Abstract
Acute pancreatitis is a painful, life-threatening disorder of the pancreas whose etiology is often multi-factorial. It is of great importance to understand the interplay between factors that predispose patients to develop the disease. One such factor is an excessive elevation in pancreatic acinar cell Ca2+. These aberrant Ca2+ elevations are triggered by release of Ca2+ from apical Ca2+ pools that are gated by the inositol 1,4,5-trisphosphate receptor (IP3R) types 2 and 3. In this study, we examined the role of IP3R type 2 (IP3R2) using mice deficient in this Ca2+ release channel (IP3R2−/−). Using live acinar cell Ca2+ imaging we found that loss of IP3R2 reduced the amplitude of the apical Ca2+ signal and caused a delay in its initiation. This was associated with a reduction in carbachol-stimulated amylase release and an accumulation of zymogen granules (ZGs). Specifically, there was a 2-fold increase in the number of ZGs (P<0.05) and an expansion of the ZG pool area within the cell. There was also a 1.6- and 2.6-fold increase in cellular amylase and trypsinogen, respectively. However, the mice did not have evidence of pancreatic injury at baseline, other than an elevated serum amylase level. Further, pancreatitis outcomes using a mild caerulein hyperstimulation model were similar between IP3R2−/− and wild type mice. In summary, IP3R2 modulates apical acinar cell Ca2+ signals and pancreatic enzyme secretion. IP3R-deficient acinar cells accumulate ZGs, but the mice do not succumb to pancreatic damage or worse pancreatitis outcomes.
Highlights
Pancreatitis is a painful, life-threatening disorder of the pancreas that results from numerous insults [1]
There was a delay among the IP3R22/2 acinar cells of 25.7 sec in the latency period, which is the time from the application of carbachol to the initiation of the Ca2+ signal (P,0.05)
Isolated acinar cells from wild type mice (WT) and IP3R22/2 mice were stimulated with a concentration range of caerulein or carbachol, and amylase secretion was measured after a 30 min incubation period (Fig. 2)
Summary
Pancreatitis is a painful, life-threatening disorder of the pancreas that results from numerous insults [1]. These include gallstones, alcohol abuse, trauma, medications, and metabolic disturbances. It is unclear why only a minority of individuals exposed to these noxious stimuli ever go on to develop pancreatitis. Most of the known gene mutations linked to pancreatitis, such as the serine protease inhibitor Kazal-type 1 (SPINK1) and cystic fibrosis transmembrane conductance regulator (CFTR), increase the likelihood of developing the disease, but do not appear to initiate it by themselves [4]. Exceptions are the gain of function mutations in the cationic trypsinogen gene, which cause acute or chronic pancreatitis with high penetrance [5]
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