OCaR1 endows exocytic vesicles with autoregulatory competence by preventing uncontrolled Ca2+ release, exocytosis, and pancreatic tissue damage
Volodymyr Tsvilovskyy, Roger Ottenheijm, Ulrich Kriebs, Aline Schütz, Kalliope N. Diakopoulos, Archana Jha, Wolfgang Bildl, Angela Wirth, Julia Böck, Dawid Jaślan, Irene Flavia Ferro, Francisco J. Taberner, Olga Kalinina, Staffan Hildebrand, Ulrich Wissenbach, Petra Weißgerber, Dominik Maximilian Vogt, Carola Eberhagen, Stefanie Mannebach, Michael Berlin, Vladimir Kuryshev, Dagmar Schumacher, Koenraad Philippaert, Juan E. Camacho Londoño, Ilka Mathar, Christoph Dieterich, Norbert Klugbauer, Martin Biel, Christian Wahl‐Schott, Peter Lipp, Veit Flockerzi, Hans Zischka, Hana Algül, Stefan G. Lechner, Marina Lesina, Christian Grimm, Bernd Fakler, Uwe Schulte, Shmuel Muallem, Marc Freichel
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.