title: CFTR-mediated inhibition of epithelial Na+ conductance in human colon is defective in cystic fibrosis.
abstract: Cystic fibrosis (CF) patients show characteristic defects in epithelial ion transport, such as failure in cAMP-dependent Cl- secretion. Because the cystic fibrosis transmembrane conductance regulator (CFTR) also functions as a downregulator of epithelial Na+ channels (ENaC), enhanced Na+ conductance was found in the airways of CF patients. Here, we examined whether enhanced epithelial Na+ conductance is also present in the colonic epithelium of CF patients and examined the underlying mechanisms. Thus transepithelial voltages were measured, and equivalent short-circuit currents (I(sc-eq)) were determined by means of a novel type of Ussing chamber. Non-CF tissues demonstrated cAMP-dependent Cl- secretion that was absent in biopsies of CF patients. Correspondingly, Isc-eq was inhibited in non-CF but not in CF epithelia when synthesis of endogenous prostaglandins was blocked by indomethacin. In the presence of indomethacin, a larger portion of amiloride-sensitive Isc-eq was detected in CF tissues, suggesting enhanced ENaC conductance in colonic mucosa of CF patients. Increase of intracellular cAMP by forskolin and IBMX inhibited amiloride-sensitive ENaC currents in non-CF tissues but not in CF biopsies. Therefore, enhanced epithelial Na+ conductance is present in the CF colon and is probably due to missing downregulation by CFTR.
authors.affiliation: University Children's Hospital, Albert-Ludwigs-University Freiburg, 79106 Freiburg, Germany. mall@ruf.uni-freiburg.de
authors.forename: M
authors.initials: M
authors.lastname: Mall
authors.forename: M
authors.initials: M
authors.lastname: Bleich
authors.forename: J
authors.initials: J
authors.lastname: Kuehr
authors.forename: M
authors.initials: M
authors.lastname: Brandis
authors.forename: R
authors.initials: R
authors.lastname: Greger
authors.forename: K
authors.initials: K
authors.lastname: Kunzelmann
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D002675:Child, Preschool; D003106:Colon / Q000378:metabolism*; D000242:Cyclic AMP / Q000502:physiology; D003550:Cystic Fibrosis / Q000378:metabolism*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000502:physiology*; D004553:Electric Conductivity; D053503:Epithelial Sodium Channels; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007413:Intestinal Mucosa / Q000378:metabolism; D017136:Ion Transport; D008875:Middle Aged; D012007:Rectum / Q000378:metabolism; D012016:Reference Values; D012964:Sodium / Q000502:physiology; D026941:Sodium Channel Blockers; D015222:Sodium Channels
chemical_list: C505032:CFTR protein, human; D053503:Epithelial Sodium Channels; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D012964:Sodium; D000242:Cyclic AMP