Calmodulin regulation of gallbladder ion transport becomes dysfunctional during gallstone formation in prairie dogs

Gallbladder absorption ii: increased prior to gallstone formation in prairi e doss and may promote cholesterol crystallization. Recent studies indicate that Ca2+-calmodulin (CaM) tonically inhibits gallbladder electrolyte abso rption in prairie dogs fed a nonlithogenic diet, We hypothesized that dieta ry cholesterol alters CaM-dependent regulation of gallbladder ion transport , a possible link between increased gallbladder absorption and gallstone fo rmation. Gallbladders from prairie dogs fed control (N = 24) or 1.2% choles terol-enriched chow (N = 32) were mounted in Ussing chambers. Electrophysio logy and ion flux were measured while exposing the epithelia sequentially t o trifluoperazine (TFP), a CaM antagonist, followed by the calcium ionophor e A23187. Animals fed the high cholesterol diet developed crystals and gall stones in a time-dependent fashion. Mucosal addition of 50 mu M TFP decreas ed short-circuit current (I-sc), transepithelial potential, and tissue cond uctance in control, crystal, and gallstone animals, but the magnitude of it s effect was significantly decreased in animals fed cholesterol. TFP stimul ated mucosa-to-serosa Na+ flux by 6.9 +/- 0.9 mu eq/cm(2)/hr in control ani mals but only 3.1 +/- 0.8 mu eq/cm(2)/hr in gallstone animals. Similarly, T FP increased mucosa-to-serosa Cl- flux by 11.9 +/- 1.4 mu eq/cm(2)/hr in co ntrols but only 4.9 +/- 1.4 mu eq/cm(2)/hr in cholesterol-fed animals. TFP effects were not reversed by A23187, which caused differential effects on I -sc and ion transport in cholesterol-fed animals. In conclusion, CaM-mediat ed inhibition of gallbladder Nai and Cl- transport is diminished in prairie dogs fed cholesterol. We conclude that gallbladder ion transport is partia lly released from basal inhibition during gallstone formation and propose t hat dysfunctional CaM regulation may be a stimulus to increased gallbladder absorption.