ENaC-CFTR interactions: the role of electrical coupling of ion fluxes explored in an epithelial cell model

CFTR and the epithelial Na channel (ENaC) are two membrane proteins expressed in the apical membrane of several epithelia. They have been shown to influence each other's function but the mechanisms of this interaction are not fully understood. We have explored the role of electrical coupling between the ion fluxes carried by these two electrogenic transporters as one among other possible mechanisms through which these two proteins could interact. For this purpose, we have built a mathematical model of an epithelial cell monolayer comprising variable apical Cl- and Na+ conductances, a basolateral Na,K-pump, basolateral Cl- and K+ conductances and a paracellular shunt conductance. The model allows us to simulate ion transport under current- or voltage-clamp conditions and to monitor individual ionic membrane currents, membrane potentials and intracellular ion concentrations. Using a set of transport parameters extrapolated from published work, we can show, first, that the model reproduces the expected effects of conductance inhibition on transepithelial transport, and transepithelial and single membrane potentials or conductances. Second, concerning the influence of CFTR on ENaC, the simulations show that: (1) under current-clamp conditions, the amplitude of the apical membrane Cl- conductance has a strong influence on the transepithelial depolarization induced by inhibition of the apical Na+ conductance, (2) under voltage-clamp conditions, the decrease of short-circuit current induced by inhibition of the apical Na+ conductance is also significantly decreased by the presence of a large apical membrane Cl- conductance. Our results show that when ENaC and CFTR are expressed in the same apical membrane, the electrical coupling of these two ion channels can explain at least part of the effect of CFTR activation on the Na+ current flowing through ENaC.