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Cluster of differentiation 38 (CD38) mediates bile acid-induced acinar cell injury and pancreatitis through cyclic ADP-ribose and intracellular calcium release.
Orabi, Abrahim I; Muili, Kamaldeen A; Javed, Tanveer A; Jin, Shunqian; Jayaraman, Thottala; Lund, Frances E; Husain, Sohail Z.
Affiliation
  • Orabi AI; Departments of Pediatrics.
  • Muili KA; Departments of Pediatrics.
  • Javed TA; Departments of Pediatrics.
  • Jin S; Departments of Pediatrics.
  • Jayaraman T; Departments of Internal Medicine, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224.
  • Lund FE; Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama 35213.
  • Husain SZ; Departments of Pediatrics. Electronic address: sohail.husain@chp.edu.
J Biol Chem ; 288(38): 27128-27137, 2013 Sep 20.
Article in En | MEDLINE | ID: mdl-23940051
ABSTRACT
Aberrant Ca(2+) 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(2+) signals due to bile acid exposure is the intracellular Ca(2+) 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(2+) 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(2+) signals were imaged using live time-lapse confocal microscopy in freshly isolated mouse acinar cells during perifusion with the bile acid taurolithocholic acid 3-sulfate (TLCS; 500 µM). To focus on intracellular Ca(2+) release and to specifically exclude Ca(2+) influx, cells were perifused in Ca(2+)-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(2+) signals and cell injury. TLCS-induced Ca(2+) 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(2+) signaling.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Pancreatitis / Bile Acids and Salts / Membrane Glycoproteins / Calcium Signaling / Cyclic ADP-Ribose / ADP-ribosyl Cyclase 1 / Acinar Cells Type of study: Prognostic_studies Limits: Animals / Humans Language: En Journal: J Biol Chem Year: 2013 Document type: Article

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Pancreatitis / Bile Acids and Salts / Membrane Glycoproteins / Calcium Signaling / Cyclic ADP-Ribose / ADP-ribosyl Cyclase 1 / Acinar Cells Type of study: Prognostic_studies Limits: Animals / Humans Language: En Journal: J Biol Chem Year: 2013 Document type: Article