Flashcards in Lecture 22: Hormone Regulation & Signal Transduction Deck (67)
Which insulin chain is longer: A or B?
B (30 AAs) vs A (21 AAs)
The uptake of what kind of AAs is stimulated by insulin?
Glucogenic = branched AAs
What 5 metabolic processes does insulin stimulate?
1. Glucose uptake by muscles, adipocytes, and heart via GLUT 4
2. FA/TAG synthesis
3. Glycogen synthesis in muscles and liver
4. Glucogenic AA uptake/protein synthesis
What 4 metabolic processes does insulin inhibit?
What 4 metabolic processes does glucagon stimulate?
1. Glycogenolysis in liver and kidney
4. Lipolysis (but not super active)
What 3 metabolic processes does glucagon inhibit?
2. Glycogen synthesis
3. FA synthesis
What metabolic processes are stimulated by catecholamines?
1. Glycogenolysis in muscle and liver
How does insulin stimulate glycogen synthesis? 3 ways
1. Activates glycogen synthase by stimulating PP1 to dephosphoralate it
2. Inhibits glycogen phosphorylase by stimulating PP1 to dephosphoralate it
3. Inhibits the inhibition of glycogen synthase by inhibiting GSK-3 to phosphorylate it
Does glucagon affect muscles?
How does glucagon stimulate glycogen breakdown? In which tissues?
1. Activates glycogen phosphorylase in liver and kidney by stimulating phosphorylase kinase to phosphorylate it
2. Inhibits the activation of glycogen synthase by inhibiting its dephosphorylation by PP1
How does glucagon inhibit glycolysis?
Lowers F-2,6-BP levels
How does glucagon stimulate lipolysis?
It binds adrenergic receptors, activating PKA to phosphorylate hormone sensitive lipase, activating it
How do catecholamines stimulate lipolysis?
They bind adrenergic receptors, activating PKA to phosphorylate hormone sensitive lipase, activating it
How do catecholamines impact metabolism when we are under high stress conditions?
They induce FA beta oxidation in muscle to preserve the body's glucose for the brain (on top of simply inhibiting glucose uptake)
How do catecholamines affect insulin and glucagon?
They inhibit insulin secretion and stimulate glucagon secretion
What stimulates the secretion of insulin?
Where does the C-peptide get cleaved off?
Describe the insulin secretion pathway.
1. Glucose enters pancreatic beta cells via GLUT2 transporters
2. Glucose is phosphorylated by hexokinase 4 to G6P (trapping it inside the cell)
3. ATP produced through glycolysis, TCA, and ETC
4. ATP binds to the K+ channels and inhibit them = cell depolarization
5. VG calcium channels on plasma membrane and ER open and calcium rushed in
6. Fusion of insulin containing granules with plasma membrane = insulin release
Describe GLUT 2 and hexokinase 4's affinities for glucose. What does this mean for the kinetics of the reactions?
Very high Kms: linear kinetics, meaning the concentration of glucose in the beta cells is proportional to the concentration of glucose in the blood because an enzyme with a high Km achieves maximum rate at a higher concentration. Thus, it will continue to respond to higher concentrations by increasing its rate. It thus "responds" to a greater range of concentrations.
Describe the glucose uptake mechanism by GLUT 4 and glycogen synthesis stimulation starting with insulin binding to its receptor (8 steps)
Where does this happen?
1. Insulin binds to α subunits insulin receptor = dimerization
2. Conformational change in cytosolic side of β subunits
3. Autophosphorylation of receptor tyrosine kinase on cytosolic side
4. Signaling cascade including phosphorylation of IRS-1
5. IRS-1 activates phosphoinositide 3-kinase (PI-3K)
6. PI-3K phosphorylates PIP2 = PIP3
7. PIP3 activates PKB which is bound to it
8a. PKB stimulates GLUT 4 vesicles to fuse with the plasma membrane
8b. PKB phosphorylates GSK-3, inactivating it = favors glycogen synthesis
Describe the insulin receptor.
1. 2 α subunits on the exterior side of plasma membrane
2. 2 β transmembrane subunits connected to the α subunits and protruding in the cytosol
How does exercise affect the insulin endocrinology?
1. Increases insulin sensitivity
2. Promotes other signaling pathways that can bypass the insulin transduction to uptake glucose by activating an AMP-dependent kinase that increases GLUT4s independently of insulin
Describe the transduction pathway of beta-adrenergic receptors on the liver. 8 steps
1. Binding releases GDP from the Gs part of the receptor and GTP binds instead
2. Gs bound to GTP binds to adenylyl cyclase to activate it
2. Adenynyl cyclase converts ATP into cAMP + PPi
3. cAMP activates PKA
4. PKA phosphorylates:
- Phosphorylase kinase
- Glycogen synthase
- Phosphoprotein phosphatase
5. Phosphorylase kinase a phosphorylates glycogen phosphorylase b and glycogen synthase a
6. Glycogen phosphorylase a breaks down glycogen into G1P
7. G1P converted to glucose G6P and then dephosphorylated by G6P phosphatase
8. Glucose released into blood via GLUT 2
What 2 substrates can bind to beta-adrenergic receptors to stimulate glucose release?
How is ATP converted to cAMP?
3' (-OH) attacks the alpha phosphate
How is the signaling pathway of activated beta adrenergic receptors stopped?
Phosphodiesterase degrades cAMP to AMP
Describe the structure of PKA
1. 2 catalytic subunits that dimerize in the inactive state
2. 2 regulatory subunits = dimer
What is another name for PKA?
cAMP-dependent protein kinase
Describe the activation of PKA by cAMP. 2 steps
1. 2 cAMP bind to each regulatory subunits of PKA
2. 2 regulatory subunits release the catalytics subunits