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.
Highlights
Bile acids cause ryanodine receptor (RyR) Ca2ϩ release and lead to injury in pancreatic acinar cells, yet the mechanism is unknown
We examined the role of CD38 and cyclic ADP-ribose (cADPR) in acinar cell Ca2؉ signals and acinar injury due to bile acids using pharmacologic inhibitors of CD38 and cADPR as well as mice deficient in Cd38 (Cd38؊/؊)
These data indicate that CD38-cADPR mediates bile acid-induced pancreatitis and acinar cell injury through aberrant intracellular Ca2؉ signaling
Summary
Bile acids cause ryanodine receptor (RyR) Ca2ϩ release and lead to injury in pancreatic acinar cells, yet the mechanism is unknown. Results: Inhibition of the RyR activator cADPR reduces bile acid-induced acinar cell Ca2ϩ release, cell injury, and pancreatitis. Cd38-deficient mice were protected against a model of bile acid infusion pancreatitis These data indicate that CD38-cADPR mediates bile acid-induced pancreatitis and acinar cell injury through aberrant intracellular Ca2؉ signaling. Aberrant Ca2ϩ signals are known to play an important role in acinar cell injury, the mechanism by which pancreatitis-inducing insults lead to the disease is unclear. The action of cADPR on the RyR requires additional protein factors, including calmodulin and FK506-binding protein (24 –26)
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