Abstract
Cystic fibrosis (CF) is the most common of rare hereditary diseases in Caucasians, and it is estimated to affect 75,000 patients globally. CF is a complex disease due to the multiplicity of mutations found in the CF transmembrane conductance regulator (CFTR) gene causing the CFTR protein to become dysfunctional. Correctors and potentiators have demonstrated good clinical outcomes for patients with specific gene mutations; however, there are still patients for whom those treatments are not suitable and require alternative CFTR-independent strategies. Although CFTR is the main chloride channel in the lungs, others could, e.g., anoctamin-1 (ANO1 or TMEM16A), compensate for the deficiency of CFTR. This review summarizes the current knowledge on calcium-activated chloride channel (CaCC) ANO1 and presents ANO1 as an exciting target in CF.
Highlights
Cystic fibrosis (CF), an autosomal recessive genetic multiorgan disease, is caused by an absent or dysfunctional CF transmembrane conductance regulator (CFTR) channel that mainly mediates chloride anion transport across the apical membrane of epithelial cells
A classification system groups mutations into six classes according to the functional consequences they generate on the CFTR protein: (1) class I: no functional CFTR protein; (2) class II: CFTR
According to several observations ((1) ANO1’s absence decreases airway secretion, (2) ANO1 is ubiquitously expressed in all the tissue affected by CF, including airway epithelial cells where ANO1 is a secondary chloride channel, (3) ANO1 provides a chloride pathway that is CFTR-independent, and (4) ANO1 is involved in HCO3 − secretion, which is highly important for fluid secretion and mucus hydration [76]), increasing ANO1 activity can probably compensate for CFTR deficiency (Figure 3)
Summary
Cystic fibrosis (CF), an autosomal recessive genetic multiorgan disease, is caused by an absent or dysfunctional CF transmembrane conductance regulator (CFTR) channel that mainly mediates chloride anion transport across the apical membrane of epithelial cells. There is an interest in finding an alternative strategy to treat patients with CF independently of CFTR mutations. Alternative ion channels have been suggested to bypass CFTR dysfunction [3,4], such as ENaC [5], the solute carrier 26A9 (SLC26A9) [6], and calcium-activated chloride channel (CaCCs), including anoctamin-1 (ANO1 or TMEM16A) [4]. Such approaches might be efficient therapies for all patients, regardless of their CF mutations
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