7.6A. Calcium metabolism. Flashcards
I. Background
1. What are the important values of calcium concentration?
Total [Ca2+] in blood plasma = 2.2 - 2.8 mM (100%)
1. Free ionized [Ca2+] = 1.0 - 1.3 mM (45%)
2. Protein-bound = 1.0 - 1.3 mM (45%0
3. Complexed with small ions ~ 0.2 mM (10%)
I. Background
2. What are the important values of PHOSPHATE concentration?
PO43-: Extracellular [Pi] = 0,8 – 1,5mM
I. Background
3. Which ions will be the most mineral phase of bone?
- Ca2+ and Pi will be the most mineral phase of bone hydroxyapatite
I. Background
4. [Ca2+] and [Pi] are regulated by which 3 hormones?
Regulated by the same hormones:
1. PTH (parathyroid hormone) - peptide hormone
2. Calcitriol (Vitamin D) - steroid hormone
3. Calcitonin
I. Background
5. What are the 3 organs responsible for [Ca2+] and [Pi]?
3 organs responsible for regulation: (1) bones, (2) kidney, (3) GI-system
- 2% of the kidney filtration will leave (excreted via urine)
I. Background
6. Circulatory Ca2+ exists in 3 forms. What are they?
[Ca2+]plasma/EC
- Free ionized Ca2+ - 45% (1,0 – 1,3mM)
- Protein-bound Ca2+ - 45% (1,0 – 1,3mM)
+) Ca2 can be released from protein = [Ca2+]free↑
- Complexed with anions (phosphates, citrate, HCO3-) – 10%
II. HORMONES
1A. What are the characteristics of PTH (parathyroid hormone)?
- Produced by chief/principial cells – responsible for PTH synthesis, processing, secretion
- Parathyroid gland (500mg) located on the posterior surface of the thyroid gland
II. HORMONES
1B. How is PTH (parathyroid hormone) synthesized?
Synthesis of PTH:
1) Pre-pro-PTH(115AA)
-> signal sequence removed from N-terminal
from N-terminal
2) Pro-PTH (90 AA) in the ER
3) PTH (84AA) in secretory granules
II. HORMONES
2A. What are the 3 factors that affect Regulation of PTH secretion?
1) Plasma/EC [Ca2+]
2) Calcitriol (Vitamin D)
3) [Pi] plasma increased
II. HORMONES
2B. How is regulation of PTH secretion affected by Plasma/EC [Ca2+]?
PTH secretion is increased when the [Ca2+]plasma gets low and vice versa
II. HORMONES
2C. How is Ca2+-sensor work during Regulation of PTH secretion?
Ca2+-sensor: Ca2+-sensing receptor (CaSR)
- PM receptor that senses [Ca2+]EC
- 7TM-GPCR -> activates Gq
- Bind Ca2+-ions (ligands) in mM-range -> low affinity binding,
but extremely high specificity
- Since it is a Gq-coupled receptor, it will induce a Ca2+-
signal ([Ca2+]IC↑), PKC activation
-> ↓PTH secretion
-> Mutation of CaSR -> affinity↓ -> receptor cannot bind Ca2+-ions
+) There will be shift to higher Ca2+-concentrations, because the receptor will now work in a higher cc-range, due to the decreased affinity
+) Now the Ca2+-ions are regulated again, but in a higher cc-range
-> disease: familiar hypercalcemic hypocalcemia (familiar = mutation, hypercalcemic = Ca2+-range↑, hypocalcemia = Ca2+-re.abs.↑ in kidney)
II. HORMONES
2D. Make a schematic diagram to demonstrate the relationship between Plasma/EC [Ca2+] and PTH secretion?
II. HORMONES
2E. Make a schematic diagram to demonstrate the relationship between Ca2+-sensor and PTH secretion?
II. HORMONES
2F. How does Calcitriol (Vitamin D) affect PTH regulation?
Calcitriol (Vitamin D) will decrease PTH gene expression by increasing the CaSR expression
II. HORMONES
2G. How does increased [Pi]plasma affect PTH regulation?
[Pi]plasma increased
=> PTH expression increased (because it will bind calcium and cause a decrease in free Ca2+)
II. HORMONES
2H. What are the effects of PTH?
- PTH is a peptide hormone (solved in blood plasma = does not require binding protein)
- Short half life (Thalf life = 4 minutes – fast regulation)
II. HORMONES
3A. PTH has several actions within the bones and kidneys via two receptors
=> What are they?
PTH has several actions within the bones and kidneys via two receptors, known as PTH1R
and PTH2R.
II. HORMONES
3B. What are the characteristics of PTH1R?
- PTH1R is the most important and capable of Gs-linked action (cAMP↑)
- Target cells which express PTH1R: kidney and bone
II. HORMONES
3C1. How does PTH1R work in proximal tubule of kidney?
1) activation of 1α-hydroxylase, which helps synthesize active vitamin D, increasing enteric Ca2+-absorption.
2) Decreased Pi-reabsorption by way of luminal Na+/Pi-cotransporter endocytosis
=> PTH -> endocytosis of NaPiX↑ (transporter is moved away)
=> Pi-reabsorption↓ -> Pi excretion↑
II. HORMONES
3C2. How does PTH1R work in TAL + distal convoluted tubules of kidney?
- There is an increased Ca2+-reabsorption.
- ECaC are activated via PTH -> Gs -> cAMP↑.
- Calbindin (Ca2+-binding protein) binds Ca2+ in the cell, driving further Ca2+-reabsorption.
- Ca2+ then pumped out basolaterally via Ca2+- ATPase (PMCA) and the Na+/Ca2+ exchanger (NXC1)
=> PTH -> cAMP↑ -> ECaC↑ -> expression of all other transporters↑ -> ↑Ca2+- reabsorption
II. HORMONES
3C3. Make a schematic diagram that demonstrate the operation of PTH1R in TAL + distal convoluted tubules of kidney