Steroids - What Are They and How Do They Work? Flashcards
Glucocorticoids signal through which receptor?
Glucocorticoid receptor (GR)
Glucocorticoids are dervived from what?
Cholesterol
What naturally secretes glucocorticoids in the body?
Zona fasciculata of adrenal glands
How is the release of glucocorticoid in the body regulated?
Hypothalmic-pituitary-adrenal axis
The availability of endogenous glucocorticoids in the body is regulated by what?
11β-hydroxysteroid dehydrogenase (11β-HSD) enzymes
(especially 11β-HSD2)
What are the key differences between synthetic and natural glucocorticoids?
Synthetic glucocorticoids are:
- More potent
- Not susceptible to metabolic clearance by 11β-HSD2
- Do not bind to corticosteroid binding globulin
What are the three key actions of glucocorticoids?
- Anti-inflammatory
- Anti-proliferative (aids in cancer treatment)
- Anti-angiogenic (aids in cancer treatment)
Where does the GR reside by default?
Cell cytoplasm
Before binding to steroids, the GR is bound to what?
Chaperone proteins
(especially Heat Shock Protein 90 (HSP90))
What are chaperone proteins?
Proteins which assist in conformational changes of other proteins after synthesis
They aid with unfolding and assembly/disassembly of macromolecuar structures
How do glucocorticoids enter a cell?
Diffusion
(they are lipophilic)
Describe the process which results in binding of the glucocorticoid to the GR
Glucocorticoid diffuses into cell cytoplasm
Phosphorylation and ligand binding of glucocorticoid to GR causes dissociation from accessory proteins (HSP90)
What are the three main reasons for the vast diveristy in GR signalling?
- Multiple isoforms of GR
- Multiple actions from different glucocorticoid response elements (GREs)
- Post-translational modifications of GR
GR is the product of which gene?
NR3C1
GR is a modular protein as it has many different domains. What are these 4 domains?
- N terminal transactivation domain
- Central DNA binding domain (DBD)
- C-terminal ligand-binding domain (LBD)
- Flexible “hinge region” separating the DBD and LBD
Why does the N terminal tranactivation domain have strong transcriptional activation functionality?
Presence of Activation Factor 1 (AF1)
What is the basic role of AF1?
- Recruit coregulators
- Recruit transcription machinery
AF1 is active independent of ligand (glucocorticoid) binding
True or false
True
(studies have shown AF1 can cause certain responses even with the complete absence of the LBD)
In order for Activation Factor 2 (AF2) to activate, what is required?
Ligand (glucocorticoid) binding
After a glucocortoid binds to the GR in the cell cytoplasm what happens?
Translocation to the nucleus
For what reason does glucocorticoid (ligand) binding to the GR induce translocation to the nucleus?
The DBD, hinge region and LBD possess nuclear localisation signals
This allows translocation to the nucleus via importin dependent mechanisms
How does the GR-Glucocorticoid complex “know” which DNA sequence to bind?
Two zinc “fingers” localised to the DBD can bind specific sequences on target genes
These specific sequences are glucocorticoid response elements (GREs)
Which isoforms of the GR receptors have been associated with glucocorticoid insensitivity?
- GRγ
- GR-A
- GR-P
Once translocated to the nucleus what 3 options does the GR-glucocorticoid complex?
- Complex binds directly to simple or negative GREs (with or without homodimerising previously)
- Complex binds to DNA via tethering to other transcription factors
- Complex binds by direct binding and interacting with other transcription factors
What is the outcome of the GR-Glucocorticoid complex binding to a negative GRE?
Transrepression
What is the outcome of the GR-Glucocorticoid complex tethering to a DNA-bound transcription factor?
Transrepression
(transcription factor activity is inhibited)
What is a key transcription factor which may be inhibited by glucocorticoids?
NF-kappa b
What is the outcome of the GR-Glucocorticoid complex binding directly to DNA with other transcription factors?
Transcription or transrepression may occur
(dependent on GRE bound to and activity of transcription factors)
What is TTP and what does it do?
TTP (tristetraproline)is a protein which binds to mRNA of proinflammatory genes and causes destabilisation
One way a GR-glucocorticoid complex can reduce inflammation is by inducing expression of what?
TTP (tristetraproline)
The GR-glucocorticoid complex can also modulate gene expression of arrestins 1 and 2. What is the fucntion of these proteins?
Regulate signal transduction at G-protein coupled receptor
Glucocorticoids can exert some effects via a non-genomic manner, through which pathway is this possible?
MAP kinase
By exerting effects through non-genomic mechanisms, what does this mean for novel glucocorticoid therapies?
They may be able to work in minutes versus hours
As well as activating GR receptors, which other class of receptors can glucocorticoids activate?
Mineralocorticoid receptors (MR)
What is the impact of endogenous steroids on the kidneys?
- Increase renal blood flow
- Increase glomerular filtration rate
For what reason do endogenous glucocorticoids not act excessively on MR receptors in mineralocorticoid sensitive tissues such as the kidneys?
11β-hydroxysteroid dehydrogenase 2 (11β-HSD2) can break them down
What may be a negative side effect in the kidneys to excessive synthetic glucocorticoid use?
Binding to aldosterone (MR) receptors in the kidneys
This will increase Na+ retention and elevating blood pressure independent to the RAAS
Why is it not just synthetic steroids which may be able to elevate blood pressure by acting on aldosterone receptors in the kidneys?
In the distal convoluted tubule, 11β-HSD2 concentrations are low
Endogenous glucocorticoids can evade breakdown and induce their effect as an aldosterone antagonist
In which conditions if the raise of blood pressure caused by endogenous glucocorticoids particularly impactful?
- Metabolic syndrome
- Chronic stress
Glucocorticoid levels are raised above normal
For what reason is it proposed that glucocorticoids cause thin skin?
They act on mineralocorticoid receptors in the epidermis as well as glucocorticoid receptors
Epidermal atrophy in steroid use is hypothesised to be due to what?
Binding of glucocorticoids to mineralocorticoid receptors
How may epidermal atrophy as a result of glucocorticoid application be prevented?
Co-administration of spironolactone
(an aldosterone antagonist which will block MRs)
In which part of the brain are glucocorticoid receptors found which may contribute to alcohol addiction?
Amygdala
Based on the fact that glucocorticoid receptor binding in the amygdala can contribute to alcohol addiction, what has been proposed as a future therapy for such addiction?
Glucocorticoid antagonists
