Epithelial sodium channels regulate cystic fibrosis transmembrane conductance regulator chloride channels in Xenopus oocytes

The cystic fibrosis transmembrane conductance regulator (CFTR), in addition to its well defined Cl- channel properties, regulates other ion channels, CFTR inhibits epithelial Na+ channel (ENaC) currents in many epithelial and nonepithelial cells. Because modulation of net NaCl reabsorption has impor tant implications in extracellular fluid volume homeostasis and airway flui d volume and composition, we investigated whether this regulation was recip rocal by examining whether ENaC regulates CFTR, Co-expression of human (h) CFTR and mouse (m) alpha beta gamma ENaC in Xenopus oocytes resulted in a s ignificant, 3.7-fold increase in whole-cell hCFTR Cl- conductance compared with oocytes expressing hCFTR alone, The forskolin/3-isobutyl-1-methylxanth ine-stimulated whole-cell conductance in hCFTR-mENaC co-injected oocytes wa s amiloride-insensitive, indicating an inhibition of mENaC following hCFTR activation, and it was blocked by DPC (diphenylamine-2-carboxylic acid) and was DIDS (4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid)-insensitive. Enhanced hCFTR Cl- conductance was also observed when either the alpha- or beta-subunit of mENaC was co-expressed with hCFTR, but this was not seen w hen CFTR was co-expressed with the gamma-subunit of mENaC. Single Cl- chann el analyses showed that both CFTR Cl- channel open probability and the numb er of CFTR Cl- channels detected per patch increased when hCFTR was co-expr essed with alpha beta gamma mENaC. We conclude that in addition to acting a s a regulator of ENaC, CFTR activity is regulated by ENaC.