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BIOC 311 > MD_Hormones > Flashcards

MD_Hormones Flashcards

1
Q

What type of receptor is the Estrogen Receptor? Leptin Receptor? a-/b-adregenic receptors? Insulin receptor? ATP-gated K+ Channel?

A

Estrogen receptor = Steroid receptor
Leptin receptor = Receptor with no intrinsic enzyme activity
a/b-adrenergic receptors = Serpentine receptor
Insulin receptor = Receptor enzyme
ATP-gated K+ Channel (b-cell in the pancreas when [glucose] > 5.5mM) = Gated ion channel

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2
Q

What are the 5 types of hormonal receptors signaling in metabolism?

A
  1. Steroid receptor → Steroid (enters the nucleus) binding to nuclear receptor to regulate transcription
  2. Serpentine receptor → External ligand binding to receptor activates intracellular GTP-binding protein → regulates enzyme → generates intracellular 2nd messenger
  3. Gated ion channel → Opens/closes in response to concentration of signal ligand/membrane potential
  4. Receptor enzyme → Ligand binding to extracellular domain stimulates enzyme activity in intracellular domain
  5. Receptor with no intrinsic enzyme activity → Interacts with cytosolic protein kinase → activates gene-regulating protein
  6. Adhesion receptor → Binds molecules in extracellular matrix, changes conformation → alters interaction with cytoskeleton
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3
Q

What are the 4 principles of hormone functions?

A
  1. Specificity: 1 ligand - 1 receptor
  2. Amplification: Activation of downstream effectors
  3. Duration of effect: Short term regulation (ex: phosphorylation) + Long term regulation (ex: activation/repression of transcription)
  4. Desensitization/Adaptation: Activation of negative feedback signal
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4
Q

What gives all the receptor tyrosine kinases their diversity?
What is their main structural function?

A
  • Various extracellular ligand-binding domains
  • Intracellular tyrosine-kinase activity (very similar in all of them)
  • Majority dimerize to activate
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5
Q

What are the steps of activation of the Insulin Receptor?

A
  • Extracellular alpha chain + Intracellular beta chain
  • Homodimer

Inactive receptor → alpha chains are touching and beta chains are far appart (not interacting)

  1. Insulin binds to both alpha changes
  2. Conformational change bringing alpha chains closer to each other
  3. Trans-phosphorylation of intracellular subunits (Tyrosine residues on beta-chains)
  4. Recruitement of IRS via its SH2 domains (which recognize P-Tyr residues)

*IRS = Insulin Receptor Substrate

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6
Q

What are the different metabolic effects of the Insulin Receptor Tyrosine Kinase?

A
  1. Activates Glycogen Synthase (IRS-P → Glycogen Synthase Kinase → Glycogen Synthase)
  2. stimulates recruitment of Glut4 to the plasma membrane
  3. Stimulates lipid synthesis (Activation by dephosphorylation of ACC)
    *Long term effects on transcription as well for storage
  4. Activates mitogenic cascades (through MEK signaling)
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7
Q

Which downstream pathway allows Insulin signaling to recruit Glut4 to the plasma membrane?

A
  1. Insulin receptor gets activated → phosphorylated tyrosine residues
  2. IRS’s SH2 domains recognizes and binds to P-Tyr
  3. IRS Tyrosine residues are phosphorylated themselves
  4. p85 (SH2 domains) and p110 recognize IRS-p
  5. Recruits PI3-kinase → phosphorylates PIP2: PIP2 → PIP3
  6. Akt binds PIP3 and recruits Glut4 to the plasma membrane
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8
Q

How did researchers realize that insulin was involved in mitogenic cascades?

A

Inhaled insulin was associated with higher risks of lung cancer (in former smokers)

IRS-p → Grb2/Sos → RasGTP → MEK → ERK
*RAS/RAF/MEK pathway

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9
Q

What is the role of PTP-1B?

A

Protein Tyrosine Phosphatase 1B = protein that dephosphorylates Type-P proteins
→ Shuts down Insulin-receptor → Stops signaling cascade by preventing IRS-1 association with Insulin Receptor and activation of PI3K

*Decreases Insulin Sensitivity
*Resets system to resting state (non-phosphorylated)

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10
Q

What is the effect of a PTP 1B inhibitor on insulin sensitivity?

A

It would increase insulin sensitivity → block the inhibitor

If can’t dephosphorylate the Insulin receptor → more active after insulin binding because not shut off

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11
Q

What is PTEN?

A

Phosphatase and tensin homolog:
Phosphatase that dephosphorylates PIP3 and regenrates PIP2
*In insulin receptor downstream pathway

Conteracts PI3K → prevents PDK1 recruitment → stops signaling cascade

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12
Q

What is the effect of a PTEN inhibitor on insulin sensitivity?

A

It would increase insulin sensitivity → block the inhibitor

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13
Q

What are 3 ways to shut down insulin signaling?

A
  1. PTP 1B
  2. PTEN
  3. Degradation:
    - Recycled and return to the membrane in its dephosphorylated form
    - Degraded by endocytosis of insulin:IR complex + insulin degrading enzyme (Ubiquitination)
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14
Q

What are examples of Gas and Gaq receptors?

A

Gas → Glucagon-R, β2- & β3-Adrenergic-R

Gaq → α-Adrenergic-R

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15
Q
A
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16
Q

What are some characteristics of Glucagon and its general effect?

A
  • 29-AA peptide hormone
  • Released from pancreatic α-cells in response to low blood sugar
  • The main counter-regulatory hormone to insulin
  • Insulin/Glucagon ratio controls hepatic glucose production by controlling the rates of gluconeogenesis and glycogenolysis

Glucagon secretion → increase [cAMP] → increase phosphorylation of key enzymes:
- Phosphorylase b → a
- Glycogen synthase a → b
- PFK-2 → F2,6BPase
- PK → Phosphorylated PK

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17
Q

What is a synonym for Epinephrin?

A

Adrenalin
Binds to many GPCRs in adipocytes, muscles and liver

*Glucagon only binds Gas
Epinephrin binds Gas and Gaq

18
Q

What is an inhibitor specifically of Gas-coupled GPCRs?

A

Cyclic nucleotide phosphodiesterase:
It degrades cAMP → 5’AMP

19
Q

What is an example of β3-Adrenergic-R signaling we studied in class?

A
  • β3-Adrenergic-R is highly expressed in brown adipocytes
  • Signaling leads to activation of Hormone-Sensitive Lipase (HSL) + phosphorylation of perilipin
  • In brown fat → linked to thermogenesis by activation of UCP1 uncoupler (allosterically activated by FA)
20
Q

What is the PLC reaction?

A

Phospholipase C:
PIP2 → IP3 (→ binds to Ca channel) + DAG (→ activates PKC)

*In Gaq receptor

21
Q

How can Gas and Gaq desensitization occur?

A

When PKA is too activate, it will phosphorylate other enzyme such as βARK

βARK (β-Adrenergic-R Kinase):
1. Phosphorylates (deactivates) β-Adrenergic-R
2. Phosphorylated receptor is recognized by β-arrestin
3. βArrestin → Phosphorylation of GPCR → receptor desensitization
- Serves as an adapter protein that facilitates interaction with clatrhin for internalization

22
Q

What is receptor desensitization?
Give an example.

A

Mechanism by which a receptor will no longer respond to its ligand after persistent exposure

  • One of the reasons why many drugs fail → because they target GPCRs (then need to increase the drug dose which causes many side effects)

*βArrestin serves as an adapter protein that facilitates interaction with clatrhin for internalization

23
Q

How many different GPCR (Serpentine Receptors) are there?

A

7 different transmembrane domain receptors

24
Q

What are the pathways/downstream activation of Gas and Gaq?
What are 2ndary messengers?

A

Gas → adenylate cyclase → cAMP → PKA → cellular effects

Gaq → PLC → IP3 + DAG → Ca2+ + PKC → cellular effects
*activates glycogen phosphorylase kinase for ex → breakdown glycogen

25
Q

What physiological signals activate the Insulin-R, Glucagon-R, Adrenergic-R?

A

Insulin → Fed state

Glucagon → Fasting state

Epinephrine → Signals stress

26
Q

What allows the binding of a hormone to its receptor to cause an amplification signal?

A

When the enzyme activates its substrate enzyme → the number of affected molecules increases geometrically in an enzyme cascade
Ex: Epinephrine binds to receptors → activates 10 enzymes → each of these 10 enzymes activtates 10 of its substrate enzyme (100x amplification) → etc.
*explains why don’t need high levels of hormones to have an important effect

27
Q

What are the main features of Ghrelin?
Is its inhibition a viable cure against obesity?

A
  • Hormone that stimulates apetite
  • Small peptide
  • Secreted by empty stomach

Not a viable cure against obesity because Ghrelin has pleitropic effects in the body (not just a hunger stimulator) so it would affect of vital pathways:
- Mood, cognitive functions, cardiac output, insulin secretion, etc.

28
Q

What path does Ghrelin follow from its secretion to the binding of its receptor?

A
  1. Secreted by empty stomach (inactive form)
  2. Ghrelin is acylated by GOAT → its active form (not acetylated)
    *octanoylated form = active form
  3. Activated Ghrelin travels through circulation → binds to its receptor in the neuropeptide Y (NPY)/agouti-related peptide (AgRP) neurons of the arcuate nucleus of the hypothalamus

*GOAT = Ghrelin-O-acyltransferase

29
Q

What type of receptor is the Ghrelin-receptor (GSH-R)?
What happens when this receptor is overstimulated?

A

Gaq-coupled receptor → activates PLC → produces DAG + IP3 → … → Activate hunger

*In the neuropeptide Y (NPY/agouti-related peptide (AgRP) neurons of the arcuate nucleus of the hypothalamus

When overstimulated (didn’t eat for too long), the receptor is internalized
*desensitization of GPCRs

30
Q

What is the definition of Parabiosis?

A

The anatomical joining of two individuals, especially artificially in physiological research.
- Surgically joining the circulatory system of 2 organisms
Found animals developping obesity because the mouse would never stop eating

31
Q

What are the molecular defects of db/db vs ob/ob mice? Which can we treat by injecting Leptin?

A

ob/ob:
- Discovered by jackson Laboratories in 1949
- Lack functional Leptin
- YES, you can because they have a functional receptor (proved by parabiosis experiments)

db/db:
- lack functional LEP-R
- Giving leptin to the db/db mice can not cure their obesity because they have no functional receptor

Both Hyperphagic → become obese

32
Q

What experiment was done to discover the role of leptin?

A

Parabiosis experiment with 3 setups:
1. db/db-WT → db/db has no receptor but secretes ltos of leptin which affects the WT mouse which dies by starvation (stops eating)

  1. db/db-ob/ob → ob/ob receives leptin produced by db/db and looses weight (might even die by starvation), but no change for db/db mouse
  2. ob/ob-WT → ob/ob can’t produce leptin, but can receive the leptin from the WT mouse → ob/ob will loose a bit of weight (WT supplies appropriate amounts of leptin, less than db/db mouse)
33
Q

What are some general characteristics of leptin?

A
  • 16 kDa protein produced by adipose tissue and by stomach following food intake
  • inhibits hunger
  • Leptin is from the Greek leptos = thin
  • Very rarely mutated or absent in humans → more cases of OB-R (leptin receptor) mutations in humans
34
Q

What is the mechanism of action of Leptin?

A
  1. Secreted toward the gastric lumne into the gastric juice (in stomach)
  2. In duodenum, passes into circulation → crosses the blood-brain barrier
  3. Binds the Leptin-Receptor (OB-R) in hypothalamus
  4. Inhibits hunger cues
    *Lag between eating and feeling satiety
35
Q

What is the importance of the hypothalamus?

A

Gland that controls satiety and thirst

36
Q

Can obese people be treated with leptin?

A

Yes, if they are leptin-deficient
No, if they produce leptin, but their receptors are desensitized to it

37
Q

What type of receptor is the Leptin-Receptor, what is it coupled with?
What are its characteristics?

A

Leptin-Receptor = non-enzymatic receptor
Coupled with the JaK/STAT pathway

JaK = Janus Kinase
STAT = Signal Transduction and Activation of Transcription

  • Expressed in many tissues, especially hypothalamus
  • No intrinsic enzymatic activity
38
Q

What is the pathway of activation of the Leptin-Receptor?
What is a potential inhibitor of this activation?

A
  1. Leptin binding → ∆ conformation
    - Ligand binding required for receptor dimerization
  2. Activates JaK → Autophosphorylates Tyr AND phosphorylates OB-Rb (Leptin Receptor)
  3. Recruitment if STAT to phosphorylated OB-R + activation of STAT (phosphorylation)
  4. Cellular effect = inhibition of appetite

PTP-1B resets by dephosphorylating JAK

39
Q

Summarize the metabolic control of appetite → before vs after a meal

A

Before eating:
- High levels of Ghrelin secreted by gastrointestinal cells in the stomach
- Low levels of Leptin secreted in adipose tissue

After eating:
- Low levels of Ghrelin secreted gastrointestinal
- High levels of Leptin secreted by adipose cells

40
Q

Through what pathway does Insulin signaling regulate Glycogen synthesis?

A

Insulin receptor → PI3K → (PIP2 → PIP3) → PDK1 → PD1K phosphorylates and activates AKT → inhibits GSK3 by phosphorylation → increases glycogen synthesis

41
Q

What would be the effect a mutation in FXR which prevents it from dimerizing with RXR?

A
  • Decreased cholesterol levels
  • Increased bile acids
  • Increased ASBT

BIOC 311 (14 decks)

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