Store-operated CRAC channels: function in health and disease

Parekh, Anant B.

doi:10.1038/nrd3136

Cited by 287 publications

(306 citation statements)

References 127 publications

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“…However, there is no doubt that much remains to be understood about STIM1 and SOCE in the heart, including how Ca 2ϩ influx through this pathway is segregated from large beat-to-beat changes in cytosolic Ca 2ϩ required for EC coupling and the extent to which SOCE is involved in regulating basal cardiomyocyte Ca 2ϩ homeostasis. A key limitation in the study of SOCE in general and more specifically STIM1-mediated SOCE is the lack of specificity of currently available pharmacological inhibitors (85). There are some recent studies examining derivatives of 2-ABP in SOCE inhibition, but there was no evaluation as to selectivity relative to other calcium entry pathways (32), which would be essential for use in cardiomyocytes.…”

Section: Discussionmentioning

confidence: 99%

STIM1/Orai1-mediated SOCE: current perspectives and potential roles in cardiac function and pathology

Collins

Zhu-Mauldin

Marchase

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

111

102

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Collins HE, Zhu-Mauldin X, Marchase RB, Chatham JC. STIM1/Orai1-mediated SOCE: current perspectives and potential roles in cardiac function and pathology. Am J Physiol Heart Circ Physiol 305: H446 -H458, 2013. First published June 21, 2013 doi:10.1152/ajpheart.00104.2013.-Store-operated Ca 2ϩ entry (SOCE) is critical for Ca 2ϩ signaling in nonexcitable cells; however, its role in the regulation of cardiomyocyte Ca 2ϩ homeostasis has only recently been investigated. The increased understanding of the role of stromal interaction molecule 1 (STIM1) in regulating SOCE combined with recent studies demonstrating the presence of STIM1 in cardiomyocytes provides support that this pathway co-exists in the heart with the more widely recognized Ca 2ϩ handling pathways associated with excitation-contraction coupling. There is now substantial evidence that STIM1-mediated SOCE plays a key role in mediating cardiomyocyte hypertrophy, both in vitro and in vivo, and there is growing support for the contribution of SOCE to Ca 2ϩ overload associated with ischemia/reperfusion injury. Here, we provide an overview of our current understanding of the molecular regulation of SOCE and discuss the evidence supporting the role of STIM1/Orai1-mediated SOCE in regulating cardiomyocyte function.store-operated Ca 2ϩ entry; stromal interaction molecule 1; orai1; cardiomyocytes STORE-OPERATED CA 2ϩ ENTRY (SOCE), also known as capacitative calcium entry (CCE), is the major mechanism of Ca 2ϩ entry in nearly all nonexcitable cells (97, 99). In addition, it is increasingly recognized to co-exist with voltage-gated Ca 2ϩ channels in excitable cells, including neurons, skeletal muscle cells, and cardiomyocytes (1,38,45,83,121). In response to inositol 1,4,5-triphosphate (IP 3 )-(43) or ryanodine receptor (RyR)-mediated (3) Ca 2ϩ release from ER/SR stores, SOCE facilitates the influx of Ca 2ϩ from the extracellular space, resulting in a sustained increase in cytosolic Ca 2ϩ levels. Thus, although one of the roles of SOCE is to rapidly refill the depleted ER/SR stores, the subsequent sustained increase in cytosolic Ca 2ϩ also regulates numerous gene transcription pathways (33,50,151). Indeed, aberrant SOCE has been observed in a growing number of diseases including severe combined immunodeficiency, acute pancreatitis, and Alzheimer's disease (86).The integration of SOCE into well-established models of Ca 2ϩ homeostasis was hampered for many years by the lack of specific molecular mediators; even as recently as 2004 there was considerable controversy as to the specific mechanisms regulating SOCE (90, 113). However, in 2005, stromal interaction molecule 1 (STIM1) was found to localize to the ER/SR membrane and shown to function as a primary mediator of SOCE (54, 102). The putative physiological and pathophysiological roles of SOCE and STIM1 that have been identified to date are summarized in Table 1. A number of studies have recently reported the presence of STIM1 in adult cardiomyocytes (37,59,153), and consistent with earlier evidence supporting a rol...

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Section: Discussionmentioning

confidence: 99%

STIM1/Orai1-mediated SOCE: current perspectives and potential roles in cardiac function and pathology

Collins

Zhu-Mauldin

Marchase

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

111

102

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“…This agent has recently been shown to block Ca 2+ currents through CRAC channels in human lung mast cells, T cells, and platelets (31)(32)(33)(34). The CRAC channel is emerging as a potentially important therapeutic target in a number of human diseases (52,53) and could also be important for pancreatitis (54). We have therefore used GSK-7975A (33,34), to inhibit storeoperated Ca 2+ entry in pancreatic acinar cells.…”

Section: Discussionmentioning

confidence: 99%

“…However, the effects are likely to be strongest in those cell types (like the pancreatic acinar cells) in which other types of Ca 2+ entry pathways are not quantitatively important, unlike the many types of electrically excitable cells. Mast cells and T cells, for example, will be affected by CRAC blockade (31,34,52,53), but this will be advantageous in the treatment of acute pancreatitis, where the initial damage of the acinar cells leading to necrosis is followed by a strong inflammatory response, which is known to cause very significant further damage (1). CRAC blockade would have the most pronounced effect on cells with the most strongly activated Ca 2+ entry channels, which, in cases of life-threatening severe pancreatitis, would be the pancreatic acinar cells.…”

Section: Discussionmentioning

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.

171

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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“…[8][9][10]. The transmembrane ER proteins STIM1 and STIM2 detect ER Ca 2+ content through an EF-hand domain in their respective N-termini, which face the lumen of the store.…”

mentioning

confidence: 99%

Different agonists recruit different stromal interaction molecule proteins to support cytoplasmic Ca ²⁺ oscillations and gene expression

Kar

Bakowski

Capite

et al. 2012

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

Self Cite

100

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Stimulation of cells with physiological concentrations of calciummobilizing agonists often results in the generation of repetitive cytoplasmic Ca 2+ oscillations. Although oscillations arise from regenerative Ca 2+ release, they are sustained by store-operated Ca 2+ entry through Ca 2+ release-activated Ca 2+ (CRAC) channels. Here, we show that following stimulation of cysteinyl leukotriene type I receptors in rat basophilic leukemia (RBL)-1 cells, large amplitude Ca 2+ oscillations, CRAC channel activity, and downstream Ca 2+ -dependent nuclear factor of activated T cells (NFAT)-driven gene expression are all exclusively maintained by the endoplasmic reticulum Ca 2+ sensor stromal interaction molecule (STIM) 1. However, stimulation of tyrosine kinase-coupled FCεRI receptors evoked Ca 2+ oscillations and NFAT-dependent gene expression through recruitment of both STIM2 and STIM1. We conclude that different agonists activate different STIM proteins to sustain Ca 2+ signals and downstream responses.excitation-transcription coupling | transcription S timulation of cell-surface receptors that couple to the phospholipase C pathway with physiological concentrations of agonist generally evokes repetitive cytoplasmic Ca 2+ oscillations (1). Oscillatory Ca 2+ signals enable cytoplasmic Ca 2+ to reach high levels transiently, thereby avoiding the deleterious effects of a prolonged, elevated Ca 2+ rise. Information is encoded in the oscillatory amplitude and frequency (2) and the spatial profile of the Ca 2+ signal (3), each of which can be deciphered by cells to drive selective downstream responses.Ca 2+ oscillations are triggered by inositol trisphosphate (InsP 3 )-mediated Ca 2+ release from intracellular Ca 2+ stores, primarily the endoplasmic reticulum (ER) (2). The resulting fall in Ca 2+ within the stores opens store-operated CRAC channels in the plasma membrane (4, 5). Ca 2+ entry through these channels refills the stores and, thus, sustains InsP 3 -dependent Ca 2+ oscillations (6). In addition to this supportive role, local Ca 2+ entry through Ca 2+ release-activated Ca 2+ (CRAC) channels during oscillatory responses in mast cells, and not the oscillations per se, signals to the nucleus to regulate Ca 2+ -dependent gene expression (7).The two main molecular components of store-operated Ca 2+ entry are the stromal interaction molecule (STIM) and Orai proteins (reviewed in refs. 8-10). The transmembrane ER proteins STIM1 and STIM2 detect ER Ca 2+ content through an EF-hand domain in their respective N-termini, which face the lumen of the store. Loss of luminal Ca 2+ leads to STIM aggregation within the ER followed by migration to ER-plasma membrane junctions located just below the plasma membrane. Here, they bind to and activate Orai1, a four transmembrane domain spanning plasma membrane protein, which forms the CRAC channel.Despite significant homology between STIM1 and STIM2, there are some important differences between them. First, they differ in their respective abilities to activate Orai1. STIM2 activates Ca 2+ ...

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Store-operated CRAC channels: function in health and disease

Cited by 287 publications

References 127 publications

STIM1/Orai1-mediated SOCE: current perspectives and potential roles in cardiac function and pathology

STIM1/Orai1-mediated SOCE: current perspectives and potential roles in cardiac function and pathology

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

Different agonists recruit different stromal interaction molecule proteins to support cytoplasmic Ca ²⁺ oscillations and gene expression

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Store-operated CRAC channels: function in health and disease

Cited by 287 publications

References 127 publications

STIM1/Orai1-mediated SOCE: current perspectives and potential roles in cardiac function and pathology

STIM1/Orai1-mediated SOCE: current perspectives and potential roles in cardiac function and pathology

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

Different agonists recruit different stromal interaction molecule proteins to support cytoplasmic Ca 2+ oscillations and gene expression

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Product

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

Different agonists recruit different stromal interaction molecule proteins to support cytoplasmic Ca ²⁺ oscillations and gene expression