DIFFERENT PATHWAYS MEDIATE CHOLECYSTOKININ ACTIONS IN CHOLELITHIASIS

Smooth muscle from gallbladders with cholesterol stones exhibits impai red response to cholecystokinin (CCK). This study investigated whether the impaired response is mediated by different signal-transduction pa thways responsible for CCK-induced contraction in prairie dog and huma n gallbladders with cholesterol stones. Gallbladder muscle cells were isolated enzymatically to study contraction. Protein kinase C (PKC) ac tivity was measured by examining the phosphorylation of a specific sub strate peptide from myelin basic protein Ac-MBP-(4-14). Gallbladder mu scle cells from high-cholesterol-fed prairie dogs contracted less in r esponse to CCK octapeptide (CCK-8) than those from the control group. However, inositol-1,4,5-trisphosphate (IP3), diacylglycerol, and guano sine 5'-O-(3-thiotriphosphate) induced the same magnitudes of contract ion in these two groups. In control prairie dog and human gallbladders , the maximal contraction caused by 10(-8) M CCK-8 was blocked by the calmodulin antagonist CGS9343B but not by the PRC inhibitor H-7. Conve rsely, in gallbladders with cholesterol stones from prairie dogs or hu man patients, the maximal contraction induced by 10(-8) M CCK-8 was bl ocked by H-7 and chelerythrine but not by CGS9343B. In these gallbladd ers CCK-8 caused a significant PKC translocation from the cytosol to t he membrane. High CCK concentrations may activate the calmodulin-depen dent pathway in functionally normal gallbladder muscle and the PKC-dep endent pathway in muscle from gallbladders with cholesterol stones. Th e defect of gallbladder muscle after cholesterol feeding and stones mi ght reside in the steps before G protein activation.