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Exposure to sodium butyrate leads to functional downregulation of calcium-activated potassium channels in human airway epithelial cells

  • Cell and Molecular Physiology
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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, ΔF508, 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 ΔF508-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 Ca2+-activated, anion secretion by Calu-3 cell monolayers, determined by the change in transepithelial short-circuit current in response to the Ca2+-elevating agent thapsigargin. The secretory response to 1-ethyl-2-benzimidazolinone, an activator of the basolateral Ca2+-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 Ca2+-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 Ca2+-activated secretion.

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Acknowledgements

This work was supported by grants from the Canadian Cystic Fibrosis Foundation (to P.L.) and the Natural Science and Engineering Research Council (to E.A.C.).

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Authors and Affiliations

  1. Department of Physiology and Biophysics, Dalhousie University, Halifax, Nova Scotia, B3H 1X5, Canada

    Jeremy Roy, Paul Linsdell & Elizabeth A. Cowley

  2. Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, B3H 1X5, Canada

    Eileen M. Denovan-Wright

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  1. Jeremy Roy
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  2. Eileen M. Denovan-Wright
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  4. Elizabeth A. Cowley
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Correspondence to Elizabeth A. Cowley.

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Roy, J., Denovan-Wright, E.M., Linsdell, P. et al. Exposure to sodium butyrate leads to functional downregulation of calcium-activated potassium channels in human airway epithelial cells. Pflugers Arch - Eur J Physiol 453, 167–176 (2006). https://doi.org/10.1007/s00424-006-0128-8

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  • DOI: https://doi.org/10.1007/s00424-006-0128-8

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