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Tsvilovskyy, V.* ; Ottenheijm, R.* ; Kriebs, U.* ; Schütz, A.* ; Diakopoulos, K.N.* ; Jha, A.N.* ; Bildl, W.* ; Wirth, A.* ; Böck, J.* ; Jaślan, D.* ; Ferro, I.* ; Taberner, F.J.* ; Kalinina, O.* ; Hildebrand, S.* ; Wissenbach, U.* ; Weissgerber, P.* ; Vogt, D.* ; Eberhagen, C. ; Mannebach, S.* ; Berlin, M.* ; Kuryshev, V.* ; Schumacher, D.* ; Philippaert, K.* ; Camacho-Londoño, J.E.* ; Mathar, I.* ; Dieterich, C.* ; Klugbauer, N.* ; Biel, M.* ; Wahl-Schott, C.* ; Lipp, P.* ; Flockerzi, V.* ; Zischka, H. ; Algül, H.* ; Lechner, S.G.* ; Lesina, M.* ; Grimm, C.* ; Fakler, B.* ; Schulte, U.* ; Muallem, S.* ; Freichel, M.*

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

J. Clin. Invest. 134:e169428 (2024)
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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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Calcium Signaling ; Cell Biology ; Ion Channels ; Lysosomes; Cyclic Adp-ribose; Endoplasmic-reticulum; Inositol Trisphosphate; Zymogen Granules; Calcium; Naadp; Channels; Mechanism; Roles; Identification
Language english
Publication Year 2024
HGF-reported in Year 2024
ISSN (print) / ISBN 0021-9738
e-ISSN 1558-8238
Journal Journal of Clinical Investigation
Quellenangaben Volume: 134, Issue: 7, Pages: , Article Number: e169428 Supplement: ,
Publisher American Society of Clinical Investigation
Publishing Place 2015 Manchester Rd, Ann Arbor, Mi 48104 Usa
Reviewing status Peer reviewed
Institute(s) Institute of Molecular Toxicology and Pharmacology (TOX)
POF-Topic(s) 30203 - Molecular Targets and Therapies
Research field(s) Enabling and Novel Technologies
PSP Element(s) G-505200-003
Grants NIH
Research Training Group
Collaborative Research Centre (SFB)
DZHK (German Centre for Cardiovascular Research)
BMBF (German Ministry of Education and Research)
German Research Foundation (DFG)
Transregional Collaborative Research Centre (TR-SFB)
DOI 10.1172/JCI169428
WOS ID 001198702600021
Scopus ID 85189304282
PubMed ID 38557489
Erfassungsdatum 2024-05-15
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