Carbachol desensitizes pancreatic enzyme secretion by downregulation of receptors.
First incubating guinea pig pancreatic acini with carbachol reduced the subsequent stimulation of amylase release caused by carbachol, cholecystokinin octapeptide (CCK-8), and bombesin but not that caused by vasoactive intestinal peptide, substance P, 8-bromoadenosine 3',5'-cyclic monophosphate, A23187, or 12-O-tetradecanoylphorbol-13-acetate. Carbachol also reduced the subsequent binding of N-[3H]methylscopolamine, 125I-CCK-8, and 125I-[Tyr4]bombesin. Pancreatic acini possess a high-affinity class of cholinergic receptors and a low-affinity cholinergic receptors appears to produce the reduction in carbachol-stimulated amylase release and binding of N-[3H]methylscopolamine. First incubating acini with carbachol caused a complete loss of high-affinity cholinergic receptors with no change in the number or affinity of low-affinity cholinergic receptors. Carbachol occupation of low-affinity cholinergic receptors appears to produce the reduction in CCK-8- and bombesin-stimulated amylase release and in binding of 125I-CCK-8 and 125I-[Tyr4]bombesin. Acini possess two classes of CCK receptors. One class has a high affinity for CCK-8; the other class has a low affinity for CCK-8. First incubating acini with carbachol caused a 60% decrease in the number of high-affinity CCK receptors with no change in the number of low-affinity receptors or the affinities of either class of receptors for CCK-8. Acini possess a single class of bombesin receptors, and first incubating acini with carbachol caused a 40% decrease in the number of bombesin receptors with no change in their affinity for bombesin. 12-O-tetradecanoyl phorbol-13-acetate reproduced the action of carbachol on binding of N-[3H]methylscopolamine and 125I-CCK-8 but not on binding of 125I-[Tyr4]bombesin, suggesting that carbachol activation of protein kinase C may in some way mediate the effect of carbachol on receptors for carbachol and those for CCK but not that on receptors for bombesin.
Vinayek
R
R
Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892.
Murakami
M
M
Sharp
C M
CM
Jensen
R T
RT
Gardner
J D
JD
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000681:Amylases / Q000378:metabolism*; D000818:Animals; D001839:Bombesin / Q000494:pharmacology; D000001:Calcimycin / Q000494:pharmacology; D002217:Carbachol / Q000494:pharmacology*; D003513:Cycloheximide / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects*; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D010179:Pancreas / Q000187:drug effects / Q000201:enzymology*; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D012844:Sincalide / Q000494:pharmacology; D013373:Substance P / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014660:Vasoactive Intestinal Peptide / Q000494:pharmacology
D011956:Receptors, Cell Surface; D015124:8-Bromo Cyclic Adenosine Monophosphate; D013373:Substance P; D014660:Vasoactive Intestinal Peptide; D000001:Calcimycin; D002217:Carbachol; D003513:Cycloheximide; D000681:Amylases; D012844:Sincalide; D013755:Tetradecanoylphorbol Acetate; D001839:Bombesin