2 - Calcium Homeostasis Flashcards
What 3 symptoms occur from hypocalcaemia?
Tetany (spasms)
Cardiac arrhythmia
Asphyxiation (diaphragmatic spasm)
What effect on nerves does hypocalcaemia have?
Increased nerve excitability
What complication can occur from hypocalcaemia?
Death by asphyxiation (diaphragmatic spasm)
What effect does hypercalcaemia have on nerves?
Decreased neuromuscular excitability
What symptoms / features occur with hypercalcaemia?
Cardiac arrhythmias
Lethargy
Death
In the context of plasma calcium, what percentages are distributed where?
- Bound to albumin?
- Bound to HCO3 / PO4?
- Free ionised?
Albumin: 35-40%
HCO/PO4: 5%
Free ionised: 50%
What % of calcium is hed within bones and teeth? and in what form?
99%
Hydroxyapatite
How much calcium is consumed per day on average?
1g
What percentage of dietary calcium passes straight through?
80%
How much calcium is absorbed on average?
35%
350mg
How much calcium is secreted from our gut?
15%
150mg
What two ways is calcium lost through the gut?
Bile salts
Sloughed off
What mass of calcium is in the blood (ECF) at any one moment?
1g
Which organ is the main regulator of calcium levels?
Parathyroid gland
What cells within the parathyroid gland produce parathyroid hormone (PTH) ?
Chief cells
What 2 cleavage steps results in PTH as a product?
Pre-pro PTH
Pro-PTH
PTH
How long is PTH’s half-life?
20 mins
Where does PTH cleavage occur in the body?
Liver
What relationship does PTH secretion have with serum calcium levels?
Inversely proportional
Structurally, what is the necessity behind constant bone formation and resorption?
Exposure to microfractures, which would accumulate over time.
Formation of bone requires 2 things - what are they?
Minerals (Ca2+)
Holes
How is PTH secreted from the parathyroid gland?
Pulsatile manner
What effect does PTH have on calcium levels?
Increases them
Through what 3 mechanisms does PTH stimulate the increase in circulating calcium levels?
1) Increase bone resorption
2) Increase renal reabsorption / decreasing excretion
3) Increasing production of vitamin D
PTH has what effect on phosphate within the kidney?
Why is this important?
Increases excretion.
Don’t want calcium / phosphate combining in blood = plaque formation.
What two minerals make hydroxyappatite?
Calcium
Phosphate
Graphically, what shape is the curve of calcium:PTH secretion?
steep-sigmoidal
What value is the ‘Calcium set-point’? (mM)
1.2 mM
Draw Vitamin D synthesis pathway.
Cholesterol
Intestine (pro-vitamin D3)
Skin - UVB (pre-vitamin D3 –> Vit D3)
Liver (+OH) (constitutive) –> Calcefidiol
Kidney (+OH) (PTH) (1alpha-hydroxlase) –> Calcitriol
How does calcitriol increase serum calcium levels?
Increases calbindin expression.
Thus, increases GI uptake.
Where else can calcitriol work?
Bone + kidney
amplifies effect of PTH
What protein carries vitamin D around the blood?
Vitamin D binding-protein
What is a deficiency of vitamin called?
Rickets
What two causes of rickets exist?
Insufficient proVit D intake
Insufficient light exposure
What two conditions can arise from chronic calcium deficiency?
Secondary hyperparathyroidism
Osteomalacia
What receptor does PTH bind to?
Type 1 PTH-receptor
PTH1R
What structure does PTH1R have?
7 transmembrane spanning protein
What type of receptor is PTH1R?
G protein-coupled
Gs
Through what mechanism does PTH1R work through?
Adenylate cyclase
cAMP
PKA pathway
What is PTHrP and what type of effect does it have?
PTH-related peptide
Paracrine effects - causes proliferation
Where is the PTH1R expressed?
Bone
Kidney
What two conditions arise from PTH-receptor mutations?
Jansen’s metaphyseal…
Blomstrands…
Chrondodysplasia
Jansen’s metaphyseal chondrodysplasia is what type of mutation?
What phenotype?
Activating
Short-limb dwarfism
Blomstrands chondrodysplasia is what type of mutation?
Results in what phenotype?
Inactivating
Early lethality / advanced bone maturation.
Mice K/o of PTH1-receptor results in what?
Early lethality
Activating the calcium receptor has what effect on PTH secretion?
Inhibits it
Low calcium levels have what effect on PTH secretion?
PERMITs it.
What 3 modulatory substances have an effect on the calcium receptor?
Agonists
Positive allosteric modulators
Negative allosteric modulators
Give 3 examples of Ca-receptor agonists
Cations (Ca2+ / Mg2+)
Spermine
Aminoglycosides (gentamycin)
How do positive allosteric modulators function?
They increase the receptor’s sensitivity to an agonist
Give two examples of positive allosteric modulators of the calcium receptor
Calcimimetics (Cinacalcet)
Aromatic amino acids
How do negative allosteric modulators function?
Decrease a receptor’s sensitivity to an agonist
Give an example class of allosteric receptor modulators to the calcium receptor?
Calcilytics
What effect, therefore, do calcimimetics have on circulating calcium levels?
Decrease Ca levels
What effect do calcilytics have on circulating calcium levels?
Increase Ca levels
What conditions can be treated with calcimimetics?
Primary / Secondary hyperparathyroidism
What conditions can be treated with calcilytics?
Osteoporosis
Other than calcimimetis, what other supplement can you give to reduce PTH secretion?
Vitamin D
What does vitamin D have to be given with as a result of the physiological response to it?
Phosphate binders
vitamin D increases phosphate
What type of receptor is the vitamin D receptor?
Nuclear receptor
Where in the cell is the Vitamin D receptor found?
Cytosol
K/O of the vitamin D receptor results in what phenotype?
Rickets
infertility, alopecia
Where are the calcium receptors most highly expressed?
Parathyroid gland
Kidneys
Give two advantages of calcimimetics / calcilytics besides their function
1) Don’t alter plasma concentrations of endogenous ligands
2) Don’t alter endogenous pathways
Give an example of a calcimimetic
Cinacalcet
Give an example of a calcilytic
NPS-2143
