CFBE41o(-) and 16HBE14o(-) cells. Transepithelial measurements revealed that sildenafil mediated increase (wt-CFTR) and restoration (Delta F508-CFTR) of channel activity. cGMP pathway blocker inhibited the activity increase but not CFTR/Delta F508-CFTR exocytosis. From these data we conclude that sildenafil mediates potentiation of CFTR activity by a cGMP-dependent and initiates cGMP-independent functional insertion of CFTR/Delta F508-CFTR molecules into the apical membranes. Thus, sildenafil is a corrector and potentiator of CFTR/Delta F508-CFTR. Yet, the necessary high doses of the drug for CFTR recovery demonstrate that sildenafil might not be suited as a therapeutic drug for CF lung disease. Copyright (c) 2012 S. Karger AG, Basel
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available