L10, Signalopathies II Flashcards
1
Q
Pancreatitis: Outline
A
- Disease of the pancreas in which the proteases needed for the digestion of food in the gut are inappropriately activated inside the cells which produce them
2
Q
Acute pancreatitis:
A
- Associated with gallstones or alcoholism. hundred cases per 100,000 in UK.
- Symptoms: agonising pain, extensive pancreatic necrosis, multiple organ failure, prolonged hospitalisation
- 5% mortality rate
3
Q
Chronic pancreatitis:
A
- Due to repeated attacks of acute form
- Also linked with smoking and alcohol
- 50 cases per 100,000
- Gives rise to pancreatic cancer -> very deadly
4
Q
What are zymogens? -> link to pancreatitis
A
- Inactive enzyme precursors
- They ae synthesised in pancreatic acinar cells and stored in membrane-bound granules
- Pancreatitis follows the activation of trypsin within acinar cells (from trypisonogen)
5
Q
Review: Calcium signalling in pancreatic acinar cells
A
- Ach -> PLC activation -> IP3 release -> IP3R stimulation
- CCK -> ADP ribosyl cyclase -> NAADP and cADPR -> RyR activation
- In healthy cells, CCK in pM concentrations stimulate small Ca2+ oscillations -> fusion of ZG with acinar cell PM -> release of inactive trypsin into pancreatic duct -> activation by intestinal enteropeptidase enzyme
6
Q
CCK hyperstimulation:
A
- Higher concentrations (nM)
of CCK create sustained calcium elevations - Activation of trypsin inappropriately in ZGs within acinar cells -> digestion and destruction of ZG membrane -> digestion of acinar and surrounding tissues
- Similar effects observed by fatty acids and bile salts (POA and TLC-S)
7
Q
PKD: Overview
A
- Cystic genetic disorder with a more common AD form and and AR form
- ADPKD results from mutations in both PKD1 and 2 -> rapid proliferation of cells, loss of structural relationships with neighbouring cells, formation of large cysts
- Large muliple fluid-filled cysts typically in both kidneys -> massive enlargement of the kidneys, disruption of kidney function and severe renal failure
8
Q
What do PKD1 and 2 encode? Structure and function:
A
- PC1 has a receptor-like structure, can interact with other proteins at E- and I-C sites
- PC2 is a calcium-permeable channel which is homologous to TRP channels, with an EF hand domain
- The two interact via their C-terminal domains
9
Q
PC1 and PC2 location and interactions:
A
- Found in primary cilia of kidney tubular epithelial cells
- PC1-PC2 complex responds to ciliary bending and may mediate the transduction of mechanical and chemical stimuli
10
Q
In normal kidney cells, how does calcium regulate cell proliferation?
A
- Via calcium or via cAMP…
- A number of calcium influx pathways including PC1-PC2
- When active, allows maintenance of normal calcium levels, inhibiting B-Raf via PI3K and Akt -> preventing Ras/Raf signalling for cell proliferation
- Additionally, normal levels of cAMP is produced through AC-receptor binding -> PKA activation -> phosph. of Raf-1 (similar inactivation and subsequent proliferation)
- Raf-1 and B-Raf are major players in Ras/Raf signalling
11
Q
Regulation of proliferation (Ras/Raf) in PKD kidney cells:
A
- Low calcium and PC1-PC2 knockout; relieves inhibition of B-Raf
- Additionally, leads to increased [cAMP] -> high [cAMP] activates PKA -> Ras -> B-Raf -> cell proliferative signalling
- Activity of adenylate cyclase (makes cAMP) and phosphodiesterase (produces 5’ AMP, using up cAMP) are calcium dependent -> low [Ca2+] encourages cAMP production via adenylate cyclase and inhibits breakdown via PDE1!
12
Q
MAPK remodelling hypothesis of PKD:
A
- Increasing B-Raf expression due to reduced [Ca2+] (phenotypic remodelling)
- Also, activating B-Raf
- Extreme proliferative signals as a result
13
Q
Huntington’s disease: Overview
A
- One of most common genetic disorders; 5-10 cases per 100,000
- AD neurodegenerative disease causing irregular movements, cognitive and psychiatric disorders -> fatal within 15-25 yrs of diagnosis
- Marked loss of grey matter in patients
14
Q
Huntingtin:
A
- Produced by Htt gene
- Ubiquitously expressed
- Various functions including impacting post-synaptic density signalling
15
Q
Post synaptic density signalling in healthy individuals:
A
- Htt interacts strongly with NMDAR complex, but weakly with IP3R
- As a result, activational stimulation by glutamate causes influx of calcium (through NMDAR) and increased IP3R and thus I-C calcium release (through mGluR5)
- Low sensitivity of Ip3R to Ip3
- Generation of non-pathogenic calcium signals
