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MCAT

Unit 2: Lesson 3

Foundation 3: Organ Systems

Pancreatitis and pancreatic cells

Problem

Pancreatitis is a disease where pancreatic digestive enzymes digest the pancreas organ. Typically digestive enzymes inside the pancreas are in an inactive form called zymogens, and the pancreas secretes these zymogens into the small intestine. Once inside the small intestine, the enzymes are activated by cleaving an end of the zymogen peptide. Inside the pancreas, zymogens along with other digestive enzymes like pancreatic amylase are packaged together inside of secretory organelles called zymogen granules.
Medical researchers hypothesize that failure to secrete zymogen granules can eventually result in activated digestive enzymes inside the pancreas, which can cause pancreatitis.
It is thought that an inositol trisphosphate pathway (IP3) regulates the release of zymogen granules. In an IP3 pathway the activation of a G-protein via a muscarinic M3 receptor releases inositol trisphosphate (IP3) into the cytosol. The IP3 molecule then binds to a IP3 receptor, opening calcium channels. As a result of these events, zymogen granules are released. Researchers have identified two IP3 receptors that are prevalent in pancreatic cells called IP3R-2 and IP3R-3.
To explore the role of these two receptors, researchers created genetically engineered mice with different pancreatic IP3 receptors in each model. See Table 1 for a summary of the mice models. A knocked out gene (abbreviated KO) no longer produces a functional receptor. Researchers discovered that Type 2 mice have twice as many zymogen granules in the cytosol as Type 1 cells.
Mouse ModelThe IPstart subscript, 3, end subscriptR-2 gene is mutated and knocked outThe IPstart subscript, 3, end subscriptR-3 gene is mutated and knocked out
Type 1: Wild Type (WT)NoNo
Type 2: IP3R-2 KOYesNo
Type 3: IP3R-3 KONoYes
Type 4: Double KOYesYes
Experiment 1 Scientists extracted pancreatic cells from the four mice models, stimulated the cells for 30 minutes with carbachol (CCh), a cholinergic stimulant, and recorded the amount of amylase released (Figure 2A).
Figure 1: The release of amylase for each mouse model with different levels of carbachol (CCh) stimulant, a cholinergic stimulant. The bars indicate the percent increase in amylase (relative to the initial level) present in pancreatic secretory cells after 30 minutes of exposure to carbachol.
Experiment 2 Cells were also exposed to increasing levels of acetylcholine and the changes in cytosolic Ca2+ levels were recorded. (Figure 2)
Figure 2: Pancreatic secretory cells stimulated by acetylcholine and the resultant cytosolic Ca2+ concentrations over time. The cells were exposed to acetylcholine ranging from 0.1 μM to 3 μM. The arrows indicate when the acetylcholine stimulated the cells.
Source: Adapted from Gerasimenko JV, Gerasimenko OV, and Petersen OH. (2014) The role of Ca2+ in the pathophysiology of pancreatitis. J Physiol. 592(Pt 2):269-80; Adapted from Orabi AI, Luo Y, Ahmad MU, Shah AU, Mannan Z, et al. (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.; Adapted from Futatsugi A, Nakamura T, Yamada ML, et al. (2005). IP3 receptor types 2 and 3 mediate exocrine secretion underlying energy metabolism. Science 309, 2232–2234
What receptor(s) is (are) required for the release of zymogen granules and their digestive enzymes?
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