Orai1 calcium channel inhibition prevents progression of chronic pancreatitis

Viktória Szabó; Noémi Csákány-Papp; Marietta Görög; Tamara Madacsy; Árpád Varga; Aletta Kiss; Balint Tel; Boldizsár Jójárt; Tim Crul; Krisztina Dudás; Mária Bagyánszki; Nikolett Bódi; Ferhan Ayaydin; Shyam Jee; Laszlo Tiszlavicz; Kenneth A. Stauderman; Sudarshan Hebbar; Petra Pallagi; József Maléth

doi:10.1172/jci.insight.167645

¹Department of Medicine, University of Szeged, Szeged, Hungary

²First Department of Pediatrics, Semmelweis University, Budapest, Hungary

³Department of Physiology, Anatomy and Neuroscience, University of Szeged, Szeged, Hungary

⁴Functional Cell Biology and Immunology Advanced Core Facility, University of Szeged, Szeged, Hungary

⁵Department of Pathology, University of Szeged, Szeged, Hungary

⁶CalciMedica, Inc., La Jolla, United States of America

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¹Department of Medicine, University of Szeged, Szeged, Hungary

²First Department of Pediatrics, Semmelweis University, Budapest, Hungary

³Department of Physiology, Anatomy and Neuroscience, University of Szeged, Szeged, Hungary

⁴Functional Cell Biology and Immunology Advanced Core Facility, University of Szeged, Szeged, Hungary

⁵Department of Pathology, University of Szeged, Szeged, Hungary

⁶CalciMedica, Inc., La Jolla, United States of America

Find articles by Csákány-Papp, N. in: JCI | PubMed | Google Scholar

¹Department of Medicine, University of Szeged, Szeged, Hungary

²First Department of Pediatrics, Semmelweis University, Budapest, Hungary

³Department of Physiology, Anatomy and Neuroscience, University of Szeged, Szeged, Hungary

⁴Functional Cell Biology and Immunology Advanced Core Facility, University of Szeged, Szeged, Hungary

⁵Department of Pathology, University of Szeged, Szeged, Hungary

⁶CalciMedica, Inc., La Jolla, United States of America

Find articles by Görög, M. in: JCI | PubMed | Google Scholar

¹Department of Medicine, University of Szeged, Szeged, Hungary

²First Department of Pediatrics, Semmelweis University, Budapest, Hungary

³Department of Physiology, Anatomy and Neuroscience, University of Szeged, Szeged, Hungary

⁴Functional Cell Biology and Immunology Advanced Core Facility, University of Szeged, Szeged, Hungary

⁵Department of Pathology, University of Szeged, Szeged, Hungary

⁶CalciMedica, Inc., La Jolla, United States of America

Find articles by Madacsy, T. in: JCI | PubMed | Google Scholar |

¹Department of Medicine, University of Szeged, Szeged, Hungary

²First Department of Pediatrics, Semmelweis University, Budapest, Hungary

³Department of Physiology, Anatomy and Neuroscience, University of Szeged, Szeged, Hungary

⁴Functional Cell Biology and Immunology Advanced Core Facility, University of Szeged, Szeged, Hungary

⁵Department of Pathology, University of Szeged, Szeged, Hungary

⁶CalciMedica, Inc., La Jolla, United States of America

Find articles by Varga, Á. in: JCI | PubMed | Google Scholar |

¹Department of Medicine, University of Szeged, Szeged, Hungary

²First Department of Pediatrics, Semmelweis University, Budapest, Hungary

³Department of Physiology, Anatomy and Neuroscience, University of Szeged, Szeged, Hungary

⁴Functional Cell Biology and Immunology Advanced Core Facility, University of Szeged, Szeged, Hungary

⁵Department of Pathology, University of Szeged, Szeged, Hungary

⁶CalciMedica, Inc., La Jolla, United States of America

Find articles by Kiss, A. in: JCI | PubMed | Google Scholar |

¹Department of Medicine, University of Szeged, Szeged, Hungary

²First Department of Pediatrics, Semmelweis University, Budapest, Hungary

³Department of Physiology, Anatomy and Neuroscience, University of Szeged, Szeged, Hungary

⁴Functional Cell Biology and Immunology Advanced Core Facility, University of Szeged, Szeged, Hungary

⁵Department of Pathology, University of Szeged, Szeged, Hungary

⁶CalciMedica, Inc., La Jolla, United States of America

Find articles by Tel, B. in: JCI | PubMed | Google Scholar |

¹Department of Medicine, University of Szeged, Szeged, Hungary

²First Department of Pediatrics, Semmelweis University, Budapest, Hungary

³Department of Physiology, Anatomy and Neuroscience, University of Szeged, Szeged, Hungary

⁴Functional Cell Biology and Immunology Advanced Core Facility, University of Szeged, Szeged, Hungary

⁵Department of Pathology, University of Szeged, Szeged, Hungary

⁶CalciMedica, Inc., La Jolla, United States of America

Find articles by Jójárt, B. in: JCI | PubMed | Google Scholar |

¹Department of Medicine, University of Szeged, Szeged, Hungary

²First Department of Pediatrics, Semmelweis University, Budapest, Hungary

³Department of Physiology, Anatomy and Neuroscience, University of Szeged, Szeged, Hungary

⁴Functional Cell Biology and Immunology Advanced Core Facility, University of Szeged, Szeged, Hungary

⁵Department of Pathology, University of Szeged, Szeged, Hungary

⁶CalciMedica, Inc., La Jolla, United States of America

Find articles by Crul, T. in: JCI | PubMed | Google Scholar |

¹Department of Medicine, University of Szeged, Szeged, Hungary

²First Department of Pediatrics, Semmelweis University, Budapest, Hungary

³Department of Physiology, Anatomy and Neuroscience, University of Szeged, Szeged, Hungary

⁴Functional Cell Biology and Immunology Advanced Core Facility, University of Szeged, Szeged, Hungary

⁵Department of Pathology, University of Szeged, Szeged, Hungary

⁶CalciMedica, Inc., La Jolla, United States of America

Find articles by Dudás, K. in: JCI | PubMed | Google Scholar |

¹Department of Medicine, University of Szeged, Szeged, Hungary

²First Department of Pediatrics, Semmelweis University, Budapest, Hungary

³Department of Physiology, Anatomy and Neuroscience, University of Szeged, Szeged, Hungary

⁴Functional Cell Biology and Immunology Advanced Core Facility, University of Szeged, Szeged, Hungary

⁵Department of Pathology, University of Szeged, Szeged, Hungary

⁶CalciMedica, Inc., La Jolla, United States of America

Find articles by Bagyánszki, M. in: JCI | PubMed | Google Scholar

¹Department of Medicine, University of Szeged, Szeged, Hungary

²First Department of Pediatrics, Semmelweis University, Budapest, Hungary

³Department of Physiology, Anatomy and Neuroscience, University of Szeged, Szeged, Hungary

⁴Functional Cell Biology and Immunology Advanced Core Facility, University of Szeged, Szeged, Hungary

⁵Department of Pathology, University of Szeged, Szeged, Hungary

⁶CalciMedica, Inc., La Jolla, United States of America

Find articles by Bódi, N. in: JCI | PubMed | Google Scholar |

¹Department of Medicine, University of Szeged, Szeged, Hungary

²First Department of Pediatrics, Semmelweis University, Budapest, Hungary

³Department of Physiology, Anatomy and Neuroscience, University of Szeged, Szeged, Hungary

⁴Functional Cell Biology and Immunology Advanced Core Facility, University of Szeged, Szeged, Hungary

⁵Department of Pathology, University of Szeged, Szeged, Hungary

⁶CalciMedica, Inc., La Jolla, United States of America

Find articles by Ayaydin, F. in: JCI | PubMed | Google Scholar

¹Department of Medicine, University of Szeged, Szeged, Hungary

²First Department of Pediatrics, Semmelweis University, Budapest, Hungary

³Department of Physiology, Anatomy and Neuroscience, University of Szeged, Szeged, Hungary

⁴Functional Cell Biology and Immunology Advanced Core Facility, University of Szeged, Szeged, Hungary

⁵Department of Pathology, University of Szeged, Szeged, Hungary

⁶CalciMedica, Inc., La Jolla, United States of America

Find articles by Jee, S. in: JCI | PubMed | Google Scholar |

¹Department of Medicine, University of Szeged, Szeged, Hungary

²First Department of Pediatrics, Semmelweis University, Budapest, Hungary

³Department of Physiology, Anatomy and Neuroscience, University of Szeged, Szeged, Hungary

⁴Functional Cell Biology and Immunology Advanced Core Facility, University of Szeged, Szeged, Hungary

⁵Department of Pathology, University of Szeged, Szeged, Hungary

⁶CalciMedica, Inc., La Jolla, United States of America

Find articles by Tiszlavicz, L. in: JCI | PubMed | Google Scholar

¹Department of Medicine, University of Szeged, Szeged, Hungary

²First Department of Pediatrics, Semmelweis University, Budapest, Hungary

³Department of Physiology, Anatomy and Neuroscience, University of Szeged, Szeged, Hungary

⁴Functional Cell Biology and Immunology Advanced Core Facility, University of Szeged, Szeged, Hungary

⁵Department of Pathology, University of Szeged, Szeged, Hungary

⁶CalciMedica, Inc., La Jolla, United States of America

Find articles by Stauderman, K. in: JCI | PubMed | Google Scholar |

¹Department of Medicine, University of Szeged, Szeged, Hungary

²First Department of Pediatrics, Semmelweis University, Budapest, Hungary

³Department of Physiology, Anatomy and Neuroscience, University of Szeged, Szeged, Hungary

⁴Functional Cell Biology and Immunology Advanced Core Facility, University of Szeged, Szeged, Hungary

⁵Department of Pathology, University of Szeged, Szeged, Hungary

⁶CalciMedica, Inc., La Jolla, United States of America

Find articles by Hebbar, S. in: JCI | PubMed | Google Scholar

¹Department of Medicine, University of Szeged, Szeged, Hungary

²First Department of Pediatrics, Semmelweis University, Budapest, Hungary

³Department of Physiology, Anatomy and Neuroscience, University of Szeged, Szeged, Hungary

⁴Functional Cell Biology and Immunology Advanced Core Facility, University of Szeged, Szeged, Hungary

⁵Department of Pathology, University of Szeged, Szeged, Hungary

⁶CalciMedica, Inc., La Jolla, United States of America

Find articles by Pallagi, P. in: JCI | PubMed | Google Scholar

¹Department of Medicine, University of Szeged, Szeged, Hungary

²First Department of Pediatrics, Semmelweis University, Budapest, Hungary

³Department of Physiology, Anatomy and Neuroscience, University of Szeged, Szeged, Hungary

⁴Functional Cell Biology and Immunology Advanced Core Facility, University of Szeged, Szeged, Hungary

⁵Department of Pathology, University of Szeged, Szeged, Hungary

⁶CalciMedica, Inc., La Jolla, United States of America

Find articles by Maléth, J. in: JCI | PubMed | Google Scholar |

JCI Insight. https://doi.org/10.1172/jci.insight.167645.
Copyright © 2023, Szabó et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Published May 25, 2023 - Version history

Patients with recurrent acute pancreatitis (RAP) are at significant risk of developing early chronic pancreatitis (CP), which progresses into irreversible, end-stage CP with severe symptoms. There is no specific therapy in RAP or in early CP that may hinder disease progression. The pathogenesis of CP is complex and involves interactions among multiple cell types, including pancreatic acinar, ductal, and stellate cells (PSC). Therefore, it is pivotal to identify common pathogenic pathways in these cells that could be targeted pharmacologically. The Orai1-mediated store-operated Ca²⁺ entry (SOCE) is a ubiquitous signaling mechanism, which may become overactivated in pathological states resulting intracellular Ca²⁺ overload. In this study, we used ex vivo and in vivo preclinical disease models to demonstrate that Orai1 inhibition prevents progression of RAP and early CP. The selective Orai1 inhibitor CM5480 restored the expression of SOCE-associated regulatory factor in acinar cells, prevented uncontrolled Ca²⁺ elevation, protected acinar and ductal functions, mitigated immune cell infiltration, and diminished PSC activation, proliferation and migration. We suggest that the overactivation of Orai1 is a crucial pathogenetic event in the progression of early CP, and inhibition of Orai1 could prevent the development of end-stage CP.

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Orai1 calcium channel inhibition prevents progression of chronic pancreatitis

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