title: Cl- transport by cystic fibrosis transmembrane conductance regulator (CFTR) contributes to the inhibition of epithelial Na+ channels (ENaCs) in Xenopus oocytes co-expressing CFTR and ENaC.
abstract: 1. Epithelial Na+ channels (ENaCs) are inhibited by the cystic fibrosis transmembrane conductance regulator (CFTR) when CFTR is activated by protein kinase A. Since cAMP-dependent activation of CFTR Cl- conductance is defective in cystic fibrosis (CF), ENaC currents are not inhibited by CFTR. This could explain the enhanced Na+ conductance found in CF. In the present study, we examined possible mechanisms of interaction between CFTR and ENaC co-expressed in Xenopus oocytes. 2. The magnitude of CFTR Cl- currents activated by 3-isobutyl-1-methylxanthine (IBMX) in oocytes co-expressing either wild-type or mutant CFTR and ENaC determined the degree of downregulation of ENaC currents. 3. The ability of CFTR to inhibit ENaC currents was significantly reduced either when extracellular Cl- was replaced by poorly conductive anions, e.g. SCN- or gluconate, or when CFTR was inhibited by diphenylamine-carboxylate (DPC, 1 mmol l-1). 4. Downregulation of ENaC was more pronounced at positive when compared with negative clamp voltages. This suggests that outward currents, i.e. influx of Cl- through activated CFTR most effectively downregulated ENaC. 5. Activation of endogenous Ca2+-activated Cl- currents by 1 micromol l-1 ionomycin did not inhibit ENaC current. This suggests that inhibition of ENaC mediated by Cl- currents may be specific to CFTR. 6. The present findings indicate that downregulation of ENaC by CFTR is correlated to the ability of CFTR to conduct Cl-. The data have implications for how epithelia switch from NaCl absorption to NaCl secretion when CFTR is activated by secretagogues.
authors.affiliation: Physiologisches Institut, Albert-Ludwigs-Universitat Freiburg, Hermann-Herder-Strasse 7, 79104 Freiburg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Briel
authors.forename: R
authors.initials: R
authors.lastname: Greger
authors.forename: K
authors.initials: K
authors.lastname: Kunzelmann
mesh_terms: D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000584:Amiloride / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002712:Chlorides / Q000378:metabolism*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000378:metabolism*; D003600:Cytosol / Q000737:chemistry; D004232:Diuretics / Q000494:pharmacology; D015536:Down-Regulation / Q000502:physiology; D004594:Electrophysiology; D004847:Epithelial Cells / Q000737:chemistry / Q000378:metabolism; D053503:Epithelial Sodium Channels; D005260:Female; D015870:Gene Expression / Q000502:physiology; D006801:Humans; D009154:Mutation / Q000502:physiology; D009865:Oocytes / Q000502:physiology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D051381:Rats; D026941:Sodium Channel Blockers; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism*; D012965:Sodium Chloride / Q000378:metabolism; D014162:Transfection; D014982:Xenopus laevis; D062367:ortho-Aminobenzoates / Q000494:pharmacology
chemical_list: C505032:CFTR protein, human; D002121:Calcium Channel Blockers; D002712:Chlorides; D004232:Diuretics; D053503:Epithelial Sodium Channels; D010726:Phosphodiesterase Inhibitors; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D062367:ortho-Aminobenzoates; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D012965:Sodium Chloride; D000584:Amiloride; C001209:fenamic acid; D002118:Calcium; D015056:1-Methyl-3-isobutylxanthine