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LIVER AND BILIARY TRACT

Electrogenic bicarbonate secretion by prairie dog gallbladder

Departments of ¹Surgery and ²Cell Biology and Physiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; and ³Department of Physiology and Biophysics, Rosalind Franklin School of Medicine, North Chicago, Illinois

Submitted 19 June 2006 ; accepted in final form 19 February 2007

Pathological rates of gallbladder salt and water transport may promote the formation of cholesterol gallstones. Because prairie dogs are widely used as a model of this event, we characterized gallbladder ion transport in animals fed control chow by using electrophysiology, ion substitution, pharmacology, isotopic fluxes, impedance analysis, and molecular biology. In contrast to the electroneutral properties of rabbit and Necturus gallbladders, prairie dog gallbladders generated significant short-circuit current (I_sc; 171 ± 21 µA/cm²) and lumen-negative potential difference (–10.1 ± 1.2 mV) under basal conditions. Unidirectional radioisotopic fluxes demonstrated electroneutral NaCl absorption, whereas the residual net ion flux corresponded to I_sc. In response to 2 µM forskolin, I_sc exceeded 270 µA/cm², and impedance estimates of the apical membrane resistance decreased from 200 ·cm² to 13 ·cm². The forskolin-induced I_sc was dependent on extracellular HCO₃^– and was blocked by serosal 4,4'-dinitrostilben-2,2'-disulfonic acid (DNDS) and acetazolamide, whereas serosal bumetanide and Cl^– ion substitution had little effect. Serosal trans-6-cyano-4-(N-ethylsulfonyl-N-methylamino)-3-hydroxy-2,2-dimethyl-chroman and Ba²⁺ reduced I_sc, consistent with the inhibition of cAMP-dependent K⁺ channels. Immunoprecipitation and confocal microscopy localized cystic fibrosis transmembrane conductance regulator protein (CFTR) to the apical membrane and subapical vesicles. Consistent with serosal DNDS sensitivity, pancreatic sodium-bicarbonate cotransporter protein pNBC1 expression was localized to the basolateral membrane. We conclude that prairie dog gallbladders secrete bicarbonate through cAMP-dependent apical CFTR anion channels. Basolateral HCO₃^– entry is mediated by DNDS-sensitive pNBC1, and the driving force for apical anion secretion is provided by K⁺ channel activation.

disease; ion transport; cystic fibrosis conductance membrane regulator; sodium-bicarbonate symporters