L10 Advances in drugs targeting the parathyroid glands Flashcards
Role of PTH
Maintenance of adequate levels of blood ionized calcium (free calcium)
- normal neuromuscular function
- bone mineralisation
What cells in the parathyroid gland secrete PTH, and in response to what?
Chief cells secrete PTH in response to small decreases in blood ionized calcium in order to maintain calcium homeostasis
Effect of PTH secretion on calcium
- increased intestinal absorption of calcium
- increased renal calcium reabsorption
- increased bone resorption, which increases calcium since bone is a calcium store
How is PTH synthesised?
PTH is synthesised as a prepropeptide hormone comprising 115 amino acids, but only the single chain full length polypeptide is secreted. The preprohormone and prohormone have little/no biological effect and are not released.
Factors influencing PTH synthesis
- cAMP acting via cAMP response element binding protein upregulates PTH gene transcription
- vitamin D downregulates PTH transcription
- low serum calcium levels upregulate PTH synthesis
- high serum phosphate levels upregulate PTH synthesis
PTH is a product of a single gene located on which chromosome?
11
Why is the structure of PTH important?
As many as 50 amino acids can be removed from the C-terminus without compromising biological potency. However, removal of serine at the N-terminus virtually inactivates the hormone.
How many amino acids does PTH contain?
84
Where is parathyroid hormone-related peptide (PTHrP) found?
in the plasma of patients suffering from certain malignancies and accounts for the accompanying hypercalcaemia (little/no PTHrP found in normal individuals)
What allows PTHrP to bind PTH1R with high affinity?
- similar first 13 amino acids to PTH
- similarities in the N-terminus to PTH
What type of receptor is PTH receptor?
G-protein coupled receptor
Which enzymes are important in regulation of calcium levels and are a result of Gαs and Gαq stimulation, respectively?
PKA and PKC
Rapid response to PTH
protein phosphorylation
Delayed response to PTH
altered expression of genes regulated by cAMP response element binding protein
Increased PTH causes bone resorption, so how can PTH help with osteoporosis?
Intermittent PTH administration has anabolic effects. This results in bone formation and increased osteoblast number, which is beneficial in osteoporosis treatment.