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) gen e product (cystic fibrosis transmembrane conductance regulator [CFTR]) in gallbladder epithelium using a knockout mouse model for CF, Pie fo und 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 -/- mi ce were structurally intact as shown by microscopic and physiological parameters but lacked the cyclic adenosine monophosphate (cAMP)-induce d 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 ani on channel activity through the cAMP system, resulted in net fluid sec retion 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 inhibit ion of apical sodium chloride resorption and activation of CFTR. Our d ata support the hypothesis that gallbladder disease in CF is at least in part caused by a deficient secretory response to the endogenous cAM P-linked hormones VIP and secretin.