Cystic fibrosis transmembrane conductance regulator mediates the cyclic adenosine monophosphate-induced fluid secretion but not the inhibition of resorption in mouse gallbladder epithelium.
We have studied the physiological role of the cystic fibrosis (CF) gene product (cystic fibrosis transmembrane conductance regulator [CFTR]) in gallbladder epithelium using a knockout mouse model for CF. We found that normal mouse gallbladder epithelium expresses functional CFTR as shown by reverse-transcription polymerase chain reaction (RT-PCR) analysis and Ussing chamber experiments. Gallbladders from Cftr -/- mice were structurally intact as shown by microscopic and physiological parameters but lacked the cyclic adenosine monophosphate (cAMP)-induced chloride current observed in normal gallbladders. In fluid transport measurements, normal and Cftr -/- gallbladders were equally active in basal resorption. The addition of forskolin, which activates CFTR anion channel activity through the cAMP system, resulted in net fluid secretion in normal gallbladders. In contrast, Cftr -/- gallbladders were unable to secrete fluid while a complete inhibition of resorption by forskolin was observed. We conclude that, in normal mouse gallbladder epithelium, cAMP-induced fluid secretion involves simultaneous inhibition of apical sodium chloride resorption and activation of CFTR. Our data support the hypothesis that gallbladder disease in CF is at least in part caused by a deficient secretory response to the endogenous cAMP-linked hormones VIP and secretin.
Peters
R H
RH
Cell Biology, Erasmus University, the Netherlands.
van Doorninck
J H
JH
French
P J
PJ
Ratcliff
R
R
Evans
M J
MJ
Colledge
W H
WH
Bijman
J
J
Scholte
B J
BJ
D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D002352:Carrier Proteins / Q000502:physiology; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000502:physiology*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000032:analysis / Q000502:physiology*; D004594:Electrophysiology; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism; D005122:Exudates and Transudates / Q000378:metabolism*; D005704:Gallbladder / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000032:analysis; D019831:Sodium-Calcium Exchanger
D002352:Carrier Proteins; D012333:RNA, Messenger; D019831:Sodium-Calcium Exchanger; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C074530:potassium-dependent sodium-calcium exchanger; D005576:Colforsin; D002217:Carbachol; D000242:Cyclic AMP