Ribosome-free Terminals of Rough ER Allow Formation of STIM1 Puncta and Segregation of STIM1 from IP3 Receptors

Lür, György; Haynes, Lee P.; Prior, Ian A.; Gerasimenko, Oleg Vsevolodovich; Feske, Stefan; Burgoyne, Robert D.; Tepikin, Alexei V.

doi:10.1016/j.cub.2009.07.072

Cited by 117 publications

(127 citation statements)

References 31 publications

(33 reference statements)

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“…The channels are activated and extracellular calcium is taken up from the extracelluar environment. This uptake sustains the elevated levels of intracellular calcium [34] . Importantly, it has been shown that a CRAC channel inhibitor, GSK-7975A, inhibited the calcium entry into acinar cells.…”

Section: Effects Of Ethanol On the Cellular Mobilization Of Calcium Amentioning

confidence: 88%

Alcoholic pancreatitis: New insights into the pathogenesis and treatment

Clemens

Schneider

Arkfeld

et al. 2016

WJGP

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Acute pancreatitis is a necro-inflammatory disease of the exocrine pancreas that is characterized by inappropriate activation of zymogens, infiltration of the pancreas by inflammatory cells, and destruction of the pancreatic exocrine cells. Acute pancreatitis can progress to a severe life-threatening disease. Currently there is no pharmacotherapy to prevent or treat acute pancreatitis. One of the more common factors associated with acute pancreatitis is alcohol abuse. Although commonly associated with pancreatitis alcohol alone is unable to cause pancreatitis. Instead, it appears that alcohol and its metabolic by-products predispose the pancreas to damage from agents that normally do not cause pancreatitis, or to more severe disease from agents that normally cause mild pancreatic damage. Over the last 10 to 20 years, a tremendous amount of work has defined a number of alcohol-mediated biochemical changes in pancreatic cells. Among these changes are: Sustained levels of intracellular calcium, activation of the mitochondrial permeability transition pore, endoplasmic reticulum stress, impairment in autophagy, alteration in the activity of transcriptional activators, and colocalization of lysosomal and pancreatic digestive enzymes. Elucidation of these changes has led to a deeper understanding of the mechanisms by which ethanol predisposes acinar cells to damage. This greater understanding has revealed a number of promising targets for therapeutic intervention. It is hoped that further investigation of these targets will lead to the development of pharmacotherapy that is effective in treating and preventing the progression of acute pancreatitis. Core tip: There is currently no specific pharmacotherapy for pancreatitis. Although ethanol abuse is commonly associated with both acute and chronic pancreatitis, ethanol does not itself cause pancreatitis. Instead it appears that ethanol and its metabolic by-products sensitize the pancreas to damage from other factors. Detailed understanding of the mechanisms by which ethanol sensitizes the pancreas to damage has identified a number of promising targets for therapy. It is hoped that further preclinical and clinical studies will lead to the development of successful treatment of both acute and chronic pancreatitis. REVIEWClemens DL, Schneider KJ, Arkfeld CK, Grode JR, Wells MA, Singh S. Alcoholic pancreatitis: New insights into the pathogenesis and treatment.

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Section: Effects Of Ethanol On the Cellular Mobilization Of Calcium Amentioning

confidence: 88%

Alcoholic pancreatitis: New insights into the pathogenesis and treatment

Clemens

Schneider

Arkfeld

et al. 2016

WJGP

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“…These peripheral puncta correspond at the ultrastructural level to specialized regions of smooth ER positioned within 10 -20 nm of the plasma membrane, known as ER-PM junctions (Fig. 1B) Lur et al 2009;Orci et al 2009). In Jurkat T cells expressing ER-targeted horseradish peroxidase, electron microscopic studies show that native ER-PM junctions cover ,5% of the cell surface .…”

Section: The Molecular Choreography Of Socementioning

confidence: 99%

Store-Operated Calcium Channels: New Perspectives on Mechanism and Function

Lewis¹

2011

Cold Spring Harbor Perspectives in Biology

177

201

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Store-operated calcium channels (SOCs) are a nearly ubiquitous Ca 2þ entry pathway stimulated by numerous cell surface receptors via the reduction of Ca 2þ concentration in the ER. The discovery of STIM proteins as ER Ca 2þ sensors and Orai proteins as structural components of the Ca 2þ release-activated Ca 2þ (CRAC) channel, a prototypic SOC, opened the floodgates for exploring the molecular mechanism of this pathway and its functions. This review focuses on recent advances made possible by the use of STIM and Orai as molecular tools. I will describe our current understanding of the store-operated Ca 2þ entry mechanism and its emerging roles in physiology and disease, areas of uncertainty in which further progress is needed, and recent findings that are opening new directions for research in this rapidly growing field.

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“…The molecular nature of these channels (Orai1) is now also known (15) and the link between Ca 2+ depletion of the ER and opening of the CRAC channels has been established: A reduction in the Ca 2+ concentration in the ER ([Ca 2+ ] ER ) causes translocation of a Ca 2+ -sensing protein, called STIM1, widely distributed in the ER membrane to so-called puncta in the ER close to the plasma membrane, where it can interact with and open Orai1 channels (16)(17)(18). This mechanism also operates in the pancreatic acinar cells, because stimulant-elicited release of Ca 2+ from the ER results in translocation of STIM1 to puncta close to the basolateral plasma membrane, specifically at locations where the ER is devoid of ribosomes and where interaction between STIM1 and Orai1 therefore occurs (19). Despite this, electrophysiological investigations of the currents evoked by Ca 2+ store depletion have so far failed to provide evidence for the existence in pancreatic acinar cells of Ca 2+ -selective currents of the CRAC type (20)(21)(22) originally discovered in mast cells (23), although activation of nonselective currents were shown (21,22).…”

mentioning

confidence: 99%

“…Despite this, electrophysiological investigations of the currents evoked by Ca 2+ store depletion have so far failed to provide evidence for the existence in pancreatic acinar cells of Ca 2+ -selective currents of the CRAC type (20)(21)(22) originally discovered in mast cells (23), although activation of nonselective currents were shown (21,22). Therefore, although the linkage between agonist-evoked Ca 2+ release from the ER and store-operated Ca 2+ entry, through STIM1 and Orai1, is established for the pancreatic acinar cells (19), there is uncertainty about the biophysical nature of the principal Ca 2+ entry channels. Endocytic Ca 2+ uptake (24) could also be important and does occur in pancreatic acinar cells (25).…”

mentioning

confidence: 99%

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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167

225

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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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Ribosome-free Terminals of Rough ER Allow Formation of STIM1 Puncta and Segregation of STIM1 from IP3 Receptors

Cited by 117 publications

References 31 publications

Alcoholic pancreatitis: New insights into the pathogenesis and treatment

Alcoholic pancreatitis: New insights into the pathogenesis and treatment

Store-Operated Calcium Channels: New Perspectives on Mechanism and Function

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

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Ribosome-free Terminals of Rough ER Allow Formation of STIM1 Puncta and Segregation of STIM1 from IP3 Receptors

Cited by 117 publications

References 31 publications

Alcoholic pancreatitis: New insights into the pathogenesis and treatment

Alcoholic pancreatitis: New insights into the pathogenesis and treatment

Store-Operated Calcium Channels: New Perspectives on Mechanism and Function

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

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Product

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