Nuclear Receptors, Molecular Mechanisms Of Flashcards
1
Q
What kind of dimers do nuclear receptors function as?
A
Homo- or heterodimers (similar to ECRs)
2
Q
Define: homodimer
A
A dimer made up of 2 identical units (macromolecules) i.e. 2 of the same receptor
3
Q
Define: heterodimer
A
A dimer made up of 2 similar but not identical units (macromolecules) i.e. 2 different types of receptor
4
Q
Define: dimer
A
A macromolecular complex formed by 2, usually non-covalently bound, macromolecules. = a quaternary structure of a protein = now active
5
Q
How are all nuclear receptors structurally related?
A
They all have 3 major domains
6
Q
How many receptors are there in the nuclear receptor superfamily?
A
Genome sequencing predicts only 48 receptors
7
Q
What is an orphan receptor?
A
The receptor is yet to have its agonist identified
Up to half of the nuclear receptor superfamily are termed orphan receptors
8
Q
What can nuclear receptors also been known as?
A
Ligand-activated gene regulatory proteins or transcription factors
9
Q
Where are nuclear receptors found in the cell?
A
In the cytosol or the nucleus, not associated with the lipid membrane
10
Q
How many families of nuclear receptor are there?
A
6
11
Q
How are nuclear receptors assigned a family?
A
Based on sequence
12
Q
Name the main 3 families of nuclear receptor
A
1) Thyroid Receptor-like 2) Retinoid X Receptor-like 3) Oestrogen Receptor-like
13
Q
How many terminals does a nuclear receptor have?
A
2 - N-terminal and C-terminal
14
Q
What is the function of the N-terminal/domain?
A
Binds the agonist/ligand
15
Q
What is the function of the middle domain?
A
DNA binding
16
Q
What does the C-terminal domain contain?
A
Transcription-activating domain
17
Q
What does the transcription-activating domain do?
A
The proteins will bind other transcription factors i.e. sit on top of DNA and promote or suppress transcription of DNA
18
Q
Name 4 activators of nuclear receptors.
A
1) Steroid hormones 2) Thyroid hormones 3) Fatty acids and prostaglandins 4) The retinoids
19
Q
Name 3 examples of steroid hormones.
A
1) Glucocorticoids e.g. cortisol 2) The steroid sex hormones (estradiol and testosterone) 3) Vitamin D
20
Q
What are steroid hormones made from?
A
Cholesterol - a common precursor The metabolism of cholesterol = these hormones
21
Q
What are thyroid hormones made from?
A
Tyrosine - a common precursor (an amino acid)
22
Q
Name the active forms of thyroid hormones.
A
Thyroxine (T4) and triiodothyronine (T3)
23
Q
What are fatty acids and prostaglandins derived from?
A
Lipids - they are the oxidation products
24
Q
Name 3 examples of fatty acids and prostaglandins.
A
1) Prostacyclin 2) Lysophosphatidic acid 3) Leukotriene
25
What are retinoids synthesised from?
Vitamin A (retinol)
26
Name 2 examples of retinoids.
1) Retinoic acid (vitamin A acid) 2) All trans-retinoic acid
27
Why are all these activators of nuclear receptors poorly soluble in water?
They are small **hydrophobic** molecules
28
Specific carrier proteins bind to the activators of NRs in the blood, why?
To increase the activators' **solubility** (as they must travel in the bloodstream)
29
What process occurs before the activators enter the cell, to do with the carrier proteins?
Dissociation
30
What are the main binding proteins (for transport) for the **thyroid hormones**?
1) Thyroxine-binding globulin 2) Transthyretin 3) Albumin
31
What is the major binding protein (for transport) for **sex hormones?**
Sex hormone-binding globulin
32
Which hormones does **sex hormone-binding globulin** bind to?
**Androgens** and **oestrogens**
33
What is the major **steroid-binding protein** called? (for transport)
Transcortin
34
Which steroid hormones does **transcortin** bind to?
**Progesterone**, **cortisol** and other **corticosteroids**
35
Explain the stages of the binding proteins transporting the hormones/activators
1) Hormones are **secreted** into the bloodstream from e.g. the thyroid 2) The binding protein in the bloodstream **binds** to the activator and **transports** it to the target tissue 3) The binding protein **dissociates** and the activator **enters** the tissue
36
Are agonists generally hydrophobic or hydrophilic?
**Hydrophobic** - therefore they can **freely diffuse** across the plasma membrane
37
**Where** do ligands bind on the **nuclear receptor**?
Agonists bind to the **ligand-binding domain** (and act as a molecular switch)
38
What kind of change does the ligand-binding induce in the receptor?
A **conformational** change
39
What happens to the receptor when it undergoes a **conformational change**?
The receptor can **dimerise** - become **active**
40
**Where** does the nuclear receptor **translocate** to once dimerised?
The **nucleus** - where the receptor has it effects, usually through **gene transcription**
41
Explain the stages of the **mechanism of action** of nuclear receptors.
1) The **agonist/ligand diffuses** into the cell through the plasma membrane (after using the binding proteins) 2) The agonist/ligand **binds** to the cytosolic NR 3) The NR **dimerises** and **translocates** to the nucleus 4) The **activated NR binds to the DNA** in the nucleus and **modifies gene expression** (+ve or -ve effects), 5) This causes the **secretion of molecules**
42
What type of nuclear receptor is a target for therapy?
**PPAR**s = peroxisome proliferator-activated receptors
43
How many **subtypes** of PPARs are there and what are they called?
3: **α**, **β**, **Y** All have **different amino acid sequences** and so therefore affect genes in different ways, all unique **transcription factors**
44
Which **family** of nuclear receptor do **PPAR**s belong to?
**Thyroid**-like family
45
What is different about α and β PPARs?
α and β PPARs have **distinct tissue distribution**: - **α = liver**; regulate fatty acid oxidation - **β = skeletal muscle**; regulate fatty acid oxidation i.e. **metabolism**
46
Where is **Y1** PPAR found?
It is almost **ubiquitous** (3 isoforms)
47
What kind of dimers are **PPARs functionally active** as?
**Hetero**dimers
48
**Which receptors** do PPARs (Y1) **pair** up with to form **heterodimers**?
**Retinoid X** receptors and **vitamin D** receptors
49
What is the general **role** of **PPAR**s (Y1) in the body?
**General lipid sensors** - allow body to **adjust to changes** in diet - **change metabolism** according to what is eaten
50
Name **4 processes** that the **PPAR**s (Y1) **regulate**.
1) **Lipid homeostasis** 2) Cellular **differentiation** 3) Cellular **proliferation** 4) The **immune** system
51
Name 1 **drug therapy** for **PPARα**
**Fibrates** = PPARα **agonists**
52
What are **fibrates** (drug therapy) used to treat?
**Type II diabetes**, atherosclerosis, **obesity** and hyperlipidaemia
53
How do fibrates work? (Drug therapy for PPAR alpha)
Decrease **serum triglycerides**, can be used with **statins** (type II diabetes)
54
Name 1 drug therapy for **PPAR(Y)**.
Thiazolidinediones (**glitazones**) = PPAR(Y) agonist **Pioglitazone** = only drug available on the market, licensed for **type II diabetes**
55
Name another **receptor** (other than the PPAR) that is a target for **drug therapy**.
**Glucocorticoid** receptor
56
Name 2 **natural glucocorticoids**.
1) Cortisol 2) Corticosterone
57
Name 3 things that **glucocorticoids** are **involved in**
1) **Inflammatory disorders** of the gut 2) Rheumatoid **arthritis** 3) **Autoimmune** disorders
58
Why do **glucocorticoid** **therapies** have **immunological effects**?
Due to the **upregulation** of **anti-inflammatory proteins** e.g. **lipocortins**
59
What are **lipocortins**?
Anti-inflammatory proteins
60
What do **lipocortins** do?
**Suppress** the activity of **phospholipase A2**
61
What does **phospholipase A2** do?
Phospholipase A2 contributes to **inflammation** by **producing** the key intermediate molecule, **arachidonic acid**
62
Name 1 **drug** aimed at the **glucocorticoid receptor**.
**Dexamethasone** - **anti-inflammatory** and **immunosuppressant** effects
63
What **2 genes** are mammalian **thyroid hormone receptors** **encoded** by?
Alpha and beta
64
What are the **4 known thyroid hormone receptors** called?
α1, α2, β1 and β2
65
What **forms** are **thyroid hormone receptors** **active** in?
As **monomers**, **homodimers** or as **heterodimers** with retinoid X receptors
66
What has been found to be the **cause** of a **syndrome of thyroid hormone resistance**?
**Mutations** in the **receptor beta gene** - abolishes **liga**nd (thyroid hormone) **binding** to the receptor Therefore the body produces **more thyroid** hormone = **excessive** levels in the bloodstream
67
**Mutations** in the **receptor β gene** cause what **behavioural disorder**?
**Attention-deficit disorder** - thyroid hormones are important in **brain development** Mutant receptors act in a **dominant negative manner** = the receptor will still bind in some way and will **interfere** with the other **normal receptors**
68
**High levels of thyroid** hormone (T3 and T4) in the blood is characterised by what **symptom**?
A **goiter** = swelling in the neck resulting from the enlargement of the thyroid gland
69
Name a **drug** that acts on the **thyroid receptor**?
**Levothyroxine** = thyroid receptor agonist
70
What is **Levothyroxine** used to **treat**?
**Hypothyroidism** - makes the thyroid **stop producing** hormone
71
Define: **hypothyroidism**
**Excessive** levels of thyroid hormone in the blood due to **mutant receptor beta gene** which **abolishes ligand binding** to the thryoid receptor
72
How is it **determined** if someone has **hypothyroidism**?
Take a **blood test**, see if thyroxine levels (**T3 and T4**) are **low**
73
Name **3 symptoms** of **hypothyroidism**.
1) insensitivity to **cold** 2) **constipation** 3) **depression**
74
Name **2 nuclear receptors** that are targeted for **cancer** therapy.
1) **Oestrogen** receptors 2) **Vitamin D** receptors
75
What is the **role** of **oestrogen receptors**?
Oestrogen receptors are **key regulators** of **cell growth** and **differentiation**
76
How many **types** of **oestrogen receptor** are there and what are they called?
2: ERα and ERβ
77
What effect does **oestrogen** have on **breast cancer**?
Oestrogen **promotes cancer growth** (oestrogen positive cancers)
78
How do **therapies for oestrogen** aim to do?
Disrupt the **oestrogen signalling pathway**
79
Name a **drug** used to target **oestrogen receptors**.
**Tamoxifen** - acts as an oestrogen receptor **ANTAGONIST** in **breast** tissues Acts as an oestrogen receptor **AGONIST** in **other** tissues
80
Does **Tamoxifen** act as an oestrogen receptor **agonist** or **antagonist**?
Antagonist in breast tissue and agonist in other tissues = a **selective oestrogen-receptor modulator**
81
What determines the **agonist/antagonist properties** of **Tamoxifen**?
The **ratio of co-activator:co-repressor proteins** in tissues - different in breast tissue to other tissues
82
How does **Tamoxifen** have a biological effect?
Acts on the **oestrogen receptors** to **disrupt** the oestrogen signalling pathway = cancer therapy Agonist or antagonist Not an **active** molecule, has to be metabolised
83
In which **tissue** is the concentration of **co-repressors high**?
**Breast** tissue
84
What molecule has a very **high concentration** in the **breast** tissue?
Co-repressors
85
How does **Tamoxifen** act in the **breast** tissue and why?
Tamoxifen acts as an **antagonist** in the **breast** tissue due to the high concentration of **co-repressor**. As an **antagonist**, it **shuts off gene transcription** This **stops the proliferation** of the cancer
86
How does **shutting off gene transcription** target **cancer**?
It **stops cell proliferation**
87
In which **tissue** is the **concentration of co-activators high**?
All **other** tissues (i.e. not breast tissue)
88
What **molecule** has a very **high concentration** in all **other** tissues?
Co-activators
89
How does **Tamoxifen act** in all **other** tissues and why?
Tamoxifen acts as an **agonist** - **promotes gene transcription**
90
What is the **role** of **vitamin D receptors**?
Vitamin D receptors **regulate the absorption** of **calcium**, **iron**, **magnesium** and **phosphate**
91
Why is **vitamin D** used to treat **Rickets**?
Vitamin D is important in **bone mineralisation**
92
What **bone disorder** is **vitamin D** used to treat?
Rickets
93
What do some studies suggest about the **link** between **vitamin D and cancer**?
Some suggest that **high intake of vitamin D** may **reduce** the risk of **colorectal cancer**
94
Where must nuclear receptors **translocate** to to have an **effect**?
The **nucleus**
95
**How long** does it take to see the **effects** of **nuclear receptors**?
**Days** or **weeks**
96
What **disease** is treated by the use of therapies **aimed** at the **PPARα**?
Hyperlipidaemia
97
What **disease** is treated by the use of therapies **aimed** at the **PPAR(Y)**?
Type II diabetes
98
What **disease** is treated by the use of therapies **aimed** at the **Glucocorticoid receptor**?
Inflammatory disease
99
What do the **therapies** aimed at the **oestrogen receptor** aim to treat?
Breast cancer, osteoporosis, pregnancy termination
100
**Summarise** what a **nuclear receptor** does.
Acts as a **homo** or **heterodimer**, **translocates** to the nucleus, binds to the **DNA** and selectively **regulates gene expression**
