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 Prem Singh, Mark E. Lowe, Edwin Thrower, Ju Chen, Sohail Z. Husain

Research output: Contribution to journalArticle

8 Citations (Scopus)

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

Fingerprint

Inositol 1,4,5-Trisphosphate Receptors
acinar cells
Enzyme Precursors
Acinar Cells
secretory granules
Secretory Vesicles
Amylases
Pancreatitis
calcium
Defects
receptors
pancreatitis
amylases
Trypsinogen
Ceruletide
mice
Carbachol
Pancreas
trypsinogen
pancreatic diseases

ASJC Scopus subject areas

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

Cite this

IP3 Receptor Type 2 Deficiency Is Associated with a Secretory Defect in the Pancreatic Acinar Cell and an Accumulation of Zymogen Granules. / Orabi, Abrahim I.; Luo, Yuhuan; Ahmad, Mahwish U.; Shah, Ahsan U.; Mannan, Zahir; Wang, Dong; Sarwar, Sheharyar; Muili, Kamaldeen A.; Shugrue, Christine; Kolodecik, Thomas R.; Singh, Vijay Prem; Lowe, Mark E.; Thrower, Edwin; Chen, Ju; Husain, Sohail Z.

In: PLoS One, Vol. 7, No. 11, e48465, 21.11.2012.

Research output: Contribution to journalArticle

Orabi, AI, Luo, Y, Ahmad, MU, Shah, AU, Mannan, Z, Wang, D, Sarwar, S, Muili, KA, Shugrue, C, Kolodecik, TR, Singh, VP, Lowe, ME, Thrower, E, Chen, J & Husain, SZ 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, vol. 7, no. 11, e48465. https://doi.org/10.1371/journal.pone.0048465
Orabi, Abrahim I. ; Luo, Yuhuan ; Ahmad, Mahwish U. ; Shah, Ahsan U. ; Mannan, Zahir ; Wang, Dong ; Sarwar, Sheharyar ; Muili, Kamaldeen A. ; Shugrue, Christine ; Kolodecik, Thomas R. ; Singh, Vijay Prem ; Lowe, Mark E. ; Thrower, Edwin ; Chen, Ju ; Husain, Sohail Z. / IP3 Receptor Type 2 Deficiency Is Associated with a Secretory Defect in the Pancreatic Acinar Cell and an Accumulation of Zymogen Granules. In: PLoS One. 2012 ; Vol. 7, No. 11.
@article{ef49df4e6a8d4e2eb7ed1b8ee1d901da,
title = "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.",
author = "Orabi, {Abrahim I.} and Yuhuan Luo and Ahmad, {Mahwish U.} and Shah, {Ahsan U.} and Zahir Mannan and Dong Wang and Sheharyar Sarwar and Muili, {Kamaldeen A.} and Christine Shugrue and Kolodecik, {Thomas R.} and Singh, {Vijay Prem} and Lowe, {Mark E.} and Edwin Thrower and Ju Chen and Husain, {Sohail Z.}",
year = "2012",
month = "11",
day = "21",
doi = "10.1371/journal.pone.0048465",
language = "English (US)",
volume = "7",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "11",

}

TY - JOUR

T1 - IP3 Receptor Type 2 Deficiency Is Associated with a Secretory Defect in the Pancreatic Acinar Cell and an Accumulation of Zymogen Granules

AU - Orabi, Abrahim I.

AU - Luo, Yuhuan

AU - Ahmad, Mahwish U.

AU - Shah, Ahsan U.

AU - Mannan, Zahir

AU - Wang, Dong

AU - Sarwar, Sheharyar

AU - Muili, Kamaldeen A.

AU - Shugrue, Christine

AU - Kolodecik, Thomas R.

AU - Singh, Vijay Prem

AU - Lowe, Mark E.

AU - Thrower, Edwin

AU - Chen, Ju

AU - Husain, Sohail Z.

PY - 2012/11/21

Y1 - 2012/11/21

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84869761557&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84869761557&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0048465

DO - 10.1371/journal.pone.0048465

M3 - Article

VL - 7

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 11

M1 - e48465

ER -