[HTML][HTML] F508del-CFTR increases intracellular Ca2+ signaling that causes enhanced calcium-dependent Cl− conductance in cystic fibrosis
JR Martins, P Kongsuphol, E Sammels… - … et Biophysica Acta (BBA …, 2011 - Elsevier
JR Martins, P Kongsuphol, E Sammels, S Dahimène, F AlDehni, LA Clarke, R Schreiber…
Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease, 2011•ElsevierIn many cells, increase in intracellular calcium ([Ca2+] i) activates a Ca2+-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 …
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 …
In many cells, increase in intracellular calcium ([Ca2+]i) activates a Ca2+-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 [Ca2+]i increase is Cl− dependent, we suggested that F508del-CFTR may function as an ER chloride counter-ion channel for Ca2+. This was confirmed by expression of the double mutant F508del/G551D-CFTR, which remained in the ER but had no effects on [Ca2+]i. Moreover, F508del-CFTR could serve as a scavenger for inositol-1,4,5-trisphosphate [IP3] receptor binding protein released with IP3 (IRBIT). Our data may explain how ER-localized F508del-CFTR controls intracellular Ca2+ signaling.
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