IP3 Receptor Type 2 Deficiency Is Associated with a Secretory Defect in the Pancreatic Acinar Cell and an Accumulation of Zymogen Granules

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.

Transient High Pressure in Pancreatic Ducts Promotes Inflammation and Alters Tight Junctions via Calcineurin Signaling in Mice

“…Calcineurin is a potent downstream target of Ca 2+ and has been implicated as a critical mediator of acinar injury and pancreatitis in vivo 20, 40, 55 . The pancreatic acinar cell primarily expresses the Cnab and CnB1 isoforms of calcineurin 56 . We found that high pancreatic ductal pressures mediate pressure-induced pancreatitis through calcineurin activation and that calcineurin deletion (using Cnab knockouts) or calcineurin inhibition (with FK506) largely prevents pancreatic inflammation and the loss of tight junction expression.…”

Molecular approaches for manipulating astrocytic signaling in vivo

“…However, this model suffers in that it lacks tissue specificity, as do all germline knockout models. IP3R2 is expressed in multiple tissues outside the CNS including the heart (Li et al, 2005 ), pancreas (Orabi et al, 2012 ), lungs, liver, and kidneys (Fujino et al, 1995 ); this leads to potential confounding issues in the use of this model in vivo when assessing the role of astrocyte GPCR-dependent Ca 2+ fluxes in behavior. Additionally, concerns over compensation due to the role of intracellular Ca 2+ signaling during development have been raised regarding this model; however to date no evidence for altered development leading to compensation has been reported.…”

IP3 receptors regulate vascular smooth muscle contractility and hypertension

“…As one of the major sources of intracellular Ca 2+ release, IP 3 Rs have been implicated in regulating many biological processes. Deficiency of distinct subtypes of IP 3 Rs in mice has been shown to cause severe abnormalities and diseases, including ataxia and epileptic seizures (8), exocrine secretion defects (9)(10)(11), abnormal taste perception (12), embryonic developmental defects (13,14), and T cell acute lymphoblastic leukemia (15).…”