F508del-CFTR increases intracellular Ca(2+) signaling that causes enhanced calcium-dependent Cl(-) conductance in cystic fibrosis

Biochim Biophys Acta. 2011 Nov;1812(11):1385-92. doi: 10.1016/j.bbadis.2011.08.008. Epub 2011 Aug 30.

Abstract

In many cells, increase in intracellular calcium ([Ca(2+)](i)) activates a Ca(2+)-dependent chloride (Cl(-)) conductance (CaCC). CaCC is enhanced in cystic fibrosis (CF) epithelial cells lacking Cl(-) transport by the CF transmembrane conductance regulator (CFTR). Here, we show that in freshly isolated nasal epithelial cells of F508del-homozygous CF patients, expression of TMEM16A and bestrophin 1 was unchanged. However, calcium signaling was strongly enhanced after induction of expression of F508del-CFTR, which is unable to exit the endoplasmic reticulum (ER). Since receptor-mediated [Ca(2+)](i) increase is Cl(-) dependent, we suggested that F508del-CFTR may function as an ER chloride counter-ion channel for Ca(2+). This was confirmed by expression of the double mutant F508del/G551D-CFTR, which remained in the ER but had no effects on [Ca(2+)](i). Moreover, F508del-CFTR could serve as a scavenger for inositol-1,4,5-trisphosphate [IP3] receptor binding protein released with IP(3) (IRBIT). Our data may explain how ER-localized F508del-CFTR controls intracellular Ca(2+) signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosylhomocysteinase / metabolism
  • Animals
  • Anoctamin-1
  • Bestrophins
  • Blotting, Western
  • Calcium / metabolism*
  • Calcium Signaling
  • Cells, Cultured
  • Chloride Channels / metabolism*
  • Chlorides / metabolism*
  • Cricetinae
  • Cystic Fibrosis / genetics
  • Cystic Fibrosis / metabolism*
  • Cystic Fibrosis / pathology
  • Cystic Fibrosis Transmembrane Conductance Regulator / genetics*
  • Cystic Fibrosis Transmembrane Conductance Regulator / metabolism*
  • Endoplasmic Reticulum / metabolism
  • Epithelial Cells / metabolism
  • Eye Proteins / metabolism
  • Fluorescent Antibody Technique
  • Humans
  • Immunoprecipitation
  • Kidney / cytology
  • Kidney / metabolism
  • Membrane Proteins / metabolism
  • Nasal Mucosa / metabolism
  • Neoplasm Proteins / metabolism
  • Oocytes / cytology
  • Oocytes / metabolism
  • Sequence Deletion
  • Xenopus laevis / metabolism

Substances

  • ANO1 protein, human
  • Anoctamin-1
  • BEST1 protein, human
  • Bestrophins
  • CFTR protein, human
  • Chloride Channels
  • Chlorides
  • Eye Proteins
  • Membrane Proteins
  • Neoplasm Proteins
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • Adenosylhomocysteinase
  • IRBIT protein, mouse
  • Calcium