Direct Activation of Cytosolic Ca2+ Signaling and Enzyme Secretion by Cholecystokinin in Human Pancreatic Acinar Cells

Murphy, John A.; Criddle, David N.; Sherwood, Mark W.; Chvanov, Michael; Mukherjee, Rajarshi; McLaughlin, Euan; Booth, David T.; Gerasimenko, Julia Vladimirovna; Raraty, Michael; Ghaneh, Paula; Neoptolemos, John P.; Gerasimenko, Oleg Vsevolodovich; Tepikin, Alexei V.; Green, Gary M.; Reeve, Joseph R.; Petersen, O. H.; Sutton, Robert

doi:10.1053/j.gastro.2008.05.026

Cited by 145 publications

(130 citation statements)

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“…Irrespective of the mechanism of action, the protective effect of CaM on the granular store is of considerable interest, particularly in view of data showing that the physiological local Ca 2+ spikes in the granular region elicited by hormonal stimulation recruit CaM from the basolateral cytoplasm to the granular region (20). This recruitment of CaM occurring during physiological stimulation (20) may in view of our data be regarded as a functionally important process evolved to protect the granular region from excessive Ca 2+ liberation that could lead to the potentially dangerous intragranular trypsinogen activation (43,44) due to the ion exchange concept by Quesada and Verdugo (5,45). The results obtained by Craske et al (20) showed that supramaximal hormone stimulation, leading to a sustained [Ca 2+ ] i elevation, produces only a single transient phase of CaM recruitment to the granular pole, whereas each physiologically occurring repetitive Ca 2+ spike elicits movement of CaM from the basolateral part of the cell to the granular pole.…”

Section: Discussionmentioning

confidence: 76%

Calmodulin protects against alcohol-induced pancreatic trypsinogen activation elicited via Ca ²⁺ release through IP ₃ receptors

Gerasimenko

Lür

Ferdek

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Alcohol abuse is a major global health problem, but there is still much uncertainty about the mechanisms of action. So far, the effects of ethanol on ion channels in the plasma membrane have received the most attention. We have now investigated actions on intracellular calcium channels in pancreatic acinar cells. Our aim was to discover the mechanism by which alcohol influences calcium homeostasis and thereby understand how alcohol can trigger premature intracellular trypsinogen activation, which is the initiating step for alcohol-induced pancreatitis. We used intact or twophoton permeabilized acinar cells isolated from wild-type mice or mice in which inositol trisphosphate receptors of type 2 or types 2 and 3 were knocked out. In permeabilized pancreatic acinar cells even a relatively low ethanol concentration elicited calcium release from intracellular stores and intracellular trypsinogen activation. The calcium sensor calmodulin (at a normal intracellular concentration) markedly reduced ethanol-induced calcium release and trypsinogen activation in permeabilized cells, effects prevented by the calmodulin inhibitor peptide. A calmodulin activator virtually abolished the modest ethanol effects in intact cells. Both ethanol-elicited calcium liberation and trypsinogen activation were significantly reduced in cells from type 2 inositol trisphosphate receptor knockout mice. More profound reductions were seen in cells from double inositol trisphosphate receptor (types 2 and 3) knockout mice. The inositol trisphosphate receptors, required for normal pancreatic stimulus-secretion coupling, are also responsible for the toxic ethanol action. Calmodulin protects by reducing calcium release sensitivity.

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Section: Discussionmentioning

confidence: 76%

Calmodulin protects against alcohol-induced pancreatic trypsinogen activation elicited via Ca ²⁺ release through IP ₃ receptors

Gerasimenko

Lür

Ferdek

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…On the other hand, Northern blot, RT-PCR, and in situ hybridization methods (de Weerth et al 1993;Ji et al 2001) failed to detect any mRNA expression of the CCK1 receptor in the adult human pancreas, thereby agreeing with the lack of any acinar cell response to CCK agonists (Ji et al 2001). More recently, a study which paid special attention to quick samplings revealed that fresh tissues of the human pancreas responded to CCK without the involvement of neuronal elements, confirming the increase of enzyme secretion by hormonal CCK in such samples (Murphy et al 2008). …”

Section: Introductionmentioning

confidence: 63%

“…Early Ca 2+ imaging studies indicated that GPCRs for CCK were expressed in the basolateral region of rat acinar cells (Habara and Kanno 1991). Subsequent studies recognized the initiation of GPCR-evoked Ca 2+ waves at the apical pole and their propagation to the basal pole of mouse, rat, and human pancreatic acini (Criddle et al 2009;Li et al 2004;Murphy et al 2008;Shin et al 2001). …”

Section: Introductionmentioning

confidence: 99%

Cellular and subcellular localization of cholecystokinin (CCK)-1 receptors in the pancreas, gallbladder, and stomach of mice

Konno

Takahashi-Iwanaga

Uchigashima

et al. 2014

Histochem Cell Biol

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“…Exocytotic secretion of zymogens is controlled by local cytosolic Ca 2ϩ spikes in the apical granular region, generated by small quantities of Ca 2ϩ released from internal stores (3,4). In contrast, prolonged global cytosolic [Ca 2ϩ ] elevationsassociated with emptying the Ca 2ϩ stores-cause intracellular trypsin activation and transform the normally electron dense zymogen granules (ZGs) into empty looking vacuoles (2,(5)(6)(7).…”

mentioning

confidence: 99%

Pancreatic protease activation by alcohol metabolite depends on Ca ²⁺ release via acid store IP ₃ receptors

Gerasimenko

Lür

Sherwood

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Toxic alcohol effects on pancreatic acinar cells, causing the often fatal human disease acute pancreatitis, are principally mediated by fatty acid ethyl esters (non-oxidative products of alcohol and fatty acids), emptying internal stores of Ca 2؉ . This excessive Ca 2؉ liberation induces Ca 2؉ -dependent necrosis due to intracellular trypsin activation. Our aim was to identify the specific source of the Ca 2؉ release linked to the fatal intracellular protease activation. In 2-photon permeabilized mouse pancreatic acinar cells, we monitored changes in the Ca 2؉ concentration in the thapsigarginsensitive endoplasmic reticulum (ER) as well as in a bafilomycinsensitive acid compartment, localized exclusively in the apical granular pole. We also assessed trypsin activity in the apical granular region. Palmitoleic acid ethyl ester (POAEE) elicited Ca 2؉ release from both the ER as well as the acid pool, but trypsin activation depended predominantly on Ca 2؉ release from the acid pool, that was mainly mediated by functional inositol 1,4,5-trisphosphate receptors (IP3Rs) of types 2 and 3. POAEE evoked very little Ca 2؉ release and trypsin activation when IP3Rs of both types 2 and 3 were knocked out. Antibodies against IP3Rs of types 2 and 3, but not type 1, markedly inhibited POAEE-elicited Ca 2؉ release and trypsin activation. We conclude that Ca 2؉ release through IP3Rs of types 2 and 3 in the acid granular Ca 2؉ store induces intracellular protease activation, and propose that this is a critical process in the initiation of alcohol-related acute pancreatitis.calcium ͉ inositol trisphopshate receptors ͉ pancreatitis T he pancreatic acinar cell is potentially dangerous because it produces a range of precursor digestive enzymes (zymogens) that, if inappropriately activated inside the cells, cause autodigestion resulting in the often fatal human disease acute pancreatitis (1, 2).Exocytotic secretion of zymogens is controlled by local cytosolic Ca 2ϩ spikes in the apical granular region, generated by small quantities of Ca 2ϩ released from internal stores (3, 4). In contrast, prolonged global cytosolic [Ca 2ϩ ] elevationsassociated with emptying the Ca 2ϩ stores-cause intracellular trypsin activation and transform the normally electron dense zymogen granules (ZGs) into empty looking vacuoles (2, 5-7). The vacuoles are post-exocytotic, endocytic structures, and it is in these vacuoles that trypsin activation occurs (8).The association between alcohol abuse and acute pancreatitis is well known (1, 2, 9), but the exact mechanism by which alcohol initiates the disease is unclear. Hypertriglyceridemia is also a recognized cause of pancreatitis (10) and the presence of high concentrations of fatty acid ethyl esters [FAEEs, non-oxidative products of alcohol and fatty acids (FAs)], particularly in the pancreas, was reported in a postmortem study of subjects intoxicated by alcohol at the time of death (11). FAEEs induce trypsin activation and vacuole formation (12) and also elicit global sustained [Ca 2ϩ ] i elevations, due to e...

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Direct Activation of Cytosolic Ca2+ Signaling and Enzyme Secretion by Cholecystokinin in Human Pancreatic Acinar Cells

Cited by 145 publications

References 34 publications

Calmodulin protects against alcohol-induced pancreatic trypsinogen activation elicited via Ca ²⁺ release through IP ₃ receptors

Calmodulin protects against alcohol-induced pancreatic trypsinogen activation elicited via Ca ²⁺ release through IP ₃ receptors

Cellular and subcellular localization of cholecystokinin (CCK)-1 receptors in the pancreas, gallbladder, and stomach of mice

Pancreatic protease activation by alcohol metabolite depends on Ca ²⁺ release via acid store IP ₃ receptors

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Direct Activation of Cytosolic Ca2+ Signaling and Enzyme Secretion by Cholecystokinin in Human Pancreatic Acinar Cells

Cited by 145 publications

References 34 publications

Calmodulin protects against alcohol-induced pancreatic trypsinogen activation elicited via Ca 2+ release through IP 3 receptors

Calmodulin protects against alcohol-induced pancreatic trypsinogen activation elicited via Ca 2+ release through IP 3 receptors

Cellular and subcellular localization of cholecystokinin (CCK)-1 receptors in the pancreas, gallbladder, and stomach of mice

Pancreatic protease activation by alcohol metabolite depends on Ca 2+ release via acid store IP 3 receptors

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Calmodulin protects against alcohol-induced pancreatic trypsinogen activation elicited via Ca ²⁺ release through IP ₃ receptors

Calmodulin protects against alcohol-induced pancreatic trypsinogen activation elicited via Ca ²⁺ release through IP ₃ receptors

Pancreatic protease activation by alcohol metabolite depends on Ca ²⁺ release via acid store IP ₃ receptors