title: Epithelial sodium channels regulate cystic fibrosis transmembrane conductance regulator chloride channels in Xenopus oocytes.
abstract: 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 important implications in extracellular fluid volume homeostasis and airway fluid volume and composition, we investigated whether this regulation was reciprocal by examining whether ENaC regulates CFTR. Co-expression of human (h) CFTR and mouse (m) alphabetagammaENaC in Xenopus oocytes resulted in a significant, 3.7-fold increase in whole-cell hCFTR Cl(-) conductance compared with oocytes expressing hCFTR alone. The forskolin/3-isobutyl-1-methylxanthine-stimulated whole-cell conductance in hCFTR-mENaC co-injected oocytes was 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 when CFTR was co-expressed with the gamma-subunit of mENaC. Single Cl(-) channel analyses showed that both CFTR Cl(-) channel open probability and the number of CFTR Cl(-) channels detected per patch increased when hCFTR was co-expressed with alphabetagammamENaC. We conclude that in addition to acting as a regulator of ENaC, CFTR activity is regulated by ENaC.
authors.affiliation: Departments of Medicine and Physiology, University of Pennsylvania and Veterans Affairs Medical Center, Philadelphia, Pennsylvania 19104-6144, USA.
authors.forename: Q
authors.initials: Q
authors.lastname: Jiang
authors.forename: J
authors.initials: J
authors.lastname: Li
authors.forename: R
authors.initials: R
authors.lastname: Dubroff
authors.forename: Y J
authors.initials: YJ
authors.lastname: Ahn
authors.forename: J K
authors.initials: JK
authors.lastname: Foskett
authors.forename: J
authors.initials: J
authors.lastname: Engelhardt
authors.forename: T R
authors.initials: TR
authors.lastname: Kleyman
mesh_terms: D000818:Animals; D018118:Chloride Channels / Q000502:physiology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000502:physiology*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D015640:Ion Channel Gating; D017136:Ion Transport; D051379:Mice; D009865:Oocytes; D015398:Signal Transduction; D015222:Sodium Channels / Q000502:physiology*; D014981:Xenopus
chemical_list: C505032:CFTR protein, human; D018118:Chloride Channels; D015222:Sodium Channels; D019005:Cystic Fibrosis Transmembrane Conductance Regulator