title: Exposure to sodium butyrate leads to functional downregulation of calcium-activated potassium channels in human airway epithelial cells.
abstract: Cystic fibrosis (CF) is caused by genetic mutations that lead to dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel. The most common mutation, DeltaF508, causes inefficient trafficking of mutant CFTR protein from the endoplasmic reticulum to the cell membrane. Therapeutic efforts have been aimed at increasing the level of DeltaF508-CFTR protein in the membrane using agents such as sodium butyrate. In this study, we investigated the effects of culturing a human airway epithelial cell line, Calu-3, in the presence of 5 mM sodium butyrate. Within 24 h, butyrate exposure caused a significant decrease in the basal, as well as Ca(2+)-activated, anion secretion by Calu-3 cell monolayers, determined by the change in transepithelial short-circuit current in response to the Ca(2+)-elevating agent thapsigargin. The secretory response to 1-ethyl-2-benzimidazolinone, an activator of the basolateral Ca(2+)-activated K(+) channel KCNN4, was similarly reduced by butyrate treatment. Quantitative PCR revealed that these functional effects were associated with dramatic decreases in mRNA for both KCNN4 and CFTR. Furthermore, the KCNQ1 K(+) channel was upregulated after butyrate treatment. We suggest that prolonged exposure to sodium butyrate downregulates the expression of both KCNN4 and CFTR, leading to a functional loss of Ca(2+)-activated anion secretion. Thus, butyrate may inhibit, rather than stimulate, the anion secretory capacity of human epithelial cells that express wild-type CFTR, particularly in tissues that normally exhibit robust Ca(2+)-activated secretion.
authors.affiliation: Department of Physiology and Biophysics, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Roy
authors.forename: Eileen M
authors.initials: EM
authors.lastname: Denovan-Wright
authors.forename: Paul
authors.initials: P
authors.lastname: Linsdell
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Cowley
mesh_terms: D001562:Benzimidazoles / Q000494:pharmacology; D020148:Butyric Acid / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002120:Calcium Channel Agonists / Q000494:pharmacology; D002460:Cell Line; D002712:Chlorides / Q000378:metabolism*; D003550:Cystic Fibrosis / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000187:drug effects*; D015536:Down-Regulation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects*; D006801:Humans; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000187:drug effects*; D008168:Lung / Q000378:metabolism; D019284:Thapsigargin / Q000494:pharmacology
chemical_list: D001562:Benzimidazoles; C505032:CFTR protein, human; D002120:Calcium Channel Agonists; D002712:Chlorides; D004791:Enzyme Inhibitors; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; C496923:KCNN4 protein, human; D020148:Butyric Acid; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D019284:Thapsigargin; C102635:1-ethyl-2-benzimidazolinone; D002118:Calcium