2 - Calcium Frontiers Flashcards
How many people in the UK are currently being treated for renal failure?
47,000
What is the 5-year % survival for dialysis patients?
35%
What is the 5-year % survival if dialysis patients have diabetes?
25%
What is the most common cause of mortality in dialysis / diabetic patients?
Cardiovascular events
What is the pathophysiology of CKD-BMD leading to cardiovascular events?
1) Renal disease
2) Increase PTH (+ hyperplasia)
3) Bone demineralisation
4) Vascular calcification
5) Heart strain
6) Heart failure (death)
Other than Calcium concentrations and vitamin D having modulatory effects on PTH release, which two other aspects of CKD-MBD have been shown to affect PTH release?
Phosphate levels
(hyperphosphataemia)
Acidosis
What effect does acidosis have on PTH secretion?
What receptors are involved?
Acidosis INCREASES PTH secretion.
Inhibits CaR.
What effect does phosphate have on the CaR?
Inhibits it
What manner was phosphate inhibiting the CaR?
Non-competitively (allosteric)
How do you know that CaR is non-competitively inhibited? (pharmacology graph)
Emax was reduced.
EC50 stayed the same.
In CaR K/o mice, what effect did altered phosphate levels have on PTH secretion?
What does this prove?
No effect.
Proved phosphate was directly affecting CaR in a rapid and reversible manner.
What plant is the CaR modelled on?
Is it active when open or closed?
Venus fly trap
Closed = Active Open = Inactive
What amino acid has been shown to be important in regards to phosphate sensitivity along the length of the CaR protein?
Arginine 62
What two reasons show that arginine 62 shown is important in the CaR structure?
1) Evolutionarily conserved amongst all species.
2) Substitution of arginine 62 resulted in no phosphate response.
