PANCREATIC ACINAR-CELL DESENSITIZATION ALTERS INSP(3), PRODUCTION AND CA2+ MOBILIZATION UNDER CONDITIONS WHERE INSP(3) RECEPTOR REMAINS INTACT

Desensitization of rat pancreatic acinar cells with 0.1 mM carbamoylcholine (Cch) or 0.5 nM caerulein (CAE), a cholecystokinin (CCK) agonist, altered the subsequent secretory responses to these two agonists. Changes in receptor affinities, shifts in receptor populations, receptor internalization and phosphorylation are the major modifications affecting the muscarinic and CCK receptors in response to desensitization. In this study, post-receptor alterations were examined in order to explain the altered enzyme secretion. Cch or CAE desensitization resulted in decreased Ca2+ release in response to CAE and Cch respectively. Under desensitizing conditions, the biochemical and pharmacological properties of the InsP(3) receptor were not affected. Control and desensitized acini had similar B-max. and K-D values. The Ca2+-channel property of the InsP(3) receptor was not affected, either, since Ca2+ release in response to increasing concentrations of InsP(3) remained comparable in both groups of saponin-permeabilized acini. Finally, the quantities of InsP(3) formed in response to Cch and CAE, measured by InsP(3) radioreceptor assay, were significantly decreased in the Cch- and CAE-desensitized groups, and these decreases were not due to increased InsP(3) turnover. These new data indicate that desensitization of acinar cells with Cch and CAE causes post-receptor modifications resulting in decreased InsP(3) formation and decreased intracellular Ca2+ mobilization. It is suggested that the attenuated Ca2+ response is related to a decreased formation of InsP(3) from PtdInsP(2) hydrolysis and that phospholipase C could be the immediate target of this regulation.