Calmodulin protects against alcohol-induced pancreatic trypsinogen activation elicited via Ca
            <sup>2+</sup>
            release through IP
            <sub>3</sub>
            receptors

Gerasimenko, Julia Vladimirovna; Lür, György; Ferdek, Paweł; Sherwood, Mark W.; Ebisui, Etsuko; Tepikin, Alexei V.; Mikoshiba, Katsuhiko; Petersen, O. H.; Gerasimenko, Oleg Vsevolodovich

doi:10.1073/pnas.1016534108

Cited by 49 publications

(65 citation statements)

References 48 publications

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“…4C). Similar levels of inhibition by GSK-7975A were observed in experiments assessing trypsin activity, using the specific trypsin substrate BZIPAR (10,28,29). Preincubation of pancreatic acinar cells with POAEE (100 μM for 1 h) induced substantial increase of trypsin activity (from 3.4 ± 0.5% of cells in control to 15 ± 1.1% in the POAEE-treated groups).…”

Section: Concentration Dependence Of the Acute Effects Of Gsk-7975a Osupporting

confidence: 53%

“…It could therefore be potentially advantageous to combine CRAC blockade with inhibition of Ca 2+ release from the internal stores using a synthetic membrane permeable calmodulin activator (29). Overall, our data provide a unique proof of principle that pharmacological CRAC channel inhibition could become an effective tool for reducing the cellular Ca 2+ overload that is such an important feature of the changes occurring in the initial phase of acute pancreatitis.…”

Section: Discussionmentioning

confidence: 76%

“…Although it has been known for 40 years that cytosolic Ca 2+ signals in pancreatic acinar cells are initiated by release from internal stores (5), it has also been recognized for a long time that following the initial release from the intracellular stores there is an important Ca 2+ entry phase that is essential for refilling the stores and indeed for stimulant-evoked enzyme secretion (48)(49)(50). Previous investigations have demonstrated that the most important mediators of acinar cell damage, namely alcohol, fatty acids, fatty acid ethyl esters, and bile acids all primarily release Ca 2+ from various internal stores (28,29,37,42,43,51), but that this initial phase is followed by store-operated Ca 2+ entry, which plays a crucial role in the destruction of the cells (2,4,5,10). Our electrophysiological data (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Endocytic Ca 2+ uptake (24) could also be important and does occur in pancreatic acinar cells (25). It is also the case that there are important intracellular Ca 2+ stores (acid) outside the ER (4,(26)(27)(28)(29). Ca 2+ release from acid storeslocated in ZGs, endosomes, and lysosomes-plays a crucial role in intracellular trypsinogen activation elicited by alcohol and fatty acid ethyl esters in experiments on permeabilized pancreatic acinar cells (28,29), and trypsinogen activation induced by hyperstimulation occurs in postexocytotic endocytic (and acid) structures (25).…”

mentioning

confidence: 99%

“…It is also the case that there are important intracellular Ca 2+ stores (acid) outside the ER (4,(26)(27)(28)(29). Ca 2+ release from acid storeslocated in ZGs, endosomes, and lysosomes-plays a crucial role in intracellular trypsinogen activation elicited by alcohol and fatty acid ethyl esters in experiments on permeabilized pancreatic acinar cells (28,29), and trypsinogen activation induced by hyperstimulation occurs in postexocytotic endocytic (and acid) structures (25). In view of the complexities of pancreatic acinar cell Ca 2+ signaling in physiology and pathology and, in particular, the uncertainty about the nature of the Ca 2+ entry pathways, it is unknown whether blockade of Ca 2+ -selective CRAC channels could in principle be effective as therapy against acute pancreatitis.…”

mentioning

confidence: 99%

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Ca ²⁺ release-activated Ca ²⁺ channel blockade as a potential tool in antipancreatitis therapy

Gerasimenko

Gryshchenko

Ferdek

et al. 2013

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

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Alcohol-related acute pancreatitis can be mediated by a combination of alcohol and fatty acids (fatty acid ethyl esters) and is initiated by a sustained elevation of the Ca 2+ concentration inside pancreatic acinar cells ([Ca 2+ ] i ), due to excessive release of Ca 2+ stored inside the cells followed by Ca 2+ entry from the interstitial fluid. The sustained [Ca 2+ ] i elevation activates intracellular digestive proenzymes resulting in necrosis and inflammation. We tested the hypothesis that pharmacological blockade of store-operated or Ca 2+ release-activated Ca 2+ channels (CRAC) would prevent sustained elevation of [Ca 2+ ] i and therefore protease activation and necrosis. In isolated mouse pancreatic acinar cells, CRAC channels were activated by blocking Ca 2+ ATPase pumps in the endoplasmic reticulum with thapsigargin in the absence of external Ca 2+ . Ca 2+ entry then occurred upon admission of Ca 2+ to the extracellular solution. The CRAC channel blocker developed by GlaxoSmithKline, GSK-7975A, inhibited store-operated Ca 2+ entry in a concentrationdependent manner within the range of 1 to 50 μM (IC 50 = 3.4 μM), but had little or no effect on the physiological Ca 2+ spiking evoked by acetylcholine or cholecystokinin. Palmitoleic acid ethyl ester (100 μM), an important mediator of alcohol-related pancreatitis, evoked a sustained elevation of [Ca 2+ ] i , which was markedly reduced by CRAC blockade. Importantly, the palmitoleic acid ethyl ester-induced trypsin and protease activity as well as necrosis were almost abolished by blocking CRAC channels. There is currently no specific treatment of pancreatitis, but our data show that pharmacological CRAC blockade is highly effective against toxic [Ca 2+ ] i elevation, necrosis, and trypsin/protease activity and therefore has potential to effectively treat pancreatitis.capacitative Ca 2+ entry | alcohol metabolite | pancreas | hepatocyte Ca 2+ entry | AR42JA cute pancreatitis is a human disease mostly caused by alcohol abuse or complications from biliary disease. In this disease, against which there is currently no effective therapy, digestive proenzymes are prematurely activated inside the acinar cells leading to autodigestion and necrosis (1-3). Intracellular Ca 2+ plays a critical role in the initiation of this disease process (2-4), but intracellular Ca 2+ also plays a critical role in the physiological regulation of the normal exocytotic secretion of the digestive proenzymes (5).The pancreatic acinar cells are capable of generating multiple patterns of cytosolic Ca 2+ signals depending on the type and concentration of the stimulating agent (5). The physiological Ca 2+ signals regulating secretion-evoked by the neurotransmitter acetylcholine (ACh) or the hormone cholecystokinin (CCK)-consist of repetitive short-lasting rises in the cytosolic Ca 2+ concentration ([Ca 2+ ] i ). These are mostly confined to the apical area, in which the secretory (zymogen) granules (ZGs) are concentrated, by a belt of perigranular mitochondria operating as a firewall against...

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Section: Concentration Dependence Of the Acute Effects Of Gsk-7975a Osupporting

confidence: 53%

Section: Discussionmentioning

confidence: 76%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Ca ²⁺ release-activated Ca ²⁺ channel blockade as a potential tool in antipancreatitis therapy

Gerasimenko

Gryshchenko

Ferdek

et al. 2013

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

Self Cite

171

225

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Monitoring of intra‐ER free Ca²⁺

Gerasimenko

2014

WIREs Membr Transp Signal

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The importance of calcium signaling in cell health and disease is the major driving force in current research of intracellular calcium homeostasis. Ca2+ release from the endoplasmic reticulum (ER) and other calcium stores seems to be the crucial factor in the activation of many cellular functions. Significant changes in ER Ca2+ content and dynamics have been implicated in the activation of the ER stress response, abnormal autophagy, and cell death which leads to a variety of pathological conditions. For example, in acute pancreatitis, an inflammatory disease of the exocrine pancreas caused primarily by bile stones or alcohol, excessive intracellular calcium overload due to Ca2+ release from internal stores followed by store operated Ca2+ entry (SOCE) leads to the premature activation of digestive proenzymes within pancreatic acinar cells. Recent data show that SOCE channel blockers are capable of substantially reducing the intracellular Ca2+ overload and subsequent cell necrosis without major alteration of ER Ca2+ content. We also demonstrate here that indirect ER measurements can be misleading and only direct intra‐ER Ca2+ monitoring offers reliable conclusions. In this respect, it is essential to summarize the methods available and provide examples of direct measurements of free Ca2+ concentration [Ca2+] in the ER lumen in pancreatic acinar cells. This article is aimed at highlighting the major techniques for monitoring ER Ca2+ with reference to their advantages, limitations, and views for future improvements. WIREs Membr Transp Signal 2014,3:63–71. doi: 10.1002/wmts.106 For further resources related to this article, please visit the http://wires.wiley.com/remdoi.cgi?doi=10.1002/wmts.106. Conflict of interest: The authors have declared no conflicts of interest for this article.

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The Exocrine Pancreas: The Acinar-Ductal Tango in Physiology and Pathophysiology

Hegyi

Petersen

2013

Reviews of Physiology, Biochemistry and Pharmacology

103

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There are many reviews of pancreatic acinar cell function and also of pancreatic duct function, but there is an almost total absence of synthetic reviews bringing the integrated functions of these two vitally and mutually interdependent cells together. This is what we have attempted to do in this chapter. In the first part, we review the normal integrated function of the acinar-ductal system, with particular emphasis on how regulation of one type of cell also influences the other cell type. In the second part, we review a range of pathological processes, particularly those involved in acute pancreatitis (AP), an often-fatal human disease in which the pancreas digests itself, in order to explore how malfunction of one of the cell types adversely affects the function of the other.

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

Cited by 49 publications

References 48 publications

Ca ²⁺ release-activated Ca ²⁺ channel blockade as a potential tool in antipancreatitis therapy

Ca ²⁺ release-activated Ca ²⁺ channel blockade as a potential tool in antipancreatitis therapy

Monitoring of intra‐ER free Ca²⁺

The Exocrine Pancreas: The Acinar-Ductal Tango in Physiology and Pathophysiology

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

Cited by 49 publications

References 48 publications

Ca 2+ release-activated Ca 2+ channel blockade as a potential tool in antipancreatitis therapy

Ca 2+ release-activated Ca 2+ channel blockade as a potential tool in antipancreatitis therapy

Monitoring of intra‐ER free Ca2+

The Exocrine Pancreas: The Acinar-Ductal Tango in Physiology and Pathophysiology

Contact Info

Product

Resources

About

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

Ca ²⁺ release-activated Ca ²⁺ channel blockade as a potential tool in antipancreatitis therapy

Ca ²⁺ release-activated Ca ²⁺ channel blockade as a potential tool in antipancreatitis therapy

Monitoring of intra‐ER free Ca²⁺