Hormone synthesis, Action and Disease Flashcards
Describe peptide hormones and what they’re made from
- Water-soluble - This means they’re unable to cross cell membranes
- Made from large precursor molecules - prohormones
Describe steroids and iodinated tyrosine hormones (thyroid hormones) and what they’re made from
- Lipid soluble - Means they require plasma binding proteins for transport, but also means they can cross cell membranes for signalling
- Made from low molecular weight precursors
Briefly explain how peptide hormones are synthesised by transcription and translation
- Transcription of DNA to RNA
- Post-transcriptional processing- RNA → Mature RNA - (RNA splicing, 3’ polyadenylation and 5’ capping)
- Translation of mature RNA into protein using tRNA to transfer amino acids
- Post-translational processing - Cleavage of large pre-prohormone, folding of proteins, addition of sugars (glycosylation) - This produces the large pre-prohormone.
How is the large precursor protein synthesised into the active peptide hormone?
Cleavage of signal sequence from pre-prohormone, leaving only the hormone + peptide sequence
What type of hormone is insulin?
Peptide
How is insulin synthesised and secreted?
- Transcription to mRNA
- Excision of introns to mRNA (mRNA processing)
- Removal of signal sequence and formation of disulphide bonds in rER
- Pre-proinsulin → proinsulin
- Transfer to Golgi, excision of C peptide and packaging into secretory granules (vesicles)
What glands are controlled by the hypothalmic- pituitary axis?
- Hypothalamus releases or inhibits the transmission of neurohormones onto the anterior pituitary gland
- Pituitary gland stimulates release of trophic (growth) hormones that act at the thyroid, Adrenal cortex and Gonads
- Thyroids - Produces T3/T4
- T4 = 4 iodide ions
- T3 = 3 iodide ions
- Adrenal cortex - Releases cortisol and aldosterone
- Gonads - Oestrogen/Testosterone
- Thyroids - Produces T3/T4
How are steroid hormones synthesised from cholesterol?
- Cholesterol bound to sterol carrier protein- transported to mitochondria
- StAR protein transports cholesterol to inner mitochondrial membrane (rate limiting step)
- StAR = steriodogenic acute regulatory protein
- Cholesterol is cleaved by side chain cleavage enzyme P450scc (rate limiting) into pregnenolone
- Between mitochondria and sER, steroids synthesised by hyroxylase enzymes
How are thyroid hormones synthesised?
- Active uptake of iodide into follicular cell (cell in thyroid gland) via sodium iodide symporter - This transports 2 sodium ions and 1 iodide ion across the cell membrane into the follicular cell
- Transport across the apical membrane, where it reaches another transport molecule called pendrin, which allows iodide to be incorporated into tyrosine residue.
- Oxidation of iodide to iodinated intermediate by thyroid peroxidase (TPO) which is activated by H2O2 (hydrogen peroxide)
- Iodination of tyrosine residues of thyroglobulin
- Coupling of iodinated tyrosine residues
- Storage of T3 and T4 in colloid
- Uptake of thyroglobulin droplets into follicle cell
- Release and secretion of T3 and T4 stimulated by TSH
How do peptide hormones act on cell surface receptors and stimulate cell signalling pathways?
- Peptide and protein hormones are water soluble and act on cell surface receptors
- They activate second messengers and/or enzymes by causing a signal transduction after binding to the cell surface receptors
- They then have cytoplasmic and nuclear effects
What 2 types of receptor are the cell surface receptors that peptide hormones bind to?
- G- proteins linked receptors (G protein = guanosine)
- Receptors with tyrosine kinase domain
Explain the 2 cell signalling pathways that peptide hormones stimulate when acting on G-protein receptors
-
Adenyl cyclase and cAMP signalling pathway
- G-protein alpha subunit activates adenyl cyclase
- Subsequent phosphorylation steps
- cAMP activity + PKA
- Activate transcription factors or enzymes
-
Phosphoinositide signalling pathway
- Stimulated by ligand binding
- G-protein alpha subunit dissociates
- Activates downstream signalling through PLC pathway
- Activates intracellular messages
- IP3 will induce Ca2+ release from SR OR DAG can phosphorylate with PKC to activate enzymes downstream or other transcription factors
Explain the 3 cell signalling pathways that peptide hormones stimulate when acting on tyrosine kinase receptors
- Rad/MEK/ERK1/2 signalling pathway
- Ligand binds to tyrosine kinase receptor and dimerises
- Stimulates phosphorylation events that activate secondary messengers
- End result = transcription within the cell
- Phosphatidylinositol kinase/ AKT signalling pathway
- Ligand binds to tyrosine kinase receptor and dimerises
- AKT is phosphorylated and so is protein called M2
- End results can be:
- Promoting ribosome production, stimulating protein synthesis
- Inhibiting protein degradation
- Stimulating nutrient uptake and metabolism
- JAK/STAT signalling pathway
- Ligand binds to tyrosine kinase receptor
- JAK phosphorylate and this phosphorylates STAT downstream, which activates transcription
- These are transcription factors, so bind to hormone response elements within the DNA of target proteins
How do steroid and thyroid hormones cross cell membranes and act on intracellular receptors?
- Lipophilic (means they are able to cross cell membrane)
- Act on intracellular receptors in cytoplasm or nucleus.
- The receptors are transcription factors, so are able to act on DNA
What type of receptor are the intracellular receptors that steroid and thyroid hormones bind to?
Nuclear receptors as steroid hormone receptors are a family of transcription factors
