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Pharmacology and Toxicology > Enzyme-coupled and Nuclear receptors > Flashcards

Enzyme-coupled and Nuclear receptors Flashcards

1
Q

What are the types of receptors?

A

G Protein-Coupled Receptors (Metabotropic Receptors)

Ligand-Gated Ion Channels (Ionotropic Receptors)

Enzyme-Coupled Receptors

Nuclear Receptors

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2
Q

What are the 6 classes of enzyme coupled receptors?

A
  1. Receptor tyrosine kinases
  2. Tyrosine kinase-associated receptors
  3. Receptor serine/threonine kinases
  4. Histidine-kinase-associated receptors
  5. Receptor guanylyl cyclases
  6. Receptor-like tyrosine phosphatases
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3
Q

What are important examples of receptor tyrosine kinases?

A 
Insulin
and
Involved in cell proliferation:
Epidermal Growth Factor
Platelet-Derived Growth Factor
Vascular Endothelial  Growth Factor
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4
Q

How does Autophosphorylation Cause Biological Effects?

A

Dimerization of Receptors
Autophosphorylation of tyrosine
Activation of Intracellular Tyrosine Kinase Domains
Increase in tyrosine kinase activity
Phosphorylation/Binding of Intracellular Signaling Proteins
Formation of Signaling Complexes

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5
Q

What signals are generated by epidermal growth factor?

A

assoication of GRB2 and SOS activates membrane RAS protein exchanging GDP for GTP

further activates RAF1 MEK and ERK in a phosphorylation cascade using ATP

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6
Q

What happens to ERK in a signalling cascade for cell proliferation?

A

ERK phosphorylated by MEK and then travels into nucleus

activates transcription factor c-Fos

c-Fos binds to DNA inducing transcription of AP-1 and Elk-1 genes

genes help aid in cell proliferation

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7
Q

explain how signalling occurs via the insulin receptor

A

Exist as Tetramers:
linked by disulphide bridges

Insulin binding reorders intracellular kinase domains

Autophosphorylation and activation of signaling cascades

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8
Q

How Does Insulin Promote Glycogen Synthesis?

A

phosphorylated insulin receptor binds insulin receptor substrate 1 and then a PI3 kinase

PI3 kinase phosphorylates PIP2 to PIP3 activating a protein kinase series (PKD1, Akt, GSK3, glycogen synthase)

Glycogen synthase phosphorylation promotes glycogen synthesis

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9
Q

During the phosphorylation series for glycogen synthesis what does Akt also do?

A

activates mobile glucose transporters from intracellular location to cell surface

promoting uptake of glucose from the blood

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10
Q

True or False?

Oligomerization plays an important role in ECR signalling.

A

True

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11
Q

True or False?

Insulin promotes internalization of glucose transporters

A

False

Glucose transporters move to cell surface

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12
Q

True or False?

Monoclonal antibodies can be used to treat cancers

A

True

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13
Q

True or False?

ECRs promote DNA synthesis

A

True

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14
Q

True or False?

Autophosphorylation occurs on tyrosine residues

A

True

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15
Q

At which subcellular locations are enzyme-coupled receptors found?

a) Nucleus
b) Cell-surface (plasma membrane)
c) Endoplasmic Reticulum
d) Endosome
e) Lysosome

A

b
c
d
e

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16
Q

Which enzyme-coupled receptor promotes translocation of glucose transporters to the cell-surface?

a) epidermal growth factor
b) growth hormone receptor
c) insulin receptor
d) transforming growth factor beta receptor
e) platelet-derived growth factor receptor

A

insulin receptors

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17
Q

Why is dimerization or oligermerisation required for ECRs

A

to activate signalling cascades (usually phosphorylation cascades)

18
Q

What are the 6 classes of nuclear receptors?

A
  1. Thyroid Receptor-like
  2. Retinoid X Receptor-like
  3. Oestrogen Receptor-like
  4. Nerve Growth Factor IB-like
  5. Steroidogenic Factor-like
  6. Germ Cell Nuclear Factor-like
19
Q

Describe the nuclear receptor superfamily

A

Genome sequencing predicts 48 receptors

All are structurally related (3 domains)

Up to half are termed orphan receptors i.e., endogenous ligand has yet to be identified

Function as either homo- or heterodimers

Sometimes termed ligand-activated gene regulatory proteins (transcription factors)

Located in the cytosol or nucleus, but not associated with lipid membranes

20
Q

Which terminus has the ligand binding domain for a nuclear receptor?

A

C terminus

21
Q

Which terminus has the Transcription-activating domain for a nuclear receptor?

A

N terminus

22
Q

Where is the DNA binding domain for a nuclear recetpor?

A

middle

23
Q

What are the activators of nuclear receptors?

A

All are small hydrophobic molecules
Therefore are poorly soluble in water
Must be transported around the body in the blood stream
Specific carrier proteins bind to increase solubility
Dissociation occurs before entering the cell

24
Q

What are the The major serum thyroid hormone-binding proteins?

A

thyroxine-binding globulin, transthyretin and albumin

25
Q

What is the major sex hormone-binding protein?

A

sex hormone-binding globulin, binds androgens and oestrogens

26
Q

What is the major steroid-binding protein?

A

transcortin, binds progesterone, cortisol and other corticosteroids

27
Q

Why can agonists usually freely diffuse across the plasma membrane?

A

hydrophobic

28
Q

What do agonists do whilst bound to the ligand binding domain?

A

act as switches

29
Q

What disorders are glucocorticoid receptors involved in?

A

Involved in inflammatory disorders of the gut, rheumatoid arthritis, autoimmune disorders

30
Q

What do lipocortins do?

A

Lipocortins suppress the activity of phospholipase A2

31
Q

What does phospholipase A2 do?

A

Phospholipase A2 contributes to inflammation by producing the key intermediate molecule arachidonic acid

32
Q

What does dexamethasone do?

A

Anti-inflammatory and immunosuppressant effects

Treatment of rheumatic disorders, skin diseases, severe allergic reactions

Up to 25 times more potent on the glucocorticoid receptor than cortisol

Acts on glucocorticoid receptors

33
Q

What oestrogen receptors mediate its biological effects?

A

ERa and ERb

34
Q

What is tamoxifen?

A

Nuclear receptor drug for cancer therapies

Acts as a oestrogen receptor antagonist in breast tissues and other tissues

Selective estrogen-receptor modulator

The ratio of co-activator to co-repressor proteins in tissues determines the agonist/antagonistic properties of the drug

Tamoxifen itself is inactive; must be metabolized by cytochromes to produce 4-hydroxytamoxifen, N-desmethyl-4-hydroxytamoxifen and endoxifen

35
Q

How Can Tamoxifen Work as an Agonist and an Antagonist in Different Tissues?

A

In breast tissue:
high levels of co-represser
which has a negative affect and antagonises effect of oestrogen receptors in the tissue

In other tissue:
high levels of co-activator
Has positive affect and agonises oestrogen receptors in the tissue

36
Q

Nuclear receptors enter the cell by:

by diffusion

via endocytosis

by primary active transport

with a specific binding protein

by secondary active transport

A

by diffusion

37
Q

(a) Name TWO of the three domains found within a nuclear receptor (2 marks)

A

(a) Ligand-binding, DNA-binding, transcription-activating

38
Q

(b) Briefly describe how agonists of nuclear receptors are transported around the body (3 marks)

A

(b) Agonists are secreted (1) and transported in the blood stream (1) with binding proteins (1) to the target tissue

39
Q

What specifically about the action of Tamoxifen is beneficial for the treatment of breast cancers?

A Tamoxifen metabolite targets cell-surface receptors to alter gene expression

A Tamoxifen metabolite targets a cytosolic nuclear receptor to alter gene expression

Tamoxifen acts as a transcription factor to alter gene expression

Tamoxifen targets cell-surface receptors to alter gene expression

Tamoxifen targets a cytosolic nuclear receptor to alter gene expression

A

A Tamoxifen metabolite targets a cytosolic nuclear receptor to alter gene expression

40
Q

Tamoxifen targets which nuclear receptor?

A

Oestrogen receptor

Pharmacology and Toxicology (7 decks)

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