Diminished agonist-stimulated inositol trisphosphate generation blocks stimulus-secretion coupling in mouse pancreatic acini during diet-induced experimental pancreatitis
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 (Kd or the maximal number of binding sites) for muscarinic cholinergic receptors as tested using the antagonist (/sup 3/H)N-methylscopolamine 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 (/sup 3/H)inositol phosphates (inositol trisphosphate, inositol bisphosphate, and inositol monophosphate) from acini labeled with (/sup 3/H)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.
- Research Organization:
- Beth Israel Hospital, Boston, MA
- OSTI ID:
- 5687887
- Journal Information:
- J. Clin. Invest.; (United States), Journal Name: J. Clin. Invest.; (United States) Vol. 5; ISSN JCINA
- Country of Publication:
- United States
- Language:
- English
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59 BASIC BIOLOGICAL SCIENCES
ALCOHOLS
ALKALINE EARTH METALS
AMINES
AMINO ACIDS
AMMONIUM COMPOUNDS
AMYLASE
ANIMALS
ANTIMETABOLITES
BIOCHEMICAL REACTION KINETICS
BODY
CALCIUM
CARBOHYDRATES
CARBOXYLIC ACIDS
CHOLINE
DIET
DIGESTIVE SYSTEM
DIGESTIVE SYSTEM DISEASES
DISEASES
DRUGS
ELEMENTS
ENDOCRINE GLANDS
ENZYMES
ETHIONINE
FLUORESCENCE
GLANDS
GLYCOSYL HYDROLASES
HYDROLASES
HYDROXY COMPOUNDS
INOSITOLS
ISOTOPE APPLICATIONS
KINETICS
LABELLED COMPOUNDS
LIPOTROPIC FACTORS
LUMINESCENCE
MAMMALS
MEMBRANE PROTEINS
METALS
MICE
MONOSACCHARIDES
O-GLYCOSYL HYDROLASES
ORGANIC ACIDS
ORGANIC COMPOUNDS
ORGANIC SULFUR COMPOUNDS
ORGANS
OXYGEN COMPOUNDS
PANCREAS
PATHOGENESIS
PHOSPHATES
PHOSPHORUS COMPOUNDS
PROTEINS
QUATERNARY COMPOUNDS
REACTION KINETICS
RECEPTORS
RODENTS
SACCHARIDES
TRACER TECHNIQUES
TRITIUM COMPOUNDS
VERTEBRATES