CFTR and calcium-activated chloride currents in pancreatic duct cells of a transgenic CF mouse.
We have studied the cystic fibrosis transmembrane conductance regulator (CFTR) and calcium-activated chloride currents in pancreatic duct cells isolated from a transgenic cf/cf mouse created by targeted insertional mutagenesis. Adenosine 3',5'-cyclic monophosphate (cAMP)-activated CFTR chloride currents were detected in 78% (29/37) of wild-type cells, in 81% (35/43) of heterozygote cells, and in 61% (29/47) of homozygous cf/cf duct cells (P > 0.05, cf/cf vs. wild-type and heterozygote). The CFTR current density measured at membrane potentials of +/- 60 mV averaged 22-26 pA/pF in wild-type and heterozygote groups but only 13 pA/pF in cells derived from cf/cf animals (P < 0.05, cf/cf vs. wild-type and cf/cf vs. heterozygotes). In contrast, duct cells from animals of all three genotypic groups exhibited calcium-activated chloride currents that were of similar magnitude and up to 11-fold larger than the CFTR currents. We speculate that these transgenic insertional null mice do not develop the pancreatic pathology that occurs in cystic fibrosis patients because their duct cells contain 1) some wild-type CFTR generated by exon skipping and aberrant splicing and 2) a separate anion secretory pathway mediated by calcium-activated chloride channels.
Gray
M A
MA
Department of Physiological Sciences, University Medical School, Newcastle upon Tyne, United Kingdom.
Winpenny
J P
JP
Porteous
D J
DJ
Dorin
J R
JR
Argent
B E
BE
D000818:Animals; D002118:Calcium / Q000502:physiology*; D002712:Chlorides / Q000502:physiology*; D003550:Cystic Fibrosis / Q000235:genetics*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D004594:Electrophysiology; D005260:Female; D006579:Heterozygote; D006720:Homozygote; D015759:Ionomycin / Q000494:pharmacology; D008297:Male; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D010183:Pancreatic Ducts / Q000166:cytology / Q000502:physiology*
D002712:Chlorides; D008565:Membrane Proteins; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D015759:Ionomycin; D002118:Calcium