scholarly journals The p.E152K-STIM1 mutation deregulates Ca2+ signaling contributing to chronic pancreatitis

2021 ◽  
Vol 134 (3) ◽  
pp. jcs244012 ◽  
Author(s):  
Miguel Burgos ◽  
Reginald Philippe ◽  
Fabrice Antigny ◽  
Paul Buscaglia ◽  
Emmanuelle Masson ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Chronic Pancreatitis ◽  
Acinar Cells ◽  
Pancreatic Acinar Cells ◽  
Endoplasmic Reticulum Calcium ◽  
Ef Hand ◽  
Pump Activity ◽  
Intracellular Ca ◽  
Serca Pump ◽  
Main Regulator

ABSTRACTSince deregulation of intracellular Ca2+ can lead to intracellular trypsin activation, and stromal interaction molecule-1 (STIM1) protein is the main regulator of Ca2+ homeostasis in pancreatic acinar cells, we explored the Ca2+ signaling in 37 STIM1 variants found in three pancreatitis patient cohorts. Extensive functional analysis of one particular variant, p.E152K, identified in three patients, provided a plausible link between dysregulated Ca2+ signaling within pancreatic acinar cells and chronic pancreatitis susceptibility. Specifically, p.E152K, located within the STIM1 EF-hand and sterile α-motif domain, increased the release of Ca2+ from the endoplasmic reticulum in patient-derived fibroblasts and transfected HEK293T cells. This event was mediated by altered STIM1–sarco/endoplasmic reticulum calcium transport ATPase (SERCA) conformational change and enhanced SERCA pump activity leading to increased store-operated Ca2+ entry (SOCE). In pancreatic AR42J cells expressing the p.E152K variant, Ca2+ signaling perturbations correlated with defects in trypsin activation and secretion, and increased cytotoxicity after cholecystokinin stimulation.This article has an associated First Person interview with the first author of the paper.

scholarly journals p.E152K-STIM1 mutation deregulates Ca2+ signaling contributing to chronic pancreatitis

2020 ◽  
Author(s):  
Miguel Burgos ◽  
Reginald Philippe ◽  
Fabrice Antigny ◽  
Paul Buscaglia ◽  
Emmanuelle Masson ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Chronic Pancreatitis ◽  
Acinar Cells ◽  
Pancreatic Acinar Cell ◽  
Pancreatic Acinar Cells ◽  
Endoplasmic Reticulum Calcium ◽  
Store Operated Calcium Entry ◽  
Intracellular Ca ◽  
Intracellular Changes ◽  
Main Regulator

ABSTRACTSince deregulation of intracellular Ca2+ can lead to intracellular trypsin activation and STIM1 (stromal interaction molecule-1) protein is the main regulator of Ca2+ homeostasis in pancreatic acinar cells, we explored the Ca2+ signaling in 37 STIM1 variants found in three pancreatitis patient cohorts. Extensive functional analysis of one particular variant, p.E152K, identified in three patients, provided a plausible link between dysregulated Ca2+ signaling within pancreatic acinar cells and chronic pancreatitis susceptibility. Specifically, p.E152K, located within the STIM1 EF-hand and sterile α-motif domain, increased the release of Ca2+ from the endoplasmic reticulum in patient-derived fibroblasts and transfected HEK293T cells. This event was mediated by altered STIM1-sarco/endoplasmic reticulum calcium transport ATPase (SERCA) interactions and enhanced SERCA pump activity leading to increased Store Operated Calcium Entry (SOCE). In the pancreatic AR42J cells expressing the p.E152K variant, Ca2+-signaling perturbations correlated with defects in trypsin activation and secretion, and increased cytotoxicity after cholecystokinin stimulation.Summary statementp.E152K-STIM1 variant found in pancreatitis patients leads to intracellular changes in calcium homeostasis through SERCA interaction, enabling intracellular trypsin activation and pancreatic acinar cell death.

Partial inhibition of SERCA is responsible for extracellular Ca2+ dependence of AlF–4-induced [Ca2+]i oscillations in rat pancreatic

2003 ◽  
Vol 285 (5) ◽  
pp. C1142-C1149 ◽  
Author(s):  
Seon Ah Chong ◽  
Soo Young Hong ◽  
Seok Jun Moon ◽  
Jee Won Park ◽  
Jeong-Hee Hong ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
G Proteins ◽  
Acinar Cells ◽  
Cell Types ◽  
Pancreatic Acinar Cells ◽  
Protein Activation ◽  
Partial Inhibition ◽  
G Protein Activation ◽  
Inositol 1,4,5 Trisphosphate ◽  
Intracellular Ca

AlF4-is known to generate oscillations in intracellular Ca2+ concentration ([Ca2+]i) by activating G proteins in many cell types. However, in rat pancreatic acinar cells, AlF4--evoked [Ca2+]i oscillations were reported to be dependent on extracellular Ca2+, which contrasts with the [Ca2+]i oscillations induced by cholecystokinin (CCK). Therefore, we investigated the mechanisms by which AlF4- generates extracellular Ca2+-dependent [Ca2+]i oscillations in rat pancreatic acinar cells. AlF4--induced [Ca2+]i oscillations were stopped rapidly by the removal of extracellular Ca2+ and were abolished on the addition of 20 mM caffeine and 2 μM thapsigargin, indicating that Ca2+ influx plays a crucial role in maintenance of the oscillations and that an inositol 1,4,5-trisphosphate-sensitive Ca2+ store is also required. The amount of Ca2+ in the intracellular Ca2+ store was decreased as the AlF4--induced [Ca2+]i oscillations continued. Measurement of 45Ca2+ influx into isolated microsomes revealed that AlF4-directly inhibited sarco/endoplasmic reticulum Ca2+-ATPase (SERCA). The activity of plasma membrane Ca2+-ATPase during AlF4- stimulation was not significantly different from that during CCK stimulation. After partial inhibition of SERCA with 1 nM thapsigargin, 20 pM CCK-evoked [Ca2+]i oscillations were dependent on extracellular Ca2+. This study shows that AlF4- induces [Ca2+]i oscillations, probably by inositol 1,4,5-trisphosphate production via G protein activation but that these oscillations are strongly dependent on extracellular Ca2+ as a result of the partial inhibition of SERCA.

scholarly journals Transgenic expression of cyclooxygenase-2 in pancreatic acinar cells induces chronic pancreatitis

2019 ◽  
Vol 316 (1) ◽  
pp. G179-G186
Author(s):  
Haojie Huang ◽  
Jiaxiang Chen ◽  
Lisi Peng ◽  
Yao Yao ◽  
Defeng Deng ◽  
...  
Keyword(s):  
Chronic Pancreatitis ◽  
Transgenic Mice ◽  
Fibrous Tissue ◽  
Acinar Cells ◽  
Cyclooxygenase 2 ◽  
Therapeutic Interventions ◽  
Pancreatic Stellate Cells ◽  
Pancreatic Acinar Cells ◽  
Transgenic Expression ◽  
Cox 2

Replacement of the exocrine parenchyma by fibrous tissue is a main characteristic of chronic pancreatitis. Understanding the mechanisms of pancreatic fibrogenesis is critical for the development of preventive and therapeutic interventions. Cyclooxygenase-2 (COX-2), a rate-limiting enzyme for prostaglandin synthesis, is expressed in patients with chronic pancreatitis. However, it is unknown whether COX-2 can cause chronic pancreatitis. To investigate the roles of pancreatic acinar COX-2 in fibrogenesis and the development of chronic pancreatitis, COX-2 was ectopically expressed specifically in pancreatic acinar cells in transgenic mice. Histopathological changes and expression levels of several profibrogenic factors related to chronic pancreatitis were evaluated. COX-2 was expressed in the pancreas of the transgenic mice, as detected by Western blot analysis. Immunohistochemical staining showed COX-2 was specifically expressed in pancreatic acinar cells. COX-2 expression led to progressive changes in the pancreas, including pancreas megaly, persistent inflammation, collagen deposition, and acinar-to-ductal metaplasia. Quantitative RT-PCR and immunostaining showed that profibrogenic factors were upregulated and pancreatic stellate cells were activated in the COX-2 transgenic mice. Expression of COX-2 in pancreatic acinar cells is sufficient to induce chronic pancreatitis. Targeting this pathway may be valuable in the prevention of chronic pancreatitis. NEW & NOTEWORTHY COX-2 expression is observed in pancreatic tissues of human chronic pancreatitis. In this study, we showed that COX-2 expression caused the development of chronic pancreatitis in transgenic mice, supporting the idea that COX-2 inhibition may be an effective preventive and therapeutic strategy.

scholarly journals Increased Chromogranin A–Positive Hormone-Negative Cells in Chronic Pancreatitis

2018 ◽  
Vol 103 (6) ◽  
pp. 2126-2135 ◽  
Author(s):  
Abu Saleh Md Moin ◽  
Megan Cory ◽  
Jennifer Choi ◽  
Allison Ong ◽  
Sangeeta Dhawan ◽  
...  
Keyword(s):  
Chronic Pancreatitis ◽  
Chromogranin A ◽  
Endocrine Cells ◽  
Acinar Cells ◽  
Pancreatic Acinar Cells ◽  
Cell Regeneration ◽  
Inflammation Marker ◽  
Β Cells ◽  
Cell Frequency ◽  
Endogenous Expression

Abstract Context Chronic pancreatitis (CP) is characterized by inflammation, fibrosis, and a loss of pancreatic acinar cells, which can result in exocrine and eventually endocrine deficiency. Pancreatitis has been reported to induce formation of new endocrine cells (neogenesis) in mice. Our recent data have implicated chromogranin A–positive hormone-negative (CPHN) cells as potential evidence of neogenesis in humans. Objective We sought to establish if CPHN cells were more abundant in CP in humans. Design, Setting, and Participants We investigated the frequency and distribution of CPHN cells and the expression of the chemokine C-X-C motif ligand 10 (CXCL10) and its receptor chemokine C-X-C motif receptor 3 in pancreas of nondiabetic subjects with CP. Results CPHN cell frequency in islets was increased sevenfold in CP [2.1% ± 0.67% vs 0.35% ± 0.09% CPHN cells in islets, CP vs nonpancreatitis (NP), P < 0.01], as were the CPHN cells found as scattered cells in the exocrine areas (17.4 ± 2.9 vs 4.2 ± 0.6, CP vs NP, P < 0.001). Polyhormonal endocrine cells were also increased in CP (2.7 ± 1.2 vs 0.1 ± 0.04, CP vs NP, % of polyhormonal cells of total endocrine cells, P < 0.01), as was expression of CXCL10 in α and β cells. Conclusion There is increased islet endogenous expression of the inflammation marker CXCL10 in islets in the setting of nondiabetic CP and an increase in polyhormonal (insulin-glucagon expressing) cells. The increase in CPHN cells in CP, often in a lobular distribution, may indicate foci of attempted endocrine cell regeneration.

scholarly journals Redox-assisted regulation of Ca2+ homeostasis in the endoplasmic reticulum by disulfide reductase ERdj5

2016 ◽  
Vol 113 (41) ◽  
pp. E6055-E6063 ◽  
Author(s):  
Ryo Ushioda ◽  
Akitoshi Miyamoto ◽  
Michio Inoue ◽  
Satoshi Watanabe ◽  
Masaki Okumura ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Disulfide Bond ◽  
Plasma Membranes ◽  
Dependent Manner ◽  
Cellular Functions ◽  
Endoplasmic Reticulum Calcium ◽  
Disulfide Reductase ◽  
Intracellular Ca ◽  
Activity Dependent ◽  
Er Calcium

Calcium ion (Ca2+) is an important second messenger that regulates numerous cellular functions. Intracellular Ca2+ concentration ([Ca2+]i) is strictly controlled by Ca2+ channels and pumps on the endoplasmic reticulum (ER) and plasma membranes. The ER calcium pump, sarco/endoplasmic reticulum calcium ATPase (SERCA), imports Ca2+ from the cytosol into the ER in an ATPase activity-dependent manner. The activity of SERCA2b, the ubiquitous isoform of SERCA, is negatively regulated by disulfide bond formation between two luminal cysteines. Here, we show that ERdj5, a mammalian ER disulfide reductase, which we reported to be involved in the ER-associated degradation of misfolded proteins, activates the pump function of SERCA2b by reducing its luminal disulfide bond. Notably, ERdj5 activated SERCA2b at a lower ER luminal [Ca2+] ([Ca2+]ER), whereas a higher [Ca2+]ER induced ERdj5 to form oligomers that were no longer able to interact with the pump, suggesting [Ca2+]ER-dependent regulation. Binding Ig protein, an ER-resident molecular chaperone, exerted a regulatory role in the oligomerization by binding to the J domain of ERdj5. These results identify ERdj5 as one of the master regulators of ER calcium homeostasis and thus shed light on the importance of cross talk among redox, Ca2+, and protein homeostasis in the ER.

scholarly journals Icariin Promote Stem Cells Regeneration and Repair Acinar Cells in L-arginine / Radiation -Inducing Chronic Pancreatitis in Rats

Dose-Response ◽  
2020 ◽  
Vol 18 (4) ◽  
pp. 155932582097081
Author(s):  
Enas M. Moustafa ◽  
Fatma S. M. Moawed ◽  
Gehan R. Abdel-Hamid
Keyword(s):  
Chronic Pancreatitis ◽  
Hedgehog Signaling ◽  
Histopathological Examination ◽  
Acinar Cells ◽  
Pancreatic Acinar Cells ◽  
Myeloperoxidase Activity ◽  
Significant Amelioration ◽  
Gli 1 ◽  
Patched 1

Objective: Chronic Pancreatitis (CP) is a multifactorial disease. It was characterized by severe inflammation and acinar cell destruction. Thus, the present study was initiated to evaluating the ability of bone marrow-based mesenchymal stem cell (MSCs) combined with Icariin to restore and regenerate acinar cells in the pancreas of rats suffering chronic pancreatitis. Methods: Chronic pancreatitis was induced in rats via both L-arginine plus radiation, repeated L-arginine injection (2.5g/Kg body-weight, 1, 4,7,10,13,16,19 days), then, on day 21, rats were exposed to a single dose of gamma-radiation (6 Gy), which exacerbate injury of pancreatic acinar cells. One day after irradiation, rats were treated with either MSCs (1 × 107 /rat, once, tail vein injection) labeled PKH26 fluorescent linker dye and/or Icariin (100 mg/Kg, daily, orally) for 8 weeks. Results: Icariin promotes MSCs proliferation boosting its productivity in vitro. MSCs, and/or icariin treatments has regulated molecular factors TGF-β/PDGF and promoted the regeneration of pancreatic tissues by releasing PDX-1 and MafA involved in the recruitment of stem/progenitor cell in the tissue, and confirmed by histopathological examination. Moreover, a significant decrease in IL-8 and TNF-α cytokines with significant amelioration of myeloperoxidase activity were noted. As well as, reduction in MCP-1 and collagen type-1 levels along with Hedgehog signaling down-regulating expression in such cells, Patched-1, Smoothened, and GLi-1. Conclusion: The potent bioactive therapeutic Icariin combined with MSCs induces a significantly greater improvement, compared to each therapy alone.

794e Lack of Basal Autophagy in Pancreatic Acinar Cells Develops Chronic Pancreatitis in Mice

2014 ◽  
Vol 146 (5) ◽  
pp. S-138
Author(s):  
Kiyoshi Iwahashi ◽  
Hayato Hikita ◽  
Minoru Shigekawa ◽  
Kenji Ikezawa ◽  
Satoshi Shimizu ◽  
...  
Keyword(s):  
Chronic Pancreatitis ◽  
Acinar Cells ◽  
Pancreatic Acinar Cells

Visualizing formation and dynamics of vacuoles in living cells using contrasting dextran-bound indicator: endocytic and nonendocytic vacuoles

2007 ◽  
Vol 293 (6) ◽  
pp. G1333-G1338 ◽  
Author(s):  
Svetlana G. Voronina ◽  
Mark W. Sherwood ◽  
Oleg V. Gerasimenko ◽  
Ole H. Petersen ◽  
Alexei V. Tepikin
Keyword(s):  
Endoplasmic Reticulum ◽  
Confocal Microscopy ◽  
Acinar Cells ◽  
Cell Types ◽  
Living Cells ◽  
Pancreatic Acinar Cells ◽  
Extracellular Solution ◽  
Whole Cell Patch Clamp ◽  
Patch Pipette ◽  
Cellular Organelles

Here we describe a technique that allows us to visualize in real time the formation and dynamics (fusion, changes of shape, and translocation) of vacuoles in living cells. The technique involves infusion of a dextran-bound fluorescent probe into the cytosol of the cell via a patch pipette, using the whole-cell patch-clamp configuration. Experiments were conducted on pancreatic acinar cells stimulated with supramaximal concentrations of cholecystokinin (CCK). The vacuoles, forming in the cytoplasm of the cell, were revealed as dark imprints on a bright fluorescence background, produced by the probe and visualized by confocal microscopy. A combination of two dextran-bound probes, one infused into the cytosol and the second added to the extracellular solution, was used to identify endocytic and nonendocytic vacuoles. The cytosolic dextran-bound probe was also used together with a Golgi indicator to illustrate the possibility of combining the probes and identifying the localization of vacuoles with respect to other cellular organelles in pancreatic acinar cells. Combinations of cytosolic dextran-bound probes with endoplasmic reticulum (ER) or mitochondrial probes were also used to simultaneously visualize vacuoles and corresponding organelles. We expect that the new technique will also be applicable and useful for studies of vacuole dynamics in other cell types.

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