OCaR1 endows exocytic vesicles with autoregulatory competence by preventing uncontrolled Ca2+ release, exocytosis, and pancreatic tissue damage

  • J Clin Invest. 2024 Apr 1;134(7):e169428. doi: 10.1172/JCI169428.
Volodymyr Tsvilovskyy  1  2 ,  Roger Ottenheijm  1  2 ,  Ulrich Kriebs  1 ,  Aline Schütz  1 ,  Kalliope Nina Diakopoulos  3 ,  Archana Jha  4 ,  Wolfgang Bildl  5 ,  Angela Wirth  1  2 ,  Julia Böck  6 ,  Dawid Jaślan  6 ,  Irene Ferro  6 ,  Francisco J Taberner  1  7 ,  Olga Kalinina  8 ,  Staffan Hildebrand  9 ,  Ulrich Wissenbach  10 ,  Petra Weissgerber  10 ,  Dominik Vogt  1 ,  Carola Eberhagen  11 ,  Stefanie Mannebach  10 ,  Michael Berlin  1  2 ,  Vladimir Kuryshev  1 ,  Dagmar Schumacher  1 ,  Koenraad Philippaert  1  2 ,  Juan E Camacho-Londoño  1 ,  Ilka Mathar  1 ,  Christoph Dieterich  12 ,  Norbert Klugbauer  13 ,  Martin Biel  14 ,  Christian Wahl-Schott  15 ,  Peter Lipp  16 ,  Veit Flockerzi  10 ,  Hans Zischka  11  17 ,  Hana Algül  3 ,  Stefan G Lechner  1 ,  Marina Lesina  3 ,  Christian Grimm  6  18 ,  Bernd Fakler  5 ,  Uwe Schulte  5 ,  Shmuel Muallem  4 ,  Marc Freichel  1
Affiliations
  • 1. Institute of Pharmacology, Heidelberg University, Heidelberg, Germany.
  • 2. DZHK (German Centre for Cardiovascular Research), partner site Heidelberg/Mannheim, Heidelberg, Germany.
  • 3. Comprehensive Cancer Center München, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
  • 4. Epithelial Signaling and Transport Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, USA.
  • 5. Institute for Physiology, University of Freiburg, Freiburg, Germany.
  • 6. Walther-Straub-Institut für Pharmakologie und Toxikologie, Ludwig-Maximilians-Universität München, Munich, Germany.
  • 7. Instituto de Neurociencias de Alicante, Universidad Miguel Hernández-Consejo Superior de Investigaciones Científicas, Sant Joan d'Alacant, Spain.
  • 8. Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research (HZI), Saarbrücken, Germany.
  • 9. Institut für Pharmakologie und Toxikologie, Universität Bonn, Bonn, Germany.
  • 10. Experimental and Clinical Pharmacology and Toxicology, Center for Molecular Signaling (PZMS), Saarland University, Homburg, Germany.
  • 11. Institute of Molecular Toxicology and Pharmacology, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany.
  • 12. University Hospital Heidelberg, Department of Medicine III: Cardiology, Angiology and Pneumology, Heidelberg, Germany.
  • 13. Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Fakultät für Medizin, Albert-Ludwigs-Universität Freiburg, Freiburg, Germany.
  • 14. Center for Integrated Protein Science Munich (CIPS-M) and Center for Drug Research, Department of Pharmacy, Ludwig-Maximilians-Universität München, and DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany.
  • 15. Walter Brendel Centre of Experimental Medicine, Biomedical Center, Institute of Cardiovascular Physiology and Pathophysiology, Medical Faculty, Ludwig-Maximilians-Universität München, Planegg-Martinsried, Germany.
  • 16. Institute for Molecular Cell Biology, Center for Molecular Signaling (PZMS), Universität des Saarlandes, Homburg, Germany.
  • 17. Institute of Toxicology and Environmental Hygiene, Technical University Munich, School of Medicine, Munich, Germany.
  • 18. Immunology, Infection and Pandemic Research (IIP), Fraunhofer Institute for Translational Medicine and Pharmacology (ITMP), Munich, Germany.
PMID: 38557489 DOI: 10.1172/JCI169428
Abstract

Regulated exocytosis is initiated by increased Ca2+ concentrations in close spatial proximity to secretory granules, which is effectively prevented when the cell is at rest. Here we showed that exocytosis of zymogen granules in acinar cells was driven by Ca2+ directly released from acidic Ca2+ stores including secretory granules through NAADP-activated two-pore channels (TPCs). We identified OCaR1 (encoded by Tmem63a) as an organellar Ca2+ regulator protein integral to the membrane of secretory granules that controlled Ca2+ release via inhibition of TPC1 and TPC2 currents. Deletion of OCaR1 led to extensive Ca2+ release from NAADP-responsive granules under basal conditions as well as upon stimulation of GPCR receptors. Moreover, OCaR1 deletion exacerbated the disease phenotype in murine models of severe and chronic pancreatitis. Our findings showed OCaR1 as a gatekeeper of Ca2+ release that endows NAADP-sensitive secretory granules with an autoregulatory mechanism preventing uncontrolled exocytosis and pancreatic tissue damage.

Keywords
Calcium signaling; Cell biology; Ion channels; Lysosomes.
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