ArticleGastroenterology2015
Inhibitors of ORAI1 Prevent Cytosolic Calcium-Associated Injury of Human Pancreatic Acinar Cells and Acute Pancreatitis in 3 Mouse Models.
Article in Gastroenterology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 126 papers, 1 of them a synthesis that pooled it.
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Who cites it
126 citing papers in PubMed, 1 synthesis or guideline pooled it, 227 citations in OpenAlex.
- Experimental Acute Pancreatitis Models: History, Current Status, and Role in Translational Research.Frontiers in physiology · 2020Pooled it
- Auxora versus standard of care for the treatment of severe or critical COVID-19 pneumonia: results from a randomized controlled trial.Critical care (London, England) · 2020Trial
- Mechanistic insights into Orai dynamics during pore opening.Channels (Austin, Tex.) · 2026Review
- Breaking the Calcium Overload Cycle in Acute Pancreatitis: Emerging Pharmacological Strategies.Digestive diseases and sciences · 2026Review
- CRAC channels as targets for immunotherapy.Current opinion in immunology · 2026Review
- BCL2 inhibition in acute and chronic pancreatitis - is there a therapeutic perspective?Cell death discovery · 2026Review
- Zegocractin for acute pancreatitis with systemic inflammatory response syndrome: a randomized, controlled, dose-ranging, phase 2b trial.EClinicalMedicine · 2026Article
- From single-pathway cascade to network pathophysiology: how genetically engineered mouse models reshaped our understanding of pancreatitis.Frontiers in physiology · 2026Review
- Blautia coccoides Alleviates Acute Pancreatitis via Bile Salt Hydrolase-mediated Deoxycholic Acid Production and Farnesoid X Receptor Signaling.Cellular and molecular gastroenterology and hepatology · 2026Article
- The Role of Macrophages in Acute Pancreatitis: From Inflammatory Drivers to Therapeutic Targets.International journal of medical sciences · 2026Review
- Targeted therapeutics for pancreatitis.Frontiers in physiology · 2026Review
- Nanotherapy for Pancreatitis: From Single-Cell Targeting Toward Multicellular-Coordinated Regulation.International journal of nanomedicine · 2026Review
- Mitochondrial dysfunction as a bridge to pathology in acute pancreatitis: From molecular insights to novel therapeutic strategies.World journal of gastroenterology · 2025Review
- Defining the interactome of the pancreas-specific SPCA2 isoform (SPCA2C) identifies unique links to store-operated CaThe FEBS journal · 2025Article
- Potent Preorganized Pyrazolidine Cyclophilin D Inhibitors Prevent Mitochondrial and Organ Injury in a Mouse Pancreatitis Disease Model.Journal of medicinal chemistry · 2025Article
- Modulation of Ryanodine Receptors on Microglial Ramification, Migration, and Phagocytosis in an Alzheimer's Disease Mouse Model.Neuroscience bulletin · 2025Article
- Store-operated calcium entry-based targets for novel cancer therapeutic development.The Journal of pharmacology and experimental therapeutics · 2025Review
- Acute pancreatitis experimental models, advantages and disadvantages.Journal of physiology and biochemistry · 2025Review
- Repurposing BCL2 inhibitors: Venetoclax protects against acinar cell necrosis in acute pancreatitis by promoting apoptosis.Cell death & disease · 2025Article
- Identification of Potential Hub Genes Related to Acute Pancreatitis and Chronic Pancreatitis via Integrated Bioinformatics Analysis and In Vitro Analysis.Molecular biotechnology · 2025Article
66 more citing papers are in PubMed but not listed here.
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Authors and funding
22 authors at 5 institutions in 3 countries.
Funding
Abstract
BACKGROUND &
aimsSustained activation of the cytosolic calcium concentration induces injury to pancreatic acinar cells and necrosis. The calcium release-activated calcium modulator ORAI1 is the most abundant Ca(2+) entry channel in pancreatic acinar cells; it sustains calcium overload in mice exposed to toxins that induce pancreatitis. We investigated the roles of ORAI1 in pancreatic acinar cell injury and the development of acute pancreatitis in mice.
methodsMouse and human acinar cells, as well as HEK 293 cells transfected to express human ORAI1 with human stromal interaction molecule 1, were hyperstimulated or incubated with human bile acid, thapsigargin, or cyclopiazonic acid to induce calcium entry. GSK-7975A or CM_128 were added to some cells, which were analyzed by confocal and video microscopy and patch clamp recordings. Acute pancreatitis was induced in C57BL/6J mice by ductal injection of taurolithocholic acid 3-sulfate or intravenous' administration of cerulein or ethanol and palmitoleic acid. Some mice then were given GSK-7975A or CM_128, which inhibit ORAI1, at different time points to assess local and systemic effects.
resultsGSK-7975A and CM_128 each separately inhibited toxin-induced activation of ORAI1 and/or activation of Ca(2+) currents after Ca(2+) release, in a concentration-dependent manner, in mouse and human pancreatic acinar cells (inhibition >90% of the levels observed in control cells). The ORAI1 inhibitors also prevented activation of the necrotic cell death pathway in mouse and human pancreatic acinar cells. GSK-7975A and CM_128 each inhibited all local and systemic features of acute pancreatitis in all 3 models, in dose- and time-dependent manners. The agents were significantly more effective, in a range of parameters, when given at 1 vs 6 hours after induction of pancreatitis.
conclusionsCytosolic calcium overload, mediated via ORAI1, contributes to the pathogenesis of acute pancreatitis. ORAI1 inhibitors might be developed for the treatment of patients with pancreatitis.
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