title: A novel function of Noc2 in agonist-induced intracellular Ca2+ increase during zymogen-granule exocytosis in pancreatic acinar cells.
abstract: Noc2, a putative Rab effector, contributes to secretory-granule exocytosis in neuroendocrine and exocrine cells. Here, using two-photon excitation live-cell imaging, we investigated its role in Ca(2+)-dependent zymogen granule (ZG) exocytosis in pancreatic acinar cells from wild-type (WT) and Noc2-knockout (KO) mice. Imaging of a KO acinar cell revealed an expanded granular area, indicating ZG accumulation. In our spatiotemporal analysis of the ZG exocytosis induced by agonist (cholecystokinin or acetylcholine) stimulation, the location and rate of progress of ZG exocytosis did not differ significantly between the two strains. ZG exocytosis from KO acinar cells was seldom observed at physiological concentrations of agonists, but was normal (vs. WT) at high concentrations. Flash photolysis of a caged calcium compound confirmed the integrity of the fusion step of ZG exocytosis in KO acinar cells. The decreased ZG exocytosis present at physiological concentrations of agonists raised the possibility of impaired elicitation of calcium spikes. When calcium spikes were evoked in KO acinar cells by a high agonist concentration: (a) they always started at the apical portion and traveled to the basal portion, and (b) calcium oscillations over the 10 µM level were observed, as in WT acinar cells. At physiological concentrations of agonists, however, sufficient calcium spikes were not observed, suggesting an impaired [Ca(2+)](i)-increase mechanism in KO acinar cells. We propose that in pancreatic acinar cells, Noc2 is not indispensable for the membrane fusion of ZG per se, but instead performs a novel function favoring agonist-induced physiological [Ca(2+)](i) increases.
authors.affiliation: Department of Cell Physiology, National Institute for Physiological Sciences, and Graduate University of Advanced Studies, SOKENDAI, Okazaki, Aichi, Japan. sogata@ndmc.ac.jp
authors.forename: Sho
authors.initials: S
authors.lastname: Ogata
authors.forename: Takashi
authors.initials: T
authors.lastname: Miki
authors.forename: Susumu
authors.initials: S
authors.lastname: Seino
authors.forename: Seiichi
authors.initials: S
authors.lastname: Tamai
authors.forename: Haruo
authors.initials: H
authors.lastname: Kasai
authors.forename: Tomomi
authors.initials: T
authors.lastname: Nemoto
mesh_terms: D061354:Acinar Cells / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology; D005089:Exocytosis / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins; D008561:Membrane Fusion / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D010179:Pancreas / Q000378:metabolism*; D046790:Pancreas, Exocrine / Q000378:metabolism; D011506:Proteins / Q000378:metabolism*; D022142:Secretory Vesicles / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; C484660:Rph3al protein, mouse; D002118:Calcium