Cluster of differentiation 38 (CD38) mediates bile acid-induced acinar cell injury and pancreatitis through cyclic ADP-ribose and intracellular calcium release

Academic Article

Abstract

  • Aberrant Ca signals within pancreatic acinar cells are an early and critical feature in acute pancreatitis, yet it is unclear how these signals are generated. An important mediator of the aberrant Ca signals due to bile acid exposure is the intracellular Ca channel ryanodine receptor. One putative activator of the ryanodine receptor is the nucleotide second messenger cyclic ADP-ribose (cADPR), which is generated by an ectoenzyme ADP-ribosyl cyclase, CD38. In this study, we examined the role of CD38 and cADPR in acinar cell Ca signals and acinar injury due to bile acids using pharmacologic inhibitors of CD38 and cADPR as well as mice deficient in Cd38 (Cd38 ). Cytosolic Ca signals were imaged using live time-lapse confocal microscopy in freshly isolated mouse acinar cells during perfusion with the bile acid taurolithocholic acid 3-sulfate (TLCS; 500 μm). To focus on intracellular Ca release and to specifically exclude Ca influx, cells were perifused in Ca -free medium. Cell injury was assessed by lactate dehydrogenase leakage and propidium iodide uptake. Pretreatment with either nicotinamide (20 mM) or the cADPR antagonist 8-Br-cADPR (30 μm) abrogated TLCS-induced Ca signals and cell injury. TLCS-induced Ca release and cell injury were reduced by 30 and 95%, respectively, in Cd38-deficient acinar cells compared with wild-type cells (p < 0.05). Cd38-deficient mice were protected against a model of bile acid infusion pancreatitis. In summary, these data indicate that CD38-cADPR mediates bile acid-induced pancreatitis and acinar cell injury through aberrant intracellular Ca signaling. © 2013 by The American Society for Biochemistry and Molecular Biology, Inc. 2+ 2+ 2+ 2+ -/- 2+ 2+ 2+ 2+ 2+ 2+ 2+
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    Digital Object Identifier (doi)

    Author List

  • Orabi AI; Muili KA; Javed TA; Jin S; Jayaraman T; Lund FE; Husain SZ
  • Start Page

  • 27128
  • End Page

  • 27137
  • Volume

  • 288
  • Issue

  • 38