Insulin signalling Flashcards
1
Q
What is preproinsulin?
A
- signal directs it to ER and is removed making proinsulin
- In golgi further modification makes insulin
2
Q
How does high glucose cause the release of insulin?
A
- High glucose -> ATP/ADP much greater than 1
- prevents ATP dependent K channel from depolarizing
- Builds up action potential
- Ca2+ channels open through signal, releasing spike of Ca
- Ca pumped out (PMCA) and intracellular stored (SERCA)
- Opens voltage dependent channel to reduce potential
- Also releases insulin
3
Q
What is required for feedback loop oscillations?
A
- Uneven number of negative loops
4
Q
What are the layers of insulin oscillation?
A
- b cell, Ca cycle
- islet, Kir6gap junctions + diffusible factors
- pancreas, intrapancreatic nerves, diffusible factors
5
Q
How can Acetylcholine (ACh) regulate insulin release?
A
- ACh released during feeding
- G protein and second messenger IP3
- Pump Ca from ER to cytoplasm
6
Q
How is glucose imported in b cells?
A
- GLuT2 imports
- phosphorylation to G6P by glucokinase
- Consumed via mt metabolism to release ATP
7
Q
How does insulin bind to Tyrosine kinase?
A
- Translocate from vesicles
- Insulin binds to insulin receptor (InsR) dimer
- Receptor tyrosine kinases (RTKs) are commonly used by growth factors
- Regulated by forming dimers
- src homology (SH2) binds to phosphotyrosine binding domain (PTB)
8
Q
What binds to the tyrosine kinase in insulin signalling?
A
- Insulin receptor kinase (IRS)
- Has PTB domain binding to phosphotyrosines
- Has pleckstrin homology (PH) domain binding to plasma membrane
9
Q
How does phoaphatidylinositol 3 kinase (PI3K) bind to IRS?
A
- SH2 domain binds to phosphorylated tyrosine residues
- Allows many proteins to bind to IRS scaffold
- PI3 kinase binds to IRS
10
Q
What is a defining property of secondary messengers?
A
- Released in response to signal
- broken down by phosphatases to regulate signal
11
Q
How do PI3Ks produce a signal?
A
- Degrade PIP3 into PIP2
- Activated by tyrosine kinases or G proteins
- PI3Ks consist of catalytic and regulator subunit (SH2)
- Creates region of PIP3 and PIP2 which allows recruitment of signal proteins to plasma membrane
12
Q
What is PIP3’s function?
A
- Constrained to plasma membrane
- Recruits proteins to plasma membrane via PH domains
- It helps move/localize signal proteins from cytoplasm to plasma membrane
- For insulin PDK1 and Ak1 are recruited
13
Q
How are PDK1 and Akt regulated?
A
- PDK1 constitutively active by continuously autophosphorylating
- PIP3 recruits it to membrane, bringing it to target Akt
- Akt requires phosphorylation
- Akt binding site made available by binding to PIP3
- Akt is coincidence detector of PIP3 and PDK1
14
Q
How does Akt cause release of GluT4?
A
- Increases translocation of GluT4 vesicles to plasma membrane
- Akt inactivates Rab GTPase activating protein (RabGAP)
- Hydrolyses GTPases to inactivate them
- Hypothesis: GluT4 vesicles tethered to plasma membrane but bind only when Rab GTPases no longer inhibited
