Diminished agonist-stimulated inositol triphosphate generation blocks stimulus-secretion coupling in mouse pancreatic acini during diet-induced experimental pancreatitis

R. E. Powers, A. K. Saluja, M. J. Houlihan, M. L. Steer

Research output: Contribution to journalArticle

53 Scopus citations

Abstract

Young female mice fed a choline-deficient, ethionine-supplemented (CDE) diet rapidly develop acute hemorrhagic pancreatitis. We have observed that pancreatic acini prepared from these mice are unable to secrete amylase in response to addition of the cholinergic agonist carbachol, although they retain the ability to secrete amylase in response to the Ca2+ ionophore A23187. The CDE diet does not alter the binding characteristics (K(d) or the maximal number of binding sites) for muscarinic cholinergic receptors as tested using the antagonist [3H]N-methyl-scopolamine nor the competition for this binding by carbachol. Addition of carbachol to acini prepared from mice fed the CDE diet does not result in as marked an increase in cytosolic free Ca2+ levels as that noted in control samples (evaluated using quin2 fluorescence). These observations indicate that the CDE diet interferes with stimulus-secretion coupling in mouse pancreatic acini at a step subsequent to hormone-receptor binding and prior to Ca2+ release. This conclusion is confirmed by our finding that the hormone-stimulated generation of [3H]inositol phosphates (inositol triphosphate, inositol biphosphate, and inositol monophosphate) from acini labeled with [3H]myoinositol is markedly reduced in acini prepared from mice fed the CDE diet. This reduction is not due to a decrease in phosphatidylinositol-4,5-bisphosphate. This communication represents the first report of a system in which a blockade of inositol phosphate generation can be related to a physiologic defect and pathologic lesion.

Original languageEnglish (US)
Pages (from-to)1668-1674
Number of pages7
JournalJournal of Clinical Investigation
Volume77
Issue number5
DOIs
StatePublished - 1986

ASJC Scopus subject areas

  • Medicine(all)

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