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Pancreatitis studies
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[ID] => 554751
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[post_date] => 2024-12-23 18:25:09
[post_date_gmt] => 2024-12-23 23:25:09
[post_content] => Practice Passage (Question 1-6)
*This passage is the property of Khan Academy and has been reformatted into an AAMC-style interface in their entirety by MedLife Mastery. MedLife Mastery does not endorse and is not an affiliate of Khan Academy.
Pancreatitis is a disease in which the pancreas self-digests. Typically, digestive enzymes inside the pancreas are in an inactive form – the so-called zymogen form. The pancreas secretes these zymogens into the small intestine, where they are activated to become fully functional enzymes. Inside the pancreas, zymogens and other digestive enzymes, such as pancreatic amylase, are packaged together inside secretory organelles called zymogen granules. Failure to secrete zymogen granules may eventually result in activated digestive enzymes inside the pancreas, which can cause pancreatitis.
It is thought that the inositol trisphosphate (IP3) pathway regulates the release of zymogen granules. In the 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 an 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: IP3R-2 and IP3R-3. To explore the role of these two receptors, researchers created genetically engineered mice with knockouts (KOs) in the IP3R-2 and IP3R-3 genes. Next, they performed the following experiments, comparing wild-type mice to mice with IP3R-2 and/or IP3R-3 knockouts.
Experiment 1
Researchers extracted pancreatic cells from mice in each of the four groups (wild type, IP3R-2 KO, IP3R-3 KO and IP3R-2/IP3R-3 double KO). The cells were simulated with carbachol (CCh), a cholinergic stimulant. Figure 1 shows the percent increase in amylase over baseline, after 30 minutes of exposure to carbachol.
Figure 1 Percent increase in amylase release after 30 minutes of exposure to carbachol
Experiment 2
Researchers exposed pancreatic cells to increasing levels of acetylcholine (ranging from 0.1 μM to 3 μM). Changes in cytosolic Ca²⁺ levels were monitored and recorded. The results are shown in Figure 2.
Figure 2 Cytosolic Ca²⁺ concentrations over time; arrows indicate the addition of acetylcholine
Sources: Gerasimenko JV et al - The role of Ca2+ in the pathophysiology of pancreatitis (2014); Orabi AI et al - IP3 Receptor Type 2 Deficiency Is Associated with a Secretory Defect in the Pancreatic Acinar Cell and an Accumulation of Zymogen Granules (2012); Futatsugi A et al - IP3 receptor types 2 and 3 mediate exocrine secretion underlying energy metabolism (2005)
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[quiz_unique_key] => 602779517
[question] => What receptor(s) is (are) required for the release of zymogen granules and their digestive enzymes?
[value] => Array
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[answer] => 3
[description] => Reason for Correct Answer:
Amylase is a digestive enzyme that is included in zymogen granules.
Figure 1 shows amylase release after stimulation of normal pancreatic cells (wild type) or cells with a knockout (KO) in IP3R-2 and/or IP3R-3.
If “the release of zymogen granules and their digestive enzymes” is NOT occurring, then amylase release will NOT increase. This result is only seen for this group:
Because the release of amylase occurred in the IP3R-2 KO group and the IP3R-3 KO group, but NOT in the double KO group, you can conclude that zymogen granules and enzymes are released if EITHER IP3R-3 or IP3R-2 is present, but not if they are both absent.
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[answers] => Array
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[0] => Array
(
[each_answer] => A. IP3R-2 only
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[1] => Array
(
[each_answer] => B. IP₃R-3
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[2] => Array
(
[each_answer] => C. Either IP3R-2 or IP3R-3
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[3] => Array
(
[each_answer] => D. Neither IP3R-2 nor IP3R-3
)
)
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[1] => Array
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[quiz_unique_key] => 1403770772
[question] => What happens to cytosolic levels of calcium in double-KO mice when pancreatic cells are exposed to 2.0 μM acetylcholine?
[value] => Array
(
[answer] => 4
[description] => Reason for Correct Answer:
Acetylcholine will trigger the IP3 pathway via the “muscarinic M3 receptor” mentioned in Paragraph 2.
Figure 2 shows whether the cytosolic calcium levels change in the different knockout mice on exposure to acetylcholine.
In Figure 2, the double-KO mice do not show a significant change in cytosolic Ca2+ levels for either 1 μM or 3 μM of acetylcholine.
Therefore, it is reasonable to assume that the Ca2+ levels in response to 2 μM of acetylcholine will not change significantly and will remain at the normal base level.
)
[answers] => Array
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[0] => Array
(
[each_answer] => A. The Ca2+ levels increase.
)
[1] => Array
(
[each_answer] => B. The Ca2+ levels decrease.
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[2] => Array
(
[each_answer] => C. The Ca2+ levels stay the same for a little while then increase.
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[3] => Array
(
[each_answer] => D. The Ca2+ levels do not change significantly.
)
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[2] => Array
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[quiz_unique_key] => 1403770772
[question] => Researchers observed that mice with an IP3R-2 knockout have twice as many zymogen granules in the cytosol as wild-type mice. This suggests which of the following must be inhibited in IP3R-2 KO mice?
[value] => Array
(
[answer] => 2
[description] => Reason for Correct Answer:
IP3R-2 KO mice are not likely to produce more zymogen granules than wild-type mice, since the IP3 pathway does not involve zymogen granule production.
Zymogen granules are typically secreted from the cell.
If exocytosis was working normally, the secretory zymogen granule vesicles would be secreted outside the cell and would not be trapped inside the cell. Instead, the vesicles in IP3R-2 KO mice are unable to undergo exocytosis at the same level as normal wild-type mice.
)
[answers] => Array
(
[0] => Array
(
[each_answer] => A. Trypsinogen activity
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[1] => Array
(
[each_answer] => B. Exocytosis of vesicles
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[2] => Array
(
[each_answer] => C. cAMP generation
)
[3] => Array
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[each_answer] => D. An intrinsic factor
)
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[3] => Array
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[quiz_unique_key] => 1403770772
[question] => What would most likely happen if Ca²⁺ ions were introduced into the cytosol of double-KO pancreatic cells?
[value] => Array
(
[answer] => 3
[description] => Reason for Correct Answer:
The IP3 pathway and its effects are described in Paragraph 2.
Paragraph 2 states that the binding of IP3 to its receptor results in calcium channel opening, which leads to zymogen release.
Calcium is needed for exocytosis, so you can assume that the opening of these calcium channels causes intracellular calcium to increase (and that the receptors are likely on the endoplasmic reticulum, as shown).
The addition of calcium to the cells that lack IP3 receptors would likely counter the effect of the mutations, providing the calcium needed for exocytosis/secretion of amylase and other enzymes.
)
[answers] => Array
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[0] => Array
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[each_answer] => A. Nothing would happen because the KO genes alter the endoplasmic reticulum where the Ca²⁺ is stored.
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[1] => Array
(
[each_answer] => B. Ca²⁺ ions would be sequestered by the endoplasmic reticulum and would have no effect on the cell.
)
[2] => Array
(
[each_answer] => C. Amylase would be secreted because Ca²⁺ ions would counter the effect of the IP3 receptor mutations.
)
[3] => Array
(
[each_answer] => D. Amylase would not be secreted because double-KO cells can not produce amylase.
)
)
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[4] => Array
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[quiz_unique_key] => 1403770772
[question] => The enzymes chymotrypsin and trypsin are normally activated in the small intestine. Which of the following peptide sequences is most likely to be cleaved by both chymotrypsin and trypsin?
[value] => Array
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[answer] => 2
[description] => Reason for Correct Answer:
Chymotrypsin and trypsin are both serine proteases that cleave peptide bonds adjacent to specific amino acid residues.
Chymotrypsin cleaves after aromatic amino acids such as phenylalanine (F), tryptophan (W), and tyrosine (Y).
Trypsin cleaves after basic amino acids such as lysine (K) and arginine (R).
Among the given options, only Choice B contains both basic amino acids (K and R) and aromatic amino acids (Y and F) in positions that are not at the very end of the chain, making it likely to be cleaved by both chymotrypsin and trypsin.
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[answers] => Array
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[0] => Array
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[each_answer] => A. FLEEAWCSLR
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[1] => Array
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[each_answer] => B. KRSTVYILGN
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[2] => Array
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[each_answer] => C. QPDGMFTACN
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[each_answer] => D. HINQCLVPKS
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[quiz_unique_key] => 1997864699
[question] => To activate the zymogen of a particular serine protease, the peptide bond between amino acid 15 (arginine) and 16 (isoleucine) is cleaved. What might explain why this activates the enzyme?
[value] => Array
(
[answer] => 2
[description] => Reason for Correct Answer:
This question is talking about the activation of an enzyme such as chymotrypsin by the cleavage of a zymogen such as chymotrypsinogen (note that the question is NOT talking about the cleavage reaction of a peptide that is catalyzed by an enzyme such as chymotrypsin). So, it’s asking you why the cleaved form is active but the uncleaved form is not.
The catalytic residues of serine proteases (the ‘catalytical triad’) are serine, histidine and aspartic acid. The side chains (not the termini) of these residues are active in the mechanism (therefore, you can eliminate Answers C and D).
The amino acids in a peptide chain are numbered from the amino terminus (N-terminus) to the carboxyl terminus (C-terminus), and cleavage occurs between the carboxy terminus of the lower-numbered amino acid and the amino terminus of the higher-numbered amino acid.
Only arginine 15 will have a free carboxyl terminus (C-terminus), whereas only isoleucine 16 will have a free amino terminus (N-terminus), after cleavage. Therefore, you can eliminate Choices A and D.
Cleavage of zymogens usually induce structural changes that cause the catalytic residues to become correctly organized, making the enzyme functional, as in Choice B. Generally, free amino or carboxy termini do not become active as a “catalytic residue,” as in Choice C and D, as R groups on amino acids are more likely to engage as catalytic residues in the active sites of enzymes.
)
[answers] => Array
(
[0] => Array
(
[each_answer] => A. The free carboxyl terminus of isoleucine 16 causes a conformational change that results in the correct organization of the catalytical residues.
)
[1] => Array
(
[each_answer] => B. The free amino terminus of isoleucine 16 causes a conformational change that results in the correct organization of the catalytical residues.
)
[2] => Array
(
[each_answer] => C. The free carboxyl terminus of arginine 15 can now act as a catalytic residue.
)
[3] => Array
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[each_answer] => D. The free amino terminus of arginine 15 can now act as a catalytic residue.
)
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[554751|1] => C
[554751|2] => D
[554751|3] => B
[554751|4] => C
[554751|5] => B
[554751|6] => B
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Figure 1
Figure 2
