Insulin Signalling Flashcards
Name 5 things insulin has effect on in diff time frames
Glycogen synthase stimulation
Aa transport
Ion flux regulation
Regulation of txn
Stimulates cell division
What effects of insulin take hours
Cell division and regulation of txn
Insulin has long and short effects. What is this called
Acute and chronic
Does insulin only work at nucleus eg for gene txn
No , can work at membrane to have effect eg glut4
How many insulin need to bind receptor
1 because already dimerised
What produces preproinsulin
B cells
What happens to pre pro insulin 81-86 aa in the er
Gets cleaved and folded into a 51 aa chain and forms 3 ss bonds
What is the new folded, bonded 51 aa insulin called from er
Proinsulin
What acts on proinsulin 51aa in the Golgi
Carboxypeptidase e
Pro hormone convertases 1 and 2
What are carboxypeptidases and prohormoone convertases for
Release c peptide forming insulin
What is insulin stored with
Stored with zinc in secretory granules
What does insulin release due to hyperglycaemia block
Glucagon release from a cells
What causes insulin release
Glucokinase starting glycolysis
When glucose enters B cell via glut2 glucokinase starts glycolysis
The production of atp blocks k channels and causes depolarisation
Ca voltage channels open and ca floods in
Secretory granules with insulin fuse with membrane
Explain structure of insulin receptor
A and b subunits dimer
A has the insulin ligand bs
Held to eachother by s-s between a-a and each a-b = 3 ss bonds
Tyrosine residues on the tk domain of b subunits get phosphorylated, what effects do these have
Can cause irs binding , or stimulate kinase activity
What do ser/thr residues on b subunits stop
Block kinase activity
Which tyr allows irs binding
T960
There are 2 types of irs what’s the difference
Different regulation eg diff phos of ser/thr to block them
Which residue gets phos to activate irs
Tyrosine
Which domains of other proteins bind residues of Irs specifically
Sh2 of grb2 and pi3k
Which domain of irs binds phosphorylated tyrosine residues of insulin receptor
Phosphotyrosine binding PTB
What is the ph domain
Binds phosphoinositol in lipids of membrane
How is sh2 specific for binding of proteins to irs docking protein
Phosphotyrosine residues of irs are flanked by specific aa sequences recognised by either grb2 or pi3k sh2
What is sh3 on grb2
Binds proline regions of sos guanine exchange factor
Explain the steps of the Ras pathways
Grb2 sh2 binds pt residues of irs
Sh3 domain binds sos
Sos exchanges ras gdp for gtp
Ras activates raf mapkkk
Phos of Mek mapkk
Phos of erk mapk
What is the Ras pathway for
Differentiation, growth, survival
What does irs activate in the Ras independent path via sh2
Pi3k
What does pi3k phosphorylate in membrane
I bisphosphate forming pi3 - 4,5 phosphoinositol triphosphate
Which then activates akt (pkb) via phosphorylation
How does akt affect glucose uptake of adipocytes and liver
Glut4 vesicles activation
How does akt allow glycogen synthase activation
Phosphorylates glycogen synthase kinase which inactivates its action of GS
What target of akt allows protein synthesis to block high BGC
Mtor
What gets activated to block lipolysis and release of free fa/glycerol
Pde3b
What does pde3b do
Block action of HSL which causes lipolysis eg triacylgycerol lipase
What happens to free fa to allow production of acetyl coa
B oxidation
What effects does glucagon have produced by a cells to increase BGC
Reduced glycogenesis and glycolysis
Increased gluconeogenesis and glycogenolysis and lipolysis
What type of receptor is glucagon receptor and what secondary messengers is activated
Gpcr
Activates the ac so camp and pka activation
How does pka block glycogenesis
It can phosphorylate glycogen synthase to block it
Which tf for gluconeogenesis is activated by pka
Creb
What 2 enzymes for gluconeogenesis increased by creb tf
Glucose 6 phosphatase
Phosphoenolpyruvate pep kinase (oxaloacetate into pep)
Other than creb how does pka allow increased glucose via glycogenolysis
Activates glycogen phosphorylase
How is glycolysis blocked by glucagon
Reduced pfk so less fructose 1,6 bis production
Which enzyme is activated to release free fa and glycerol in glucagon signal = lipolysis
Triacylglycerol lipase (triacylglycerol to diacylglycerol)
How is free fa balance important and blocked in diabetes bc of no insulin
Free fa can be b oxidated back into acetyl coa
acetyl coa allows tca progression
Too much acetyl coa blocks glucose conversion to pyruvate so increases glucose (because blocks pyruvate dehydrogenase)
Also increases citrate through tca which blocks Pfk for glycolysis = more glucose, no energy
