Steroid Hormone Signalling Flashcards
TRUE or FALSE: All hormone action is receptor-mediated
TRUE
Describe the structure of Steroid Hormones
- Cyclopentanoperhydrophenanthrene (sterane) structure.
- 4-cyclic compounds with androstane skeleton and a side chain at carbon C-17.
- Lipophilic (lipid soluble).
All steroid hormones derived from same parental precursor molecule
Cholesterol
Where does the cholesterol come from?
Describe LDL breakdown
- Outer phospholipid layer
- Inner core of cholesterol and triglycerides
- Breakdown of LDL molecule can release choleterol for use in hormone synthesis
Describe Steroid hormone biosynthesis
Occrurs in the mitochondia
- Conversion of cholesterol into pregnenelone
- Involves the enzymes cholesteroldesmolase ad cytochrome P450
- The C17 side chain of cholesterol is cleaved to form pregnenelone
The steroidogenic pathway
There are different biosynthetic pathways within the different layers of the adrenal cortext that generate different species of steriod hormone
This is because the enzymes are expressed differently in different layers of the adrenal cortex
Describe Steroid hormone release & transport
- Steroid hormones are not stored/packaged within the synthesising cell but immediately released into the circulation.
- But – remember they are lipophilic so how do exist within the aqueous environment of the circulation?
- Reversibly bound to proteins.
Steroid hormone binding proteins: Albumen
- Non-specific binding
- Low affinity
Give examples of binding proteins and their steroid hormones
Sex steroid binding protein→Testosterone estradiol
Progesterone binding globulin→ Progesterone
Corticosteroid binding protein→ Cortisol aldosterone
Steroid hormone binding proteins
- Specific
- High affinity
Testosterone Estrodiol
Progesterone
Cortisol Aldosterone
Steroid hormones in circulation
- Constitutes inactive pool of hormone.
- Protects the hormone from metabolic and chemical alterations.
- Provides, by reversible dissociation, a buffer against sudden changes in active hormone concentrations.
Steroid hormone receptors
Explain Steroid hormone signalling
- Inactive steroid hormone receptor resides within cytoplasm – complex with Hsp90 and src.
- Steroid hormone dissociates from binding protein and diffuses across cell membrane.
- Binds to receptor and induces conformational change.
- Causes receptor complex to fall apart.
- As src is released it phosphorylates the receptor – rapid changes in cell activity.
- Activated receptor-hormone complex can now translocate to nucleus and bind to DNA (usually as an inverted dimer) causing changes in gene expression (slow)
Describe the Steroid hormone signalling pathway
Describe DNA-binding
- Activated receptor-hormone complex binds to specific sequences in DNA = hormone response element (HRE).
- Sometimes these sequences appear in genome next to each other but as mirror image = inverted repeat.
- So two activated receptor-hormone complexes will bind to adjacent HREs but facing opposite way.
DNA-binding: zinc fingers
- Interaction of activated receptor-hormone complex with the HRE is mediated via zinc finger domain within receptor.
- Zinc fingers are small protein motifs that contain multiple finger-like protrusions.
- Protrusions make tandem contacts with target molecules e.g. DNA.
- Protrusions are stabilised by binding to zinc ions – mediated by cysteine/histidine residues within the domain.
DNA-binding: Enhancers
- Upstream of the coding sequence is the promoter (contains regulatory sequences that associate with RNA polymerase-transcrptional machinery)
- Upstream of the promoter region re sequences known as the proximal control element (regulatory regions that bind to proteins such as transcription factors) this influences the rate of expression of this coding sequences
- Upstream of this region is the enhancer (another regulatory region) that binds the activated hormone receptor complex and associated HRE’s
Give examples of transcriptional responses
Depends on how receptor-hormone complex binds to DNA
Simple HRE- HRE binds to enhancer-increased gene expression
Example: cortisol-glucocorticoid receptor complex & gluconeogenesis genes
negative or nHRE- Single HRE within the enhancer region-single receptor homone complex binds, gene expression inhibited
Example: cortisol-glucocorticoid receptor complex & insulin receptor gene
Thethering HRE- Activated receptor homone complex doesnt bind to DNA dircectly, bind to other proteins e.g. transcription factors bound to regulatory regions. Causes an Induction or repression of gene expression
Example: cortisol-glucocorticoid receptor complex & NF-kB
How is signalling switched off?
- Signalling is switched off by removing hormonal stimulation.
- Steroid hormones are catabolised: reduced & conjugated to glucaronides and sulphate (water soluble).
- Excreted via the liver and kidneys.
- 70% urine, 20% faeces & rest through the skin.
Which hormones are generated frm the zona fasiculata?
- Cortisol
- Corticosterone
Which steroid hormones are generated from the zona glomerulosa?
Aldosterone
Which steroid hormones are generated from the zona reticularis?
Androstnenedine
