Cholinergic Hypothesis of Alcoholic Pancreatitis

Grönroos, Juha; Aho, Heikki; Nevalainen, Timo J.

doi:10.1159/000171342

Cited by 21 publications

(8 citation statements)

References 22 publications

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“…In fact, human exocrine pancreas contains acetylcholine receptors, and clinical pancreatitis is known to be induced by cholinergic hyperstimulation. 14,15 In this model, EtOH treatment alone has little effect on Munc18c (minimal PKC␣-induced phosphorylation) but, in the presence of postprandial cholinergic stimulation, induces maximal PKC␣-induced threonine phosphorylation of Munc18c (likely at Thr314), which causes Munc18c to dissociate from the BPM and from BPM-bound Syn-4. This would render the BPM very receptive to exocytosis by relieving and activating Syn-4 into a conformation capable of binding SNAP-23 and ZG VAMPs to form a SNARE complex, which, in the presence of Ca 2ϩ , would consummate exocytotic fusion into the interstitial space, where zymogens released could undergo activation.…”

Section: Discussionmentioning

confidence: 99%

“…14 In fact, clinical pancreatitis could be induced by conditions of cholinergic hyperstimulation (scorpion stings, antiacetylcholinesterase-containing insecticide). 15 To examine the alcohol-mediated susceptibility mechanism in human alcoholic pancreatitis, we performed studies on parallel models of in vitro dispersed rat pancreatic acini and in vivo rat pancreatitis caused by clinically relevant doses of EtOH followed by submaximal postprandial cholinergic stimulation (carbachol [Cch]). Our results demonstrate that (1) low-dose EtOH pretreatment reduced submaximal Cch-stimulated enzyme secretion by redirecting physiologic apical exocytosis to less efficient ectopic BPM sites, which led to pancreatitis; and (2) this process of pathologic basolateral exocytosis…”

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confidence: 99%

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Alcohol-Induced Protein Kinase Cα Phosphorylation of Munc18c in Carbachol-Stimulated Acini Causes Basolateral Exocytosis

et al. 2007

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Alcohol-Induced Protein Kinase Cα Phosphorylation of Munc18c in Carbachol-Stimulated Acini Causes Basolateral Exocytosis

et al. 2007

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“…After the stimulation of pancreatic parasympathetic nerves (e.g., after food intake), acetylcholine (ACh) is released from vagal (cholinergic) nerve terminals and interacts with muscarinic ACh receptors (mAChRs) located directly on pancreatic acinar cells to stimulate enzyme secretion (Gardner and Jensen, 1993). Interestingly, muscarinic cholinergic mechanisms may also contribute to the pathogenesis of certain forms of pancreatitis (Marsh et al, 1988;Possani et al, 1991;Grönroos et al, 1992).…”

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confidence: 99%

Cholinergic Stimulation of Amylase Secretion from Pancreatic Acinar Cells Studied with Muscarinic Acetylcholine Receptor Mutant Mice

Gautam¹,

Han²,

Heard³

et al. 2005

The Journal of Pharmacology and Experimental Therapeutics

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Muscarinic acetylcholine receptors (mAChRs) expressed by pancreatic acinar cells play an important role in mediating acetylcholine-dependent stimulation of digestive enzyme secretion. To examine the potential roles of M 1 and M 3 mAChRs in this activity, we used M 1 and M 3 receptor single knockout (KO) and M 1 /M 3 receptor double KO mice as novel experimental tools. Specifically, we examined the ability of the muscarinic agonist carbachol to stimulate amylase secretion in vitro, using dispersed pancreatic acini prepared from wild-type and mAChR mutant mice. Quantitative reverse transcription-polymerase chain reaction studies using RNA prepared from mouse pancreatic acini showed that deletion of the M 1 or M 3 mAChR genes did not lead to significantly altered mRNA levels of the remaining mAChR subtypes. Moreover, immunoprecipitation studies with M 1 and M 3 mAChR-selective antisera demonstrated that both mAChR subtypes are expressed by mouse pancreatic acini. Strikingly, carbachol-induced stimulation of amylase secretion was significantly impaired in acinar preparations from both M 1 and M 3 receptor single KO mice and abolished in acinar preparations from M 1 /M 3 receptor double KO mice. However, another pancreatic secretagogue, bombesin, retained its ability to fully stimulate amylase secretion in acinar preparations from M 1 /M 3 receptor double KO mice. Together, these studies support the concept that cholinergic stimulation of pancreatic amylase secretion is mediated by a mixture of M 1 and M 3 mAChRs and that other mAChR subtypes do not make a significant contribution to this activity. These findings clarify the long-standing question regarding the molecular nature of the mAChR subtypes mediating the secretion of digestive enzymes from the exocrine pancreas.

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“…It is well known that chronic ethanol intake is the most important etiologic factor in chronic pancreatitis (10,24,32) although the mechanisms by which ethanol causes pancreatic injury are poorly understood.…”

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confidence: 99%

“…Among the possible explanations for the actions of ethanol on the exocrine pancreas, the so-called "cholinergic hypothesis" has received special attention: GR0NROOS et al (10) suggested that chronic alcohol consumption induces alterations in the control of exocrine pancreatic secretion resulting in hyperstimulation of these cells and their muscarinic receptors. A participation of cholinergic routes in the effects of acute alcoholization on the pancreas has also been reported: we have demonstrated the existence of both stimulatory and inhibitory cholinergic mechanisms that are activated by acute intraduodenal (2) or intravenous (1) ethanol administration to rats.…”

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Influence of chronic ethanol consumption on the muscarinic cholinergic control of rat pancreatic acinar cells

Acosta

Román

López

et al. 2000

J. Physiol. Biochem.

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There are a number of hypothetical explanations for the actions of ethanol on the exocrine pancreas; among them, the cholinergic hypothesis has received special attention. According to this hypothesis, chronic alcohol consumption induces alterations in the control of exocrine pancreatic function resulting in cholinergic hyperstimulation of pancreatic acinar cells and their muscarinic receptors. Our aim was to investigate the cholinergic control of pancreatic enzyme secretion and the number and affinity of muscarinic receptors in the pancreatic acinar cells of rats subjected to chronic ethanol ingestion. We also investigated whether a high-fibre diet modifies the actions of ethanol on these aspects of the exocrine pancreatic function. Four groups of rats received either a standard or a high fibre diet, and either water or 20% (v/v) ethanol. After 6 months of treatment, isolated pancreatic acini were used for the determination of carbachol-stimulated amylase secretion and for the analysis of muscarinic receptors, using 1-[N-methyl-3H]scopolamine as a radioligand. Neither chronic ethanol intake nor a high fibre diet caused any apparent alteration in pancreatic histology, neither did them modify plasmatic amylase levels. Chronic alcoholization resulted in a significant increase in the amylase released from pancreatic acini in response to carbachol stimulation, but it did not affect either the number or the affinity of pancreatic acinar muscarinic receptors. The actions of ethanol are not significantly modified by the simultaneous consumption of a high fibre diet.

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Cholinergic Hypothesis of Alcoholic Pancreatitis

Cited by 21 publications

References 22 publications

Alcohol-Induced Protein Kinase Cα Phosphorylation of Munc18c in Carbachol-Stimulated Acini Causes Basolateral Exocytosis

Alcohol-Induced Protein Kinase Cα Phosphorylation of Munc18c in Carbachol-Stimulated Acini Causes Basolateral Exocytosis

Cholinergic Stimulation of Amylase Secretion from Pancreatic Acinar Cells Studied with Muscarinic Acetylcholine Receptor Mutant Mice

Influence of chronic ethanol consumption on the muscarinic cholinergic control of rat pancreatic acinar cells

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