Calcium-pump inhibitors induce functional surface expression of Delta F508-CFTR protein in cystic fibrosis epithelial cells.
The most common mutation in cystic fibrosis, Delta F508, results in a cystic fibrosis transmembrane conductance regulator (CFTR) protein that is retained in the endoplasmic reticulum (ER). Retention is dependent upon chaperone proteins, many of which require Ca(++) for optimal activity. Interfering with chaperone activity by depleting ER Ca(++) stores might allow functional Delta F508-CFTR to reach the cell surface. We exposed several cystic fibrosis cell lines to the ER Ca(++) pump inhibitor thapsigargin and evaluated surface expression of Delta F508-CFTR. Treatment released ER-retained Delta F508-CFTR to the plasma membrane, where it functioned effectively as a Cl(-) channel. Treatment with aerosolized calcium-pump inhibitors reversed the nasal epithelial potential defect observed in a mouse model of Delta F508-CFTR expression. Thus, ER calcium-pump inhibitors represent a potential target for correcting the cystic fibrosis defect.
Egan
Marie E
ME
Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut, USA.
Glöckner-Pagel
Judith
J
Ambrose
Catherine
C
Cahill
Paula A
PA
Pappoe
Lamiko
L
Balamuth
Naomi
N
Cho
Edward
E
Canny
Susan
S
Wagner
Carsten A
CA
Geibel
John
J
Caplan
Michael J
MJ
D000584:Amiloride / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002462:Cell Membrane / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D003550:Cystic Fibrosis / Q000503:physiopathology*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D004847:Epithelial Cells / Q000187:drug effects / Q000502:physiology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D017384:Sequence Deletion; D019284:Thapsigargin / Q000494:pharmacology*
C505032:CFTR protein, human; D002121:Calcium Channel Blockers; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D019284:Thapsigargin; D000584:Amiloride; D007545:Isoproterenol