5 Insulin 2 Flashcards
What channel so Sulphonylurea drugs act on?
the K+ ATP channel
What does pleiotropic?
When one factor (gene/hormone etc) influences multiple different phenotypes/systems
How does insulin act in a pleiotropic way?
Fuels homeostasis and also acts as a growth factor
In what ways does insulin fuel homeostasis? (6)
clue - it promotes and also inhibits
Promotes glucose uptake (principally muscle & adipose) • Promotes conversion of glucose glycogen (liver & muscle) • Increases FA synthesis from acetyl CoA (adipose & liver) • Inhibits lipolysis • Inhibits glycogenolysis • Inhibits gluconeogenesis
In what ways does insulin act as a growth factor? (5) (clue - think DNA)
Increases amino acid uptake • Promotes DNA synthesis i.e transcription • Promotes protein synthesis i.e. translation • Affects gene transcription of >100 genes (+ & -) • Survival factor protects from apoptosis
What is the structure of the insulin receptor?
a2b2 - 2 alpha subunits and 2 beta subunits linked by disulfide bonds.
Alpha subunits are extracallular
B subunits contain the ATP binding domain and penetrate the plasma membrane
What is the response of the insulin receptor to insulin ligand binding?
Trans autophosphorylation of B subunits at tyrosine residues.
What are the interaction domains in insulin signalling? and their function? (4)
(clue - Src, Phosphotyrosine, Pleckstrin)
1) SH2: recognise and bind to short aa sequences containing pY residues
2) PTB: recognise phosphotyrosine residues. Help to assemble large protein complexes at the insulin receptor
3) PH: Promote lipid:protein interactions. Important for activation of PI3 Kinase
4) SH3: Recognise proline-rich regions of 8-10 residues in proteins.
What allows the IRS to attach to the membrane?
a PH domain.
Explain the signal transduction by the insulin receptor, starting with the insulin receptor binding insulin.
0) Ligand binds to receptor causing dimerisation
1) Transautophosphorylation
2) The cytoplasmic domain of the receptor binds to the PTB domain of the docking protein on the insulin receptor substrate.
3) IRS becomes phophorylated by the receptor at multiple tyrosine residues
4) IRS is transformed into a docking centre for proteins with SH2 and PTB domains.
What are the 4 advantages of the IRS-multifunctional docking protein system
1) Signal amplification
2) Allow signal to propagate independently of the receptor once the IRS is phosphortlation
3) Multiple signals from a signal receptor type (allows interaction of different proteins -> different signals)
4) Signalling cross talk (shared components that can interact with either pathway)
Translocation of glucose transporters: 1. IR* -> \_\_\_\_\_ 2. PI-3K recruited to \_\_\_ via \_\_\_ domains 3. PI-3K*: \_\_\_\_ -> PIP3 4. PIP3 binds via \_\_ domain to: PDK-1 (\_\_\_\_\_\_\_\_\_\_-dependent protein kinase) 5. Activated PDK1 activate and \_\_\_\_\_\_\_\_\_ PKB (\_\_\_\_\_) and \_\_\_ (\_\_\_\_\_) 6. Downstream signalling from these kinases will lead to \_\_\_\_\_ translocation.
- IR* -> IRS-P
- PI-3K recruited to IRS via SH2
domains - PI-3K*: PIP2 -> PIP3
- PIP3 binds via PH domain to: PDK-1
(phosphoinositide-dependent protein kinase) - Activated PDK1 activate and
phosphorylate PKB (Protein Kinase B
/AKT) and PKC (protein Kinase C) - Downstream signalling from these
kinases will lead to GLUT4 translocation
Insulin signalling -> alteration of gene expression:
1. IR* trans autophosphorylation of subunits
2. IRS becomes phosphorylated (IRS-P) by the
receptor at ________ residues creating
binding sites for proteins with ___ domains
3. IRS-P interacts with the adaptor protein ____
4. ___ with its 2 SH3 domains bind to ___
5. Once activated ___ activates ___
6. Activated ___ activate the kinase ___
7. ___ phosphorylates MAP kinase leading to
activation of MAP Kinase ______ - Alteration of
gene expression
Insulin signalling -> alteration of gene expression:
1. IR* trans autophosphorylation of subunits
2. IRS becomes phosphorylated (IRS-P) by the
receptor at multiple tyrosine residues creating
binding sites for proteins with SH2 domains
3. IRS-P interacts with the adaptor protein GRB2
4. GRB2 with its 2 SH3 domains bind to Sos
5. Once activated Sos activates Ras
6. Activated Ras (Ras-GTP) activate the kinase Raf
7. Raf phosphorylates MAP kinase leading to
activation of MAP Kinase cascade - Alteration of
gene expression
What affects to Insulin and glycogen synthase kinase have on glycogen synthase?
Insulin activates glycogen synthase = glycogen synthesis
Glycogen synthase kinase phosphorylates glycogen synthase = inactive = no glycogen synthesis
What affect does insulin have on glycogen synthase kinase?
Insulin inactivates GSK by PKB and PI-3K
