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Pancreatic acinar-cell desensitization alters InsP3 production and Ca2+ mobilization under conditions where InsP3 receptor remains intact.

ABSTRACT: 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 InsP3 receptor were not affected. Control and desensitized acini had similar Bmax. and KD values. The Ca(2+)-channel property of the InsP3 receptor was not affected, either, since Ca2+ release in response to increasing concentrations of InsP3 remained comparable in both groups of saponin-permeabilized acini. Finally, the quantities of InsP3 formed in response to Cch and CAE, measured by InsP3 radioreceptor assay, were significantly decreased in the Cch- and CAE-desensitized groups, and these decreases were not due to increased InsP3 turnover. These new data indicate that desensitization of acinar cells with Cch and CAE causes post-receptor modifications resulting in decreased InsP3 formation and decreased intracellular Ca2+ mobilization. It is suggested that the attenuated Ca2+ response is related to a decreased formation of InsP3 from PtdInsP2 hydrolysis and that phospholipase C could be the immediate target of this regulation.

SUBMITTER: Servant M

PROVIDER: S-EPMC1136436 | biostudies-other | 1995 Jan

REPOSITORIES: biostudies-other

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Project description:Maintenance of the pancreatic acinar cell phenotype suppresses tumor formation. Hence, repetitive acute or chronic pancreatitis, stress conditions in which the acinar cells dedifferentiate, predispose for cancer formation in the pancreas. Dedifferentiated acinar cells acquire a large panel of duct cell-specific markers. However, it remains unclear to what extent dedifferentiated acini differ from native duct cells and which genes are uniquely regulating acinar cell dedifferentiation. Moreover, most studies have been performed on mice since the availability of human cells is scarce. Here, we applied a non-genetic lineage tracing method of human pancreatic exocrine acinar and duct cells that allowed cell-type-specific gene expression profiling by RNA sequencing. Subsequent to this discovery analysis, one transcription factor that was unique for dedifferentiated acinar cells was functionally characterized. RNA sequencing analysis showed that human dedifferentiated acinar cells expressed genes in "Pathways of cancer" with a prominence of MECOM (EVI-1), a transcription factor that was not expressed by duct cells. During mouse embryonic development, pre-acinar cells also transiently expressed MECOM and in the adult mouse pancreas, MECOM was re-expressed when mice were subjected to acute and chronic pancreatitis, conditions in which acinar cells dedifferentiate. In human cells and in mice, MECOM expression correlated with and was directly regulated by SOX9. Mouse acinar cells that, by genetic manipulation, lose the ability to upregulate MECOM showed impaired cell adhesion, more prominent acinar cell death, and suppressed acinar cell dedifferentiation by limited ERK signaling. In conclusion, we transcriptionally profiled the two major human pancreatic exocrine cell types, acinar and duct cells, during experimental stress conditions. We provide insights that in dedifferentiated acinar cells, cancer pathways are upregulated in which MECOM is a critical regulator that suppresses acinar cell death by permitting cellular dedifferentiation.

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Pancreatic acinar-cell desensitization alters InsP3 production and Ca2+ mobilization under conditions where InsP3 receptor remains intact.

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