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SMP - MNE Exam 2 > Lecture 22: Hormone Regulation & Signal Transduction > Flashcards

Lecture 22: Hormone Regulation & Signal Transduction Flashcards

1
Q

Which insulin chain is longer: A or B?

A

B (30 AAs) vs A (21 AAs)

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2
Q

The uptake of what kind of AAs is stimulated by insulin?

A

Glucogenic = branched AAs

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3
Q

What 5 metabolic processes does insulin stimulate?

A
  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
  5. Glycolysis
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4
Q

What 4 metabolic processes does insulin inhibit?

A
  1. Glycogenolysis
  2. Lipolysis
  3. Proteolysis
  4. Gluconeogenesis
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5
Q

What 4 metabolic processes does glucagon stimulate?

A
  1. Glycogenolysis in liver and kidney
  2. Gluconeogenesis
  3. Ketogenesis
  4. Lipolysis (but not super active)
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6
Q

What 3 metabolic processes does glucagon inhibit?

A
  1. Glycolysis
  2. Glycogen synthesis
  3. FA synthesis
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7
Q

What metabolic processes are stimulated by catecholamines?

A
  1. Glycogenolysis in muscle and liver
  2. Gluconeogenesis
  3. Lipolysis
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8
Q

How does insulin stimulate glycogen synthesis? 3 ways

A
  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
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9
Q

Does glucagon affect muscles?

A

NOPE

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10
Q

How does glucagon stimulate glycogen breakdown? In which tissues?

A
  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
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11
Q

How does glucagon inhibit glycolysis?

A

Lowers F-2,6-BP levels

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12
Q

How does glucagon stimulate lipolysis?

A

It binds adrenergic receptors, activating PKA to phosphorylate hormone sensitive lipase, activating it

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13
Q

How do catecholamines stimulate lipolysis?

A

They bind adrenergic receptors, activating PKA to phosphorylate hormone sensitive lipase, activating it

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14
Q

How do catecholamines impact metabolism when we are under high stress conditions?

A

They induce FA beta oxidation in muscle to preserve the body’s glucose for the brain (on top of simply inhibiting glucose uptake)

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15
Q

How do catecholamines affect insulin and glucagon?

A

They inhibit insulin secretion and stimulate glucagon secretion

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16
Q

What stimulates the secretion of insulin?

A

GLUCOSE ONLY

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17
Q

Where does the C-peptide get cleaved off?

A

The Golgi

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18
Q

Describe the insulin secretion pathway.

A
  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
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19
Q

Describe GLUT 2 and hexokinase 4’s affinities for glucose. What does this mean for the kinetics of the reactions?

A

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.

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20
Q

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?

A
  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

Muscles/adipocytes

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21
Q

Describe the insulin receptor.

A
  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

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22
Q

How does exercise affect the insulin endocrinology?

A
  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
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23
Q

Describe the transduction pathway of beta-adrenergic receptors on the liver. 8 steps

A
  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
  3. Adenynyl cyclase converts ATP into cAMP + PPi
  4. cAMP activates PKA
  5. PKA phosphorylates:
    - Phosphorylase kinase
    - Glycogen synthase
    - Phosphoprotein phosphatase
  6. Phosphorylase kinase a phosphorylates glycogen phosphorylase b and glycogen synthase a
  7. Glycogen phosphorylase a breaks down glycogen into G1P
  8. G1P converted to glucose G6P and then dephosphorylated by G6P phosphatase
  9. Glucose released into blood via GLUT 2
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24
Q

What 2 substrates can bind to beta-adrenergic receptors to stimulate glucose release?

A
  1. Catecholamines

2. Glucagon

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25
Q

How is ATP converted to cAMP?

A

3’ (-OH) attacks the alpha phosphate

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26
Q

How is the signaling pathway of activated beta adrenergic receptors stopped?

A

Phosphodiesterase degrades cAMP to AMP

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27
Q

Describe the structure of PKA

A
  1. 2 catalytic subunits that dimerize in the inactive state

2. 2 regulatory subunits = dimer

28
Q

What is another name for PKA?

A

cAMP-dependent protein kinase

29
Q

Describe the activation of PKA by cAMP. 2 steps

A
  1. 2 cAMP bind to each regulatory subunits of PKA

2. 2 regulatory subunits release the catalytics subunits

30
Q

Describe the transduction pathway of alpha-adrenergic receptors. 4 steps

A
  1. Binding releases GDP from the Gq part of the receptor and GTP binds instead
  2. Gq bound to GTP binds to phospholipase C (PLC) to activate it
  3. PLC hydrolyses membrane phospholipid PIP2 into DAG (stays in membrane) and IP3
    4a. IP3 travels to ER to release calcium to activate TCA
    4b. DAG binds PKC which is then activated by the calcium: transduction cascade
31
Q

What substrates can bind to alpha-adrenergic receptors to stimulate glucose release?

A

Catecholamines

32
Q

What are the 2 ways to synthesize glycerol-3-phosphate for TAG synthesis? When is each used?

A
  1. Glycerol kinase phosphorylates glycerol using ATP: when glucose is low
  2. Glycerol 3-phosphate dehydrogenase converts DHAP to glycerol-3-phosphate: when glucose is high
33
Q

Which ONLY 2 tissues can synthesize tryacylglycerols when glucose is low? Why?

A
  1. Liver
  2. Kidney
    They have the glycerol kinase enzyme meaning that glycerol-3-phosphate can be made by glycerol phosphorylation (without DHAP)
34
Q

Where does the DHAP used for TAG synthesis come from? 2 possibilities
Which is faster?

A
  1. Glycolysis (FASTER)

2. AAs

35
Q

How is FA synthesis in the liver inhibited under fasting/starvation conditions?

A

Beta adrenergic receptors activated by catecholamines/glucagon = PKA activated = PKA phosphorylates acetyl CoA carboxylase, inhibiting it = less malonyl CoA = more FAs brought in mito for beta oxidation

36
Q

How is FA synthesis in the liver stimulated under well-fed conditions?

A

Insulin promotes dephosphorylation of acetyl CoA carboxylase, activating it

37
Q

Describe McArdle’s disease.

3 symptoms? Explain each. Why is there a contracture once the muscle is initially excited and why is it electrically silent? How are the calcium intracellular levels affected and what does this cause? What kind of exercises can these patients perform? How can this be tested for?

A

Symptoms:
1. Lactate levels are lower (no post exercise pH drop) instead of increasing during exercise because patients lack the enzyme glycogen phosphorylase IN THEIR MUSCLES which breaks down glycogen into glucose for glycolysis where lactic acid is a by-product and the little lactate available is used for gluconeogensis in the liver
2. White fibers are defective because of the enzyme missing.
3. Myoglobinuria because red fibers are damaged because abused since no white fibers available to do work.
The muscle can initiate the initial contraction, but there is not enough ATP (usually produced by glycolysis) to return calcium to the SR and to go through cross-bridge cycles: causing cramps that are electrically silent.
Calcium levels are constantly high meaning his muscles keep trying to contract.
Patients can only perform endurance exercises.
Test: western blot to look for the enzyme glycogen phosphorylase or genetic test

38
Q

How is the glycemic response of McArdle disease patients to epinephrine? Why?

A

Normal because their liver has its own glycogen phosphorylase so it can regulate blood glucose levels just fine

39
Q

Describe Von Gierke disease: Cause? 2 symptoms?

A

Impaired breakdown of glycogen due to glucose-6-phosphatase deficiency = glucose cannot be released in blood = excess G1P inhibiting glycogenolysis

Causes an enlargement of the liver and hypoglycemia

40
Q

What is another name for Von Gierke disease?

A

Type 1 glycogen storage disease

41
Q

What is another name for McArdle’s disease?

A

Type 4 glycogen storage disease

42
Q

Describe Andersen’s disease. How is the glycemic response affected?

A

Defect in glycogen branching enzyme causing the synthesis of abnormal glycogen = long strands in the liver cause cirrhosis
Glycemic response to epinephrine is muted because glycogen has less non-reducing ends

43
Q

What 3 metabolic processes are inhibited by catecholamines?

A
  1. Glucose uptake by muscles
  2. FA synthesis
  3. Glycogen synthesis
44
Q

What does IRS-1 stand for?

A

Insulin Receptor Substrate-1

45
Q

Describe Von Gierke patients’ glycemic response to epinephrine.

A

None at all because they cannot perform glycogenolysis

46
Q

What is the main determinant of TAG synthesis vs TAG breakdown to liberate FFAs?

A

Availability of DHAP => glycerol-3P

47
Q

What does the liver do with glucose in the well-fed state?

A

Synthesizes FAs to send them to adipose tissues as TAGs in VLDLs

48
Q

What does the liver do in the starvation state?

A
  1. Gluconeogenesis
  2. Glycogenolysis
  3. Ketogenesis
49
Q

Describe preproinsulin to insulin.

A
  1. 19 AA signal sequence cleaved off in RER
  2. C peptide removed in Golgi
  3. A and B left attached by 2 disulfide bond (also 1 DSB on A chain)
  4. C peptide and insulin released in blood
50
Q

What is the main target of glucagon?

A

Liver

51
Q

What is the main regulator of adipocytes?

A

Catecholamines

52
Q

How does glucagon inhibit FA synthesis?

A
  1. Inhibits glycolysis/Promotes gluconeogenesis: lower levels of pyruvate
  2. Inhibits actetyl-CoA carboxylase
53
Q

Main difference between metabolic effects of glucagon and catecholamines?

A

Catecholamines act on the skeletal muscles, glucagon does not

54
Q

Why do we say that FAs and proteins stimulate insulin and why is this irrelevant?

A

Because FAs and proteins stimulate gluconeogenesis producing glucose that stimulates insulin secretion
The spike in glucose produced is so much smaller than the spike produced by ingesting carbs that this is pretty irrelevant

55
Q

What does PIP2 stand for?

A

Phosphatidylinositol-4,5-bisphosphate

56
Q

What does DAG stand for?

A

1,2-diacylglycerol

57
Q

What does IP3 stand for?

A

Inositol-1,4,5-triphosphate

58
Q

What deactivates a G protein?

A

GTP hydrolysis to GDP

59
Q

Main purpose of G protein coupled receptors?

A

Regulate the lifetime of an enzyme’s activity

60
Q

What are the 2 mechanisms that can stop the beta adrenergic receptor activation cascade?

A
  1. Phosphodiesterase converting cAMP to AMP

2. Gs hydrolysis of GTP causing adenylyl cyclase to no longer work be active

61
Q

What does the liver do when it receives FFAs? 2 options

What regulates what it does?

A
  1. Collects them and repackages FAs into TAGs + cholesterol into VLDLs
  2. FA beta oxidation to make acetyl-CoA for ketogenesis

Regulation of acetyl-CoA carboxylase:

  1. Beta adrenergic receptors activated by catecholamines/glucagon => PKA phosphorylates acetyl-CoA carboxylase => inactive
  2. Insulin promotes dephosphorylation of acetyl CoA carboxylase, activating it
62
Q

Descrive the insulin transduction pathway leading to transcription/translation?

A
  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 and many other substrates leading to the regulation of gene expression in the nucleus
63
Q

How can insulin have so many effects on a cell?

A

It creates a myriad of phosphorylation signal transduction cascades

64
Q

2 mechanisms of catecholamine secretion?

A
  1. Adrenal medulla as hormones

2. Sympathetic NS as NTs

65
Q

Describe the potential created by the ATP-gated K+ channels of the beta-cells of the pancreas.

A

Electropositive potential outside the cell

66
Q

What regulates what the liver does when it receives FFAs from adipocytes: packages them as TAGs in VLDLs or uses them to make ketone bodies?

A

Regulation of acetyl-CoA carboxylase:

  1. Beta adrenergic receptors activated by catecholamines/glucagon => PKA phosphorylates acetyl-CoA carboxylase => inactive => CAT1 not inhibited and FAs transported to mitosol for beta-oxidation => ketogenesis promoted
  2. Insulin promotes dephosphorylation of acetyl CoA carboxylase, activating it => high malonyl-CoA => low FA being transported to mito for beta-oxidation => high FAs in cytosol being packaged into VLDLs as TAGs
67
Q

Does the liver need insulin to uptake glucose? Why?

A

NOPE because it uses GLUT 2, not GLUT 4

SMP - MNE Exam 2 (17 decks)

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