Week 2: Pancreas Physiology

Question 1

Describe intracellular signaling pathways activated by CCK and Ach.

Answer 1

• CCK or Ach attaches to CCKR or M3AChR respectively
• which are coupled with Gaq and Ga11
• activated, they activate phospholipase Cbeta, which hydrolyzes PIP2. IP3 and DAG are released
• second messengers: IP3 interacts with IP3 receptor on ER, permits flow of stored Ca to cytosol
• DAG and Ca activate PKC
• Ca activates Ca calmodulin dependent kinase

Question 2

Steps in secretory vesicle exocytosis

Answer 2

• Ca promotes docking
• T-SNARES and V-SNARES bind with each other. Ca activates confirmation change in Snares to cause fusion
• actin physically blocks docking, and Ca causes actin filaments to reorganize and activates myosin motors to more forcefully expel contents of vesicle into lumen
• the secretory vesicle membrane is retrieved for recycling

Question 3

Ca2+ oscillations and supra maximal stimulation

Answer 3

• process of secretory vesicle exocytosis depends on cytosolic Ca oscillations
• supramaximal stimulation: when CCK exceeds optimal dose, secretion of amylase decreases. Ca levels remain elevated but oscillations cease. Gaq and Ga11 are constantly active
• this doesn’t happen with Ach because it is short lived and easily hydrolyzed by cholinesterase
• exocytosis stops because actin filament network stays disrupted and does not reform, unable to form around secretory vesicles.

Question 4

Pathogenesis of acute hemorrhagic pancreatitis

Answer 4

• secretory vesicles with zymogen granules transformed into aqueous vacuoles
• vacuole starts to accumulate lysosomal hydrolases, which can do the same thing enterokinase does.
• activates zymogens within these vacuoles, trypsin activates the other zymogens, and destroys the cell membrane
• cell ruptures, and active pancreatic proteases released into storm. Destroys tissue and blood vessels. Inflammation mediated by PMNS, exacerbates tissue damage

Question 5

What are the lysosomal hydrolyses?

Answer 5

1. proenzymes
   - procathepsins
   - prophospholipases
2. active enzymes
   - glycohydrolases: lysozyme, b-hexosaminidase

Question 6

Normal trafficking of zymogens to granules

Answer 6

• vesicle buds from TGN
• homotypic fusion: vesicles fuse to form immature secretory vesicles
• vesicles get bigger with more contents, but changes surface area to volume ratio. Excess membrane retrieved from vesicles and go back to TGN

Question 7

Trafficking of lysosomal hydrolyses to lysosomes

Answer 7

• Path 1: TGN to recycling endosome and early endosome to late endosome to storage lysosome and prelysosome to mature lysosome
• Path 2: TGN to late endosome to storage lysosome and prelysosome to mature lysosome

Question 8

what happens when lysosomal hydrolase traffic to late endosome is blocked?

Answer 8

• with chronic elevation of Ca and exocytosis blocked. Trafficking to late endosome is also blocked.
• lysosomal hydrolases reflux into early endosome, recycling endosome, and TGN
• they are also carreid to immature secretory vesicles where they activate pancreatic enzymes