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

Abrahim I. Orabi, Yuhuan Luo, Mahwish U. Ahmad, Ahsan U. Shah, Zahir Mannan, Dong Wang, Sheharyar Sarwar, Kamaldeen A. Muili, Christine Shugrue, Thomas R. Kolodecik, Vijay P. Singh, Mark E. Lowe, Edwin Thrower, Ju Chen, Sohail Z. Husain

Research output: Contribution to journalArticle

8 Scopus citations

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.

Original languageEnglish (US)
Article numbere48465
JournalPloS one
Volume7
Issue number11
DOIs
StatePublished - Nov 21 2012

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Orabi, A. I., Luo, Y., Ahmad, M. U., Shah, A. U., Mannan, Z., Wang, D., Sarwar, S., Muili, K. A., Shugrue, C., Kolodecik, T. R., Singh, V. P., Lowe, M. E., Thrower, E., Chen, J., & Husain, S. Z. (2012). IP3 Receptor Type 2 Deficiency Is Associated with a Secretory Defect in the Pancreatic Acinar Cell and an Accumulation of Zymogen Granules. PloS one, 7(11), [e48465]. https://doi.org/10.1371/journal.pone.0048465