Signalopathies 2

Question 1

Pancreatitis

Answer 1

Proteases for food digestion in the gut are activated in the cells which produce them
Digest the pancreas

Acute pancreatitis caused by gallstones/alcohol. Pain and pancreatic necrosis
Chronic pancreatitis due to repeat acute attacks. Heavy alcohol consumption/smoking
Can lead to pancreatic cancer

Question 2

Zymogens

Answer 2

Inactive enzyme precursors synthesised in pancreatic acinar cells
Stored in membrane bound granules (zymogen granules)
Trypsinogen (zymogen) activation to trypsin in acinar cells leads to pancreatitis

Question 3

Ca2+ signalling in pancreatic acinar cells

Answer 3

CCK (cholecystokinin) binding stimulates Ca2+ oscillations in acinar cells
Triggers fusion of ZG with plasma membrane
Inactive trypsin released into pancreatic duct
Trypsin activated by intestinal enteropeptidase

Question 4

Ca2+ signalling in pancreatitis

Answer 4

Hyperstimulation of CCK causes sustained global increase in cytosolic Ca2+
Triggers trypsin activation in ZG within acinar cell
Digestion of ZG membrane and destruction of acinar cells

Question 5

Polycystic kidney disease

Answer 5

Autosomal dominant (ADPKD) is most common. Also autosomal recessive (ARPKD)
Large multiple fluid-filled cysts typically in both kidneys
Enlargement of kidneys and disruption of function

Question 6

PKD1 and PKD2

Answer 6

Genes mutated in ADPKD
Encode proteins polycystin 1/2 (PC1/2)
PC1 interacts with proteins at intracellular sites.
PC2 is Ca2+ permeable channel (homologous to TRP)
Interact via C-terminal domains
Located on primary cilia of kidney tubular epithelial cells

Question 7

Normal kidney cells

Answer 7

PC1/2 help to maintain normal levels of Ca2+ (allow influx)
Activates protein kinase B which inhibits B-raf
Normal cAMP activates protein kinase A which inhibits Raf-1
Cell proliferation inhibited

Question 8

Polycystic kidney cells

Answer 8

PC1/2 lost leading to low cellular Ca2+
Relieves protein kinase B inhibition of B-Raf
Increases cAMP (Ca2+ normally inhibits adenylate cyclase and stimulates phosphodiesterase)
High cAMP activates B-Raf via Ras
Cell proliferation stimulated through MEK/ERK

Question 9

MAPK remodelling hypothesis

Answer 9

Low Ca2+ leads to phenotypic remodelling
Increased expression of cAMP-insensitive isoform (B-Raf)
Transmission of proliferation signals

Question 10

Post synaptic density signalling

Answer 10

Htt interacts strongly with NMDAR complex and weakly with IP3R
Glutamate activates NMDAR receptor leading to Ca2+ influx and mGluR5 leading to increased IP3
Non-pathogenic Ca2+ signals

Question 11

PSD signalling in Huntington’s disease

Answer 11

PolyQ expansion in N terminus of Huntingtin
Enhances NMDAR (increased Ca2+ influx)
Sensitises IP3R to IP3 (increased Ca2+ release)
Low ER calcium increases release
Increased Ca2+ influx via vGCC
Loss of Ca2+ binding proteins
Triggers downstream pathogenic pathways

Question 12

Gene therapies for Huntington’s disease

Answer 12

Antisense oligonucleotides are DNA/RNA modify protein production
Bind RNA made by faulty genes
Suppresses mutant and healthy Htt protein
Alternative is adeno-associated virus

Question 13

CaV1.2 hypofunction

Answer 13

Deficit in memory consolidation

Involved in LTP in hippocampus

Question 14

PKD treatment

Answer 14

Tolvaptan used to slow growth of cysts