Cell signaling and regulation of CFTR expression in cystic fibrosis cells in the era of high efficiency modulator therapy

• Published in: Journal of cystic fibrosis 2023-03, Vol.22, p.S12-S16
• Main Authors: Ghigo, Alessandra, De Santi, Chiara, Hart, Merrill, Mitash, Nilay, Swiatecka-Urban, Agnieszka
• Format: Article
• Language: English
• Subjects: Cystic Fibrosis - drug therapy; Cystic Fibrosis - metabolism; Cystic Fibrosis Transmembrane Conductance Regulator - metabolism; Electrolytes - metabolism; Epithelial Sodium Channels - metabolism; Humans; Signal Transduction
• ISSN: 1569-1993; 1873-5010
• DOI: 10.1016/j.jcf.2022.12.015

•CFTR function is regulated by cell-specific, time-dependent mechanisms.•CFTR gene expression is controlled by ncRNAs, such as lncRNAs and miRNAs.•cAMP/PKA signaling activation is a primary mechanism of CFTR channel activation.•TGF-β1 signaling inhibits CFTR channel function through multiple mechanisms.•The effect of the new CFTR modulators on these pathways is incompletely understood. Cystic fibrosis transmembrane conductance regulator (CFTR) is a cAMP- and protein kinase A (PKA)-regulated channel, expressed on the luminal surface of secretory and absorptive epithelial cells. CFTR has a complex, cell-specific regulatory network playing a major role in cAMP- and Ca2+-activated secretion of electrolytes. It secretes intracellular Cl– and bicarbonate and regulates absorption of electrolytes by differentially controlling the activity of the epithelial Na+ channel (ENaC) in colon, airways, and sweat ducts. The CFTR gene expression is regulated by cell-specific, time-dependent mechanisms reviewed elsewhere [1]. This review will focus on the transcriptional, post-transcriptional, and translational regulation of CFTR by cAMP-PKA, non-coding (nc)RNAs, and TGF-β signaling pathways in cystic fibrosis (CF) cells.