title: Different pathways mediate cholecystokinin actions in cholelithiasis.
abstract: Smooth muscle from gallbladders with cholesterol stones exhibits impaired response to cholecystokinin (CCK). This study investigated whether the impaired response is mediated by different signal-transduction pathways responsible for CCK-induced contraction in prairie dog and human gallbladders with cholesterol stones. Gallbladder muscle cells were isolated enzymatically to study contraction. Protein kinase C (PKC) activity was measured by examining the phosphorylation of a specific substrate peptide from myelin basic protein Ac-MBP-(4-14). Gallbladder muscle cells from high-cholesterol-fed prairie dogs contracted less in response to CCK octapeptide (CCK-8) than those from the control group. However, inositol-1,4,5-trisphosphate (IP3), diacylglycerol, and guanosine 5'-O-(3-thiotriphosphate) induced the same magnitudes of contraction 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 PKC inhibitor H-7. Conversely, in gallbladders with cholesterol stones from prairie dogs or human patients, the maximal contraction induced by 10(-8) M CCK-8 was blocked by H-7 and chelerythrine but not by CGS9343B. In these gallbladders CCK-8 caused a significant PKC translocation from the cytosol to the membrane. High CCK concentrations may activate the calmodulin-dependent pathway in functionally normal gallbladder muscle and the PKC-dependent pathway in muscle from gallbladders with cholesterol stones. The defect of gallbladder muscle after cholesterol feeding and stones might reside in the steps before G protein activation.
authors.affiliation: Department of Medicine, Rhode Island Hospital and Brown University School of Medicine, Providence 02903, USA.
authors.forename: Q
authors.initials: Q
authors.lastname: Chen
authors.forename: G
authors.initials: G
authors.lastname: De Petris
authors.forename: P
authors.initials: P
authors.lastname: Yu
authors.forename: J
authors.initials: J
authors.lastname: Amaral
authors.forename: P
authors.initials: P
authors.lastname: Biancani
authors.forename: J
authors.initials: J
authors.lastname: Behar
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000494:pharmacology; D000470:Alkaloids; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D053119:Benzophenanthridines; D001692:Biological Transport / Q000187:drug effects; D002147:Calmodulin / Q000037:antagonists & inhibitors; D002766:Cholecystokinin / Q000502:physiology*; D002769:Cholelithiasis / Q000503:physiopathology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005704:Gallbladder / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008297:Male; D009119:Muscle Contraction; D009130:Muscle, Smooth / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D010617:Phenanthridines / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D012016:Reference Values; D012589:Sciuridae; D012844:Sincalide / Q000494:pharmacology
chemical_list: D000470:Alkaloids; D001562:Benzimidazoles; D053119:Benzophenanthridines; D002147:Calmodulin; D004791:Enzyme Inhibitors; D010617:Phenanthridines; C052087:CGS 9343B; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D002766:Cholecystokinin; C016299:chelerythrine; D011493:Protein Kinase C; D012844:Sincalide