Cluster of differentiation 38 (CD38) mediates bile acid-induced acinar cell injury and pancreatitis through cyclic ADP-ribose and intracellular calcium release.
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.
Departments of Pediatrics.
Abrahim I
AI
Orabi
Departments of Pediatrics.
Kamaldeen A
KA
Muili
Departments of Pediatrics.
Tanveer A
TA
Javed
Departments of Pediatrics.
Shunqian
S
Jin
Departments of Internal Medicine, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224.
Thottala
T
Jayaraman
Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama 35213.
Frances E
FE
Lund
Departments of Pediatrics. Electronic address: sohail.husain@chp.edu.
Sohail Z
SZ
Husain
D051997:ADP-ribosyl Cyclase 1 / Q000235:genetics / Q000378:metabolism*; D061354:Acinar Cells / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001647:Bile Acids and Salts / Q000633:toxicity*; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects* / Q000235:genetics; D036563:Cyclic ADP-Ribose / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010195:Pancreatitis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
D001647:Bile Acids and Salts; D008562:Membrane Glycoproteins; D036563:Cyclic ADP-Ribose; D007770:L-Lactate Dehydrogenase; C498154:CD38 protein, human; C498155:Cd38 protein, mouse; D051997:ADP-ribosyl Cyclase 1; D002118:Calcium
Bile Acid; CD38; Calcium Signaling; Cyclic ADP-ribose; NAADP; Pancreas; Ryanodine Receptor