Different pathways mediate cholecystokinin actions in cholelithiasis.
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.
Chen
Q
Q
Department of Medicine, Rhode Island Hospital and Brown University School of Medicine, Providence 02903, USA.
De Petris
G
G
Yu
P
P
Amaral
J
J
Biancani
P
P
Behar
J
J
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
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