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 Ca(2+). These aberrant Ca(2+) elevations are triggered by release of Ca(2+) from apical Ca(2+) 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 Ca(2+) release channel (IP3R2(-/-)). Using live acinar cell Ca(2+) imaging we found that loss of IP3R2 reduced the amplitude of the apical Ca(2+) 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 Ca(2+) signals and pancreatic enzyme secretion. IP3R-deficient acinar cells accumulate ZGs, but the mice do not succumb to pancreatic damage or worse pancreatitis outcomes.
authors.affiliation: Department of Pediatrics, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
authors.forename: Abrahim I
authors.initials: AI
authors.lastname: Orabi
authors.forename: Yuhuan
authors.initials: Y
authors.lastname: Luo
authors.forename: Mahwish U
authors.initials: MU
authors.lastname: Ahmad
authors.forename: Ahsan U
authors.initials: AU
authors.lastname: Shah
authors.forename: Zahir
authors.initials: Z
authors.lastname: Mannan
authors.forename: Dong
authors.initials: D
authors.lastname: Wang
authors.forename: Sheharyar
authors.initials: S
authors.lastname: Sarwar
authors.forename: Kamaldeen A
authors.initials: KA
authors.lastname: Muili
authors.forename: Christine
authors.initials: C
authors.lastname: Shugrue
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Kolodecik
authors.forename: Vijay P
authors.initials: VP
authors.lastname: Singh
authors.forename: Mark E
authors.initials: ME
authors.lastname: Lowe
authors.forename: Edwin
authors.initials: E
authors.lastname: Thrower
authors.forename: Ju
authors.initials: J
authors.lastname: Chen
authors.forename: Sohail Z
authors.initials: SZ
authors.lastname: Husain
mesh_terms: D061354:Acinar Cells / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D000681:Amylases / Q000097:blood / Q000378:metabolism; D000818:Animals; D020013:Calcium Signaling; D016764:Cell Polarity; D002108:Ceruletide / Q000378:metabolism; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000172:deficiency* / Q000378:metabolism; D008297:Male; D051379:Mice; D010179:Pancreas / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology* / Q000648:ultrastructure; D022142:Secretory Vesicles / Q000378:metabolism* / Q000648:ultrastructure
chemical_list: D053496:Inositol 1,4,5-Trisphosphate Receptors; C580990:Ip3r2 protein, mouse; D002108:Ceruletide; D000681:Amylases