Novel tool for the study of cholecystokinin-stimulated pancreatic enzyme secretion

H. Y. Gaisano, U. G. Klueppelberg, D. I. Pinon, M. A. Pfenning, S. P. Powers, L. J. Miller

Research output: Contribution to journalArticle

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Abstract

The molecular events that mediate cholecystokinin (CCK)-stimulated pancreatic secretion are not well defined because of the complex receptor-binding and concentration-response characteristics of this hormone. Functional models of receptor occupancy initiating the cascade leading to secretion have been complicated by the inhibition of secretion effected by supra-maximal concentrations of CCK. Recent report of a CCK analogue that does not exhibit supramaximal inhibition led us to synthesize a similar analogue that could also be radiolabeled for studies of receptor binding and affinity labeling, and for studies of second messenger activity. This probe, D-Tyr-Gly-[(Nle28,31)CCK-26-32]-phenethyl ester, was a fully efficacious secretagogue with no supramaximal inhibition, and, unlike native hormone, bound to a single class of sites present on both acini and membranes. Occupation of this site correlated well with stimulation of secretion. Evidence that this was indeed a CCK-binding site were the abilities of CCK and antagonist L-364,718 to inhibit binding of this analogue. Affinity labeling confirmed the identity of the site mediating secretory stimulation as a M(r) = 85,000-95,000 protein. Whereas the nonhydrolyzable guanosine triphosphate analogue, 5'-guanylyl-imidodiphosphate, was a potent inhibitor of CCK binding, it had no effect on binding of this secretagogue, suggesting that a novel cascade not involving a guanine nucleotide-binding protein mediates CCK stimulation of pancreatic secretion.

Original languageEnglish (US)
Pages (from-to)321-325
Number of pages5
JournalJournal of Clinical Investigation
Volume83
Issue number1
DOIs
StatePublished - 1989

ASJC Scopus subject areas

  • Medicine(all)

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    Gaisano, H. Y., Klueppelberg, U. G., Pinon, D. I., Pfenning, M. A., Powers, S. P., & Miller, L. J. (1989). Novel tool for the study of cholecystokinin-stimulated pancreatic enzyme secretion. Journal of Clinical Investigation, 83(1), 321-325. https://doi.org/10.1172/JCI113877