Flashcards in Molecular Mechanisms of Nuclear Receptors Deck (29):
What are the three main family of nuclear receptors that are based on sequence?
1. Thyroid Receptor Like
2. Retinoid X Receptor Like
3. Oestrogen Receptor Like
What is the domain structure of nuclear receptors?
1. As it's a protein it has a N and a C terminus
2. Purpose of N terminal is a ligand or agonist binding domain
3. DNA binding domain sits onto the DNA or the chromosome
4. C terminal domain contains a transcription activating domain
- combines other transcription factors together
What are the four types of molecules that activate these receptors?
1. Steroid hormones
2. Thyroid hormones
3. Fatty acids and prostaglandins
Give examples of steroid hormones which activate Nuclear Receptors and what are they made from?
1. Glucocorticoids (cortisol)
2. Steroid sex hormones (estradiol and testosterone)
3. Vitamin D
4. Made from common precursor (cholesterol)
Give examples of thyroid hormones which activate Nuclear Receptors and what are they made from?
1. Made from common precursor- tyrosine
2. Thyroxine (T4) and triiodothyronine (T3)
Give examples of fatty acids and prostaglandins which activate Nuclear Receptors and what are they made from?
1. Prostacyclin, lysophosphatidic acid
2. Leukotriene B4
3. Made from lipid derived ligands, oxidation products
Give examples of the retinoids which activate Nuclear Receptors and what are they made from?
1. Retinoic acid (vitamin A acid)
2. All trans-retinoid acid
3. Synthesised from Vitamin A (retinol)
What properties must all activators of nuclear receptors have?
1. All Small hydrophobic molecules
2. Poorly soluble in water
3. Must be transported around the body in the blood stream
4. Specific carrier proteins bind to increase solubility- carried around the body
5. Dissociation from protein occurs before entering the cell
What are the major binding proteins that are used to bind thyroid hormones to allow for transportation around the body?
1. Thyroxine binding globulin
What are the major binding proteins that are used to bind steroid hormones to allow for transportation around the body?
1. Sex hormone binding globulin which also binds androgens and oestrogens
2. Transcortin which also binds progestrone, cortisol and other corticosteroids
Explain the steps that occur for binding of proteins for transport?
1. Secretion and binding of the hormones
2. Transported across the blood stream
3. Dissociation and entry into the target tissue
What is the general mechanism of action in Nuclear Receptors after leaving the binding protein?
1. Agonists freely diffuse across the plasma membrane due to being hydrophobic
2. Agonists bind to the ligand binding domain and act as a molecular switch
3. Conformational change occurs within receptor (changes shape)
4. Receptors dimerise and translocate to the nucleus
5. Receptor binds to DNA and modifies gene expression (secretion of molecules)
6. Has an effect through gene transcription
Describe how the oestrogen receptor activates?
1. Estrodial goes to the nucleus to exert it's effect by stimulating with steroid receptors
2. Estrodial binds to the protein receptors in the cell nucleus
3. Chapperones keep it in the same ligand binding conformation
Describe the structure of PPARS and the difference between each forms?
1. Made up of three subtype forms: a, b and g
2. Belong to the thyroid like family
3. Subtype a:
- Liver, fatty acid oxidation
- Skeletal muscle, fatty acid oxidation
4. G1 is almost ubiquitous (3 isoforms) (everywhere)
What are the dimers that are connected to the PPARS and describe the main roles of PPARS?
1. Functionally active as heterodimers with retinoid X and vitamin D receptors
2. Function: general lipid sensor that allows body to adjust changes in diet
3. Diverse roles in regulating lipid homeostasis, cellular differentiation, proliferation and the immune response
What are the drugs that are used for therapy in PPAR alpha, give an example of them and how the indication of them?
1. Fibrates act as agonists
Type II diabetes, atherosclerosis, obesity and hyperlipidemia
3. Work by:
Decreasing serum triglycerides, reduces amount of fat in the blood
What are PPARS usually combined with in therapy?
Can be used with statins for Type II diabetes and for fenofibrate
What are the drugs that are used for therapy in PPARg, give an example of them and how the indication of them?
1. Thiazolidinediones (glitazones) (last resort)
2. Example: Pioglitazone
3. Indication: treatment of type II diabetes
Describe the natural ligands of Glucocorticoid receptors, what are the effects, and it's indications?
1. Cortisol and corticosterone
2. Effects are for immune system and metabolism
Involved in inflammatory disorders of the gut, rheumatoid arthritis, and autoimmune disorders
Explain the action of glucocorticoid receptors?
1. Immunological (immune system) effects due to up-regulation of anti-inflammatory proteins like lipoproteins
2. The lipoproteins suppress the activity of phospholipase A2
3. Phospholipase A2 contributes to inflammation by producing key intermediate molecule like arachidonic acid
Give examples of some of the drugs that act on Glucocorticoid receptors?
Drug agonists include:
dexametasone, mifepristone, cyproterone acetate
Describe how dexamethasone works as an anti-inflammatory drug and what does it treat?
1. Anti-inflammatory and immunosuppressant effect
2. Treatment of rheumatic disorders, skin diseases and severe allergic reactions
Describe how mifepristone works as a drug and what is it used for?
1. Antagonises the effects of cortisol
2. Possess anti-progesterone (hormone produced in ovaries) and anti-glucocorticoid properties
3. Sensitises the myometrium to prostaglandin-induced contractions
4. Used to abort pregnancies
Describe how the Thyroid receptor encoded, the four known receptors and the activeness of them?
1. Encoded by two genes a and b
2. Four known receptors of a1, a2, b1 and b2
3. Active as monomers or dimers with retinoid X receptors
Describe the disease that interrupts the thyroid receptors and the impact it can have?
1. Thyroid hormone resistance mutation in the receptor beta genes
- Cannot bind thyroid agonist
- Body produces more agonists which leads to lots of thyroid in blood stream
2. Children show attention deficit disorder as thyroid is important in brain development
3. Mutant receptors act in a dominant negative manner
4. Exhibit hypothyroidism
Give one drug that affects the thyroid and what does it treat?
1. Levothyroxine (thyroid agonist)
2. Used to treat hypothyroidism as it stops it from producing the hormone
Explain why oestrogen receptors are targeted for cancer therapy treatments and how they are targeted?
1. Oestrogen is a key regulator for cell growth and differentiation so it can cause the growth of breast cancer tissue
2. Mediated by two oestrogen receptors:
ER alpha and ER beta
3. You can interrupt the oestrogen signalling pathway
Give an example of a nuclear receptor drug that is used for cancer therapy, how it works and the mechanism of action?
2. Acts as a oestrogen receptor antagonist in breast tissue
3. Can act as a agonist in other tissues
4. Inactive by itself and must be metabolised by cytochromes