Diffusion-Like Process Can Account for Protein Secretion by the Pancreas

Isenman, Lois; Rothman, Stephen

doi:10.1126/science.451566

Cited by 20 publications

(9 citation statements)

References 8 publications

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“…Finally, the observation that neither the calcium release nor amylase secretion in response to the ATPase inhibitor thapsigargin was reduced after pancreatic duct ligation nor that the enzyme secretion elicited via cAMP-dependent and secretinstimulated pathways was impaired indicates that the secretory machinery required for enzyme exocytosis, which includes the fusion/fission events between secretory vesicles and the apical plasma membrane, were not disturbed by pancreatic duct obstruction. Taken together these data further refute the hypothesis that the secretory impairment after pancreatic duct obstruction is solely the result of a mechanical blockade of fluid secretion (12).…”

Section: Fig 9 Effect Of the Intracellular Casupporting

confidence: 75%

Early Changes in Pancreatic Acinar Cell Calcium Signaling after Pancreatic Duct Obstruction

Mooren¹,

Hlouschek²,

Finkes³

et al. 2003

Journal of Biological Chemistry

115

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Intracellular Ca2؉ -changes not only participate in important signaling pathways but have also been implicated in a number of disease states including acute pancreatitis. To investigate the underlying mechanisms in an experimental model mimicking human gallstone-induced pancreatitis, we ligated the pancreatic duct of Sprague-Dawley rats and NMRI mice for up to 6 h and studied intrapancreatic changes including the dynamics of [ influx in response to secretagogue stimulation. Serum pancreatic enzyme elevation as well as trypsinogen activation was significantly reduced by pretreatment of animals with the calcium chelator BAPTA-AM. These experiments suggest that pancreatic duct obstruction rapidly changes the physiological response of the exocrine pancreas to a Ca 2؉ -signaling pattern that has been associated with premature digestive enzyme activation and the onset of pancreatitis, both of which can be prevented by administration of an intracellular calcium chelator.Alterations in intracellular calcium signaling have previously been reported from an experimental animal model of acute pancreatitis that employs supramaximal secretagogue stimulation for the disease induction (1). Moreover, the spatial and temporal distribution of intracellular calcium signals in response to either physiological or pathological stimuli has been found to be directly related to premature digestive enzyme activation in the pancreas and to acinar cell injury (2-5). Intracellular activation of trypsinogen on the other hand can be completely prevented with agents that interfere with either the uptake of calcium, the maintenance of a calcium gradient across the plasma membrane, or the rapid release of calcium from apical intracellular stores (4, 6). All of these studies indicate clearly that the spatial and temporal distribution of intracellular calcium signals plays a critical role in the early cellular events that precede the onset of pancreatitis. The mechanism, however, that was used to induce acinar cell injury in these studies or in response to which intracellular calcium changes were characterized, supramaximal secretagogue stimulation, is not necessarily an event that is generally involved in the pathogenesis of clinical pancreatitis.In many parts of the world the most common etiological factor associated with acute pancreatitis is gallstone disease. Experimental (7) as well as clinical studies (8, 9) suggest that the onset of gallstone-induced pancreatitis requires migration of the offending stone through the biliary tract and its impaction at the duodenal papilla. Here, at the junction of the common bile duct and the pancreatic duct, the stone can impair the flow of pancreatic secretion or lead to a complete blockage of the pancreatic duct. It is now generally accepted that this impairment of pancreatic secretion (7, 10, 11), rather than a potential reflux of bile into the pancreas (13), represents the critical pathophysiological event for the development gallstoneinduced pancreatitis. To investigate whether this clinically relevant...

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Section: Fig 9 Effect Of the Intracellular Casupporting

confidence: 75%

Early Changes in Pancreatic Acinar Cell Calcium Signaling after Pancreatic Duct Obstruction

Mooren¹,

Hlouschek²,

Finkes³

et al. 2003

Journal of Biological Chemistry

115

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“…adenylate-cyclase and high Km phosphodiesterase from isolated rat pancreatic cells. On electron microscopy dissociated cells did not show evidence of exocytosis (Williams et al 1976) which has been considered as a hallmark for secretion by some (Jamieson & Palade, 1977) and contested by those who believe in a diffusionlike process accounting for protein secretion by the pancreas (Isenman & Rothman, 1979). Since previous studies would point to membrane damage during dissociation of cell, the present study was done to determine the effect of membrane-active drugs on isolated cells to validate them as a model for such studies, while maintaining a distinction between the active secretion from passive leakage of enzymes.…”

Section: Discussionmentioning

confidence: 99%

Amylase release from dissociated mouse pancreatic acinar cells stimulated by glucagon: effect of membrane stabilizers.

Singh¹

1980

The Journal of Physiology

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SUMMARY1. The effect of membrane stabilizers and cytochalasin-B on amylase secretion, basal and induced by ionophore A23187, CCK-PZ, bethanechol and glucagon, was studied in dissociated mouse pancreatic acinar cells.2. Cytochalasin-B did not affect basal or secretagogue-stimulated amylase secretion.3. Membrane stabilizers [thymol (10-7-104 M), chlorpromazine (I0-7-1 04 M) and propranolol (10-7-10-5 M) did not alter basal release of amylase. At higher concentrations of thymol (10-3 M), chlorpromazine (10-3 M) and propranolol (104M), dissociated acinar cells were lysed as indicated by an increase in release of lactic dehydrogenase (LDH).4. Ionophore A23187, CCK-PZ (maximal effective concentrations, 0*01 u. ml.-'), bethanechol (maximal effective concentrations, 10-4 M) and glucagon increased amylase secretion in a dose-dependent fashion. Concentrations of CCK-PZ and bethanechol beyond optimal levels decreased amylase secretion. Concentrations of ionophore A23187 and glucagon when tested beyond 10-6 M and 104 M respectively increased the release of LDH. In concentrations that were non-toxic, membrane stabilizers blocked the stimulating effect of chlolecystokinin-pancreozymin and bethanechol on amylase secretion but did not alter the response to A23187 and glucagon.5. Unlike bethanechol, glucagon neither increased the uptake of 45Ca nor did it alter the release of 45Ca from cells previously loaded with 45CaCl2.6. These data provide evidence that stimulus-secretion coupling in dissociated pancreatic acinar cells is basically similar to cells in situ. The effect of glucagon is consistent with the model in which hormone-dependent mobilization of Ca2+ from intra-or extracellular sources is bypassed leading to digestive enzyme secretion.

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“…Notably, physiologically relevant concentrations of caerulein cause low levels of zymogen activation, but the active enzymes are also secreted, and there is no cell injury (5). The findings of at least two studies have suggested that pancreatic duct obstruction causes reduced secretion from the pancreatic acinar cell (7,10). Although previous studies have examined the effects of pancreatic duct obstruction, the development of pancreatitis has not been fully examined.…”

mentioning

confidence: 87%