Role of Protein Kinase A-Mediated Phosphorylation in CFTR Channel Activity Regulation.

Angela Della Sala,Giulia Prono,Emilio Hirsch,Alessandra Ghigo

doi:10.3389/fphys.2021.690247

Abstract

Cystic fibrosis transmembrane conductance regulator (CFTR) is an anion channel expressed on the apical membrane of epithelial cells, where it plays a pivotal role in chloride transport and overall tissue homeostasis. CFTR constitutes a unique member of the ATP-binding cassette transporter superfamily, due to its distinctive cytosolic regulatory (R) domain carrying multiple phosphorylation sites that allow the tight regulation of channel activity and gating. Mutations in the CFTR gene cause cystic fibrosis, the most common lethal autosomal genetic disease in the Caucasian population. In recent years, major efforts have led to the development of CFTR modulators, small molecules targeting the underlying genetic defect of CF and ultimately rescuing the function of the mutant channel. Recent evidence has highlighted that this class of drugs could also impact on the phosphorylation of the R domain of the channel by protein kinase A (PKA), a key regulatory mechanism that is altered in various CFTR mutants. Therefore, the aim of this review is to summarize the current knowledge on the regulation of the CFTR by PKA-mediated phosphorylation and to provide insights into the different factors that modulate this essential CFTR modification. Finally, the discussion will focus on the impact of CF mutations on PKA-mediated CFTR regulation, as well as on how small molecule CFTR regulators and PKA interact to rescue dysfunctional channels.

Highlights

The cystic fibrosis transmembrane conductance regulator (CFTR) is a cAMP-activated chloride and bicarbonate channel expressed at the apical surface of secretory epithelia, including the airways, sweat glands, gastrointestinal tract, and other tissues (Riordan et al, 1989; Rommens et al, 1989; Riordan, 2008)
The CFTR has a critical role in transepithelial ion and fluid secretion and homeostasis, and mutations in this gene have been implied in the pathogenesis of cystic fibrosis (CF; Li and Naren, 2005)
protein kinase A (PKA)-dependent phosphorylation plays a key role in multiple steps during the life cycle of CFTR

Summary

Introduction

The cystic fibrosis transmembrane conductance regulator (CFTR) is a cAMP-activated chloride and bicarbonate channel expressed at the apical surface of secretory epithelia, including the airways, sweat glands, gastrointestinal tract, and other tissues (Riordan et al, 1989; Rommens et al, 1989; Riordan, 2008). The CFTR has a critical role in transepithelial ion and fluid secretion and homeostasis, and mutations in this gene have been implied in the pathogenesis of cystic fibrosis (CF; Li and Naren, 2005). The absence of a functional CFTR leads to a decrease in chloride ion secretion that, together with the consequent alteration of water homeostasis, results in the accumulation of dehydrated mucus, recurrent. CFTR mutations cause a multiorgan disease, respiratory failure is the major cause of morbidity and mortality for CF patients (Ratjen et al, 2015). CF nowadays remains an incurable disease, the identification of the defective CFTR gene in 1989 (Riordan et al, 1989; Rommens et al, 1989) has prompted significant advances in the development of molecular therapies aimed at addressing the underlying cellular defect (De Boeck and Amaral, 2016; Veit et al, 2016)

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