Respiratory epithelia are lined by a thin so-called airway surface liquid (ASL) layer. A balance of Na+ resorption via the epithelial sodium channel (ENaC) and Cl+ secretion via the cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channel tightly regulates the ion composition and water content of the ASL which is essential to maintain proper mucociliary clearance (MC) and thus lung defense. To keep this balance, CFTR and ENaC activity need to be tightly adjusted. CFTR inhibits ENaC activity at least in part by reducing proteolytic activation of ENaC. However, the interaction of CFTR and ENaC is complex and not well understood. Cystic fibrosis (CF) is a common autosomal recessive hereditary disease with diverse symptoms, e.g. chronic sinopulmonary disease. Typically CF patients present with loss-of-function mutations in both CFTR alleles. However, in a subgroup of patients with so-called atypical CF none or only one CFTR allele is affected. In CF respiratory epithelia apical Cl- conductance is typically reduced whereas Na+ conductance is increased. Moreover, increased airway epithelial Na+ absorption has been shown to produce CF-like lung disease in genetically modified mice overexpressing ENaC in the lower airways (1). These findings suggest that in the absence of typical CFTR mutations gain-of-function mutations in genes encoding the subunits (α, β, γ) of ENaC may cause CF-like symptoms. In fact, in some patients with atypical CF ENaC mutations were identified (2). To investigate the functional effect of the identified mutations on ENaC activity the mutants were expressed in Xenopus laevis oocytes. In agreement with the hypothesis that gain-of-function mutations of ENaC contribute to the CF phenotype of affected patients, some of the identified mutations increased ENaC activity up to ~4fold (2,4,5). However, other mutations had no effect (2) or even inhibited ENaC activity (2,3).

These results demonstrate that in a subgroup of patients with atypical CF ENaC gain-of-function mutations may explain the patient's phenotype. ENaC loss-of-function mutations are not in agreement with the hypothesis that Na+ hyperabsorption reduces MC. However, in some patients with pseudohypoaldosteronism type I, an ENaC loss-of-function disease, patients with a lung phenotype similar to CF were reported. Thus, further studies are needed to elucidate the role of ENaC in the pathophysiology of CF. A better understanding of ENaC's role in CF pathophysiology may lead to novel therapeutic strategies with ENaC or its regulatory pathways as possible drug targets.

(1) Mall et al. Nat Med 10, 2004: 487-93; (2) Azad et al. Hum Mut 30, 2009: 1093-103; (3) Huber et al. Cell Physiol Biochem 25, 2010: 145-58; (4) Rauh et al. J Physiol 588, 2010: 1211-25; (5) Rauh et al. Am J Physiol Lung Cell Mol 304, 2013: L43-55