Enzyme-coupled and Nuclear receptors

Question 1

What are the types of receptors?

Answer 1

G Protein-Coupled Receptors (Metabotropic Receptors)

Ligand-Gated Ion Channels (Ionotropic Receptors)

Enzyme-Coupled Receptors

Nuclear Receptors

Question 2

What are the 6 classes of enzyme coupled receptors?

Answer 2

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

Question 3

What are important examples of receptor tyrosine kinases?

Answer 3

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

Question 4

How does Autophosphorylation Cause Biological Effects?

Answer 4

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

Question 5

What signals are generated by epidermal growth factor?

Answer 5

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

Question 6

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

Answer 6

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

Question 7

explain how signalling occurs via the insulin receptor

Answer 7

Exist as Tetramers:
linked by disulphide bridges

Insulin binding reorders intracellular kinase domains

Autophosphorylation and activation of signaling cascades

Question 8

How Does Insulin Promote Glycogen Synthesis?

Answer 8

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

Question 9

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

Answer 9

activates mobile glucose transporters from intracellular location to cell surface

promoting uptake of glucose from the blood

Question 10

True or False?

Oligomerization plays an important role in ECR signalling.

Answer 10

True

Question 11

True or False?

Insulin promotes internalization of glucose transporters

Answer 11

False

Glucose transporters move to cell surface

Question 12

True or False?

Monoclonal antibodies can be used to treat cancers

Answer 12

True

Question 13

True or False?

ECRs promote DNA synthesis

Answer 13

True

Question 14

True or False?

Autophosphorylation occurs on tyrosine residues

Answer 14

True

Question 15

At which subcellular locations are enzyme-coupled receptors found?

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

Answer 15

b
c
d
e

Question 16

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

Answer 16

insulin receptors

Question 17

Why is dimerization or oligermerisation required for ECRs

Answer 17

to activate signalling cascades (usually phosphorylation cascades)

Question 18

What are the 6 classes of nuclear receptors?

Answer 18

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

Question 19

Describe the nuclear receptor superfamily

Answer 19

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

Question 20

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

Answer 20

C terminus

Question 21

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

Answer 21

N terminus

Question 22

Where is the DNA binding domain for a nuclear recetpor?

Answer 22

middle

Question 23

What are the activators of nuclear receptors?

Answer 23

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

Question 24

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

Answer 24

thyroxine-binding globulin, transthyretin and albumin

Question 25

What is the major sex hormone-binding protein?

Answer 25

sex hormone-binding globulin, binds androgens and oestrogens

Question 26

What is the major steroid-binding protein?

Answer 26

transcortin, binds progesterone, cortisol and other corticosteroids

Question 27

Why can agonists usually freely diffuse across the plasma membrane?

Answer 27

hydrophobic

Question 28

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

Answer 28

act as switches

Question 29

What disorders are glucocorticoid receptors involved in?

Answer 29

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

Question 30

What do lipocortins do?

Answer 30

Lipocortins suppress the activity of phospholipase A2

Question 31

What does phospholipase A2 do?

Answer 31

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

Question 32

What does dexamethasone do?

Answer 32

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

Question 33

What oestrogen receptors mediate its biological effects?

Answer 33

ERa and ERb

Question 34

What is tamoxifen?

Answer 34

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

Question 35

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

Answer 35

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

Question 36

Nuclear receptors enter the cell by: by diffusion via endocytosis by primary active transport with a specific binding protein by secondary active transport

Answer 36

by diffusion

Question 37

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

Answer 37

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

Question 38

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

Answer 38

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

Question 39

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

Answer 39

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

Question 40

Tamoxifen targets which nuclear receptor?

Answer 40

Oestrogen receptor