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

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.