Calcium homeostasis is abnormal in cystic fibrosis airway epithelial cells but is normalized after rescue of F508del-CFTR

Cell Calcium. 2008 Feb;43(2):175-83. doi: 10.1016/j.ceca.2007.05.002. Epub 2007 Jun 27.

Abstract

Retention of F508del-CFTR proteins in the endoplasmic reticulum (ER) is dependent upon chaperone proteins, many of which require Ca(2+) for optimal activity. Here, we show in human tracheal gland CF-KM4 cells, that after correction of F508del-CFTR trafficking by miglustat (N-butyldeoxynojirimycin) or low temperature (27 degrees C), the Ca(2+) mobilization is decreased compared to uncorrected cells and becomes identical to the Ca(2+) response observed in non-CF MM39 cells. In CF-KM4 and human nasal epithelial CF15 cells, we also show that inhibiting vesicular trafficking by nocodazole prevents not only the rescue of F508del-CFTR but also the Ca(2+) mobilization decrease. Finally, experiments using the CFTR inhibitor CFTR(inh)-172 showed that the presence but not the channel activity of F508del-CFTR at the plasma membrane is required to decrease the Ca(2+) mobilization in corrected CF cells. These findings show that correction of the abnormal trafficking of F508del-CFTR proteins might have profound consequences on cellular homeostasis such as the control of intracellular Ca(2+) level.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Deoxynojirimycin / analogs & derivatives
  • 1-Deoxynojirimycin / pharmacology
  • Adenosine Triphosphate / pharmacology
  • Benzoates / pharmacology
  • Boron Compounds / pharmacology
  • Calcium Signaling / drug effects
  • Calcium Signaling / physiology*
  • Cell Line
  • Cystic Fibrosis / physiopathology*
  • Cystic Fibrosis Transmembrane Conductance Regulator / genetics
  • Cystic Fibrosis Transmembrane Conductance Regulator / physiology*
  • Endoplasmic Reticulum / drug effects
  • Endoplasmic Reticulum / physiology
  • Epithelial Cells / physiology*
  • Histamine / pharmacology
  • Humans
  • Inositol 1,4,5-Trisphosphate Receptors / physiology
  • Nocodazole / pharmacology
  • Protein Transport / physiology
  • Respiratory Mucosa / physiology*
  • Sequence Deletion
  • Temperature
  • Thiazolidines / pharmacology

Substances

  • 3-((3-trifluoromethyl)phenyl)-5-((3-carboxyphenyl)methylene)-2-thioxo-4-thiazolidinone
  • Benzoates
  • Boron Compounds
  • CFTR protein, human
  • Inositol 1,4,5-Trisphosphate Receptors
  • Thiazolidines
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • 1-Deoxynojirimycin
  • Histamine
  • Adenosine Triphosphate
  • miglustat
  • 2-aminoethoxydiphenyl borate
  • Nocodazole