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
II. HORMONES
3C4. Make a schematic diagram that demonstrate the operation of PTH1R in Proximal tubule of kidney
II. HORMONES
3D. How does PTHR1 work in bone?
Bone (osteoblast):
- PTH receptors located on osteoblasts
- Ca2+ + Pi mobilization from the bone↑ (↑[Ca2+]pl + [Pi]pl)
II. HORMONES
3E. Make a summary of PTH effects
II. HORMONES
3F1. What are the characteristics of PTH-related peptide?
- Coded by a different gene than PTH, but the N-terminal 13 AAs (responsible for
biological effect) are the same - Can also activate PTH1R
=> Consequence: PTH-like effect (e.g. synthesis of PTH-related peptide will ↑[Ca2+])
II. HORMONES
3F2. How are PTH-related peptide secreted?
- Lactating breast (milk contains ↑ amount of Ca2+)
- Development (many cells secrete PTH-related peptide -> Ca2+ required for
development) - Tumor cells -> hypercalcemia (can be the marker for the presence of tumor cells)
II. HORMONES
4A. What is the chemical name of Calcitriol?
1,25-dihydroxyvitamin D (steroid hormone)
II. HORMONES
4B. How does synthesis of Calcitriol occur?
II. HORMONES
4C. Make a schematic diagram to explain Regulation of Calcitriol production?
II. HORMONES
4D. What are the effects of calcitriol?
- Steroid hormone = binding proteins in the blood plasma
- Intracellular vitamin D receptor forms heterodimer with retinoid X receptor (RXR) to regulate gene expression
II. HORMONES
4E1. What are the organs having receptors for Active vitamin D?
Vitamin D receptor expressed in:
- Gut (small intestine)
- Kidney
- Bone (osteoblast)
II. HORMONES
4E2. What are the Active vitamin D effects in Gut (small intestine)?
- Ca2+-absorption↑ (ECaC, binding proteins, all proteins – expression↑)
- Pi-absorption↑ (transporter expression↑=)
II. HORMONES
4E3. What are the Active vitamin D effects in Kidney?
- Ca2+ and Pi reabsorption↑
- 1α-hydroxylase activity↑
- 24α-hydroxylase activity↑
II. HORMONES
4E4. What are the Active vitamin D effects in Bone (osteoblast)?
- Short effect: Ca2+, Pi mobilization (decreases mass of bone)
- Long-term effect: required for normal bone development (Ca2+ and Pi absorption – maintenance of normal bone mass)
II. HORMONES
5A. Give the Summary of the regulation of plasma calcium ion concentration in case of SHORT-TERM RESPPONSE
- Hypocalcemia
-> ↑PTH
-> ↑Ca2+- reabsorption + ↑bone turnover
-> ↑blood [Ca2+]
II. HORMONES
5B. Give the Summary of the regulation of plasma calcium ion concentration in case of LONG-TERM RESPPONSE
- If the hypocalcemia occurs for a long time, we need a continuous Ca2+-input from the diet
- ↑Ca2+-absorption form small intestine is required - PTH cannot directly stimulate it
- But PTH can ↑production of vitamin D (via CYP1α) -> ↑Ca2+-absorption from diet -> maintain blood [Ca2+]
II. HORMONES - Deficiency of vitamin D
6A. What are the characteristics of RICKETS?
- Un-mineralization of bone, because of impaired absorption of Ca2+ and Pi from GI
- PROBLEM: deformation of long bones
- Can result in cardiac + respiratory issues due to deformities of the
thoracic cage
II. HORMONES - Deficiency of vitamin D
6B. What are the characteristics of ‘’Angolkór’’ = English disease?
- English: no sunshine = no endogenous vitamin D production
- Starvation -> ↓exogenous input of vitamin D
=> Vitamin D deficiency
II. HORMONES
7A. What are the characteristics of Calcitonin?
- Synthesized in thyroid gland by C-cells
- Peptide hormone (32 AAs)
- Physiological importance is questionable
II. HORMONES
7B. How is calcitonin regulated?
- Regulation is opposite to that of PTH – with increased [Ca2+], calcitonin secretion will also
increase - Inhibits bone resorption activity of the osteoclasts
=> ↑bone formation -> ↓[Ca2+]plasma + [Pi]plasma
II. HORMONES
7C. Make a schematic diagram to demonstrate the regulation of Calcitonin?
II. HORMONES - Clinical importance
7D1. What are the 3 diseases related to calcitonin?
- Paget’s disease
- Salmon-calcitonin
- Hypocalcemia
II. HORMONES - Clinical importance
7D2. What are the characteristics of Paget’s disease?
Paget’s disease: osteoclast cells have a very high activity
=> calcitonin (inhibitor of osteoclasts) can be used as a treatment
II. HORMONES - Clinical importance
7D3. What are the characteristics of Salmon-calcitonin ?
Salmon-calcitonin is used, because it has higher activity (sea animals = ↑[calcitonin])
II. HORMONES - Clinical importance
7D4-1. What are the characteristics of Hypocalcemia?
Hypocalcemia (more severe condition than hypercalemia) [Ca2+]EC/plasma < 1,0mM
II. HORMONES - Clinical importance
7D4-2. What are the 3 causes of Hypocalcemia?
- No PTH
- No vitamin D (calcitriol)
- Hyperventilation
II. HORMONES - Clinical importance
7D4-3. Why is no PTH a cause of Hypocalcemia?
- Usually when there is a removal of the thyroid gland, parathyroid glands (4 glands located behind the thyroid) can also be affected/removed
- No PTH -> [Ca2+]plasma ↓
II. HORMONES - Clinical importance
7D4-4. Why is no vitamin D (calcitriol) a cause of Hypocalcemia?
Long-term effect: calcium stores (bones) are empty => [Ca2+]plasma ↓
II. HORMONES - Clinical importance
7D4-5. Why is Hyperventilation a cause of Hypocalcemia?
Metabolic alkalosis:
- ↓ in H+ (↑pH), which are normally bound to albumin
- H+ will dissociate from albumin, and the free calcium will then bind to albumin
instead
- Free [Ca2+]↓ -> hypocalcemia
II. HORMONES - Clinical importance
7D4-6. Why does hypocalcemia cause a problem?
- A change in the [Ca2+]plasma
-> threshold potential of the VG-Ca2+-channels (+ Na+-ch.) will be changed -> the threshold will be more negative - Threshold potential will be more negative, because of decreased [Ca2+]plasma -> the entire process occurs a little bit earlier
=> Increases the sensitivity of the nerve cells
=> Easier to activate the AP generation of nerve cells
II. HORMONES - Clinical importance
7D4-7. What happen if we have severe hypocalcemia?
In the case of severe hypocalcemia, we can f.ex. detect spontaneous contractions of the skeletal muscles. It affects the:
- Motor nerves -> spontaneous contraction/tetanus
- Sensory nerves -> sensation of burning, numbness, tingling
- Autonomic/vegetative nerves -> cardiovascular effects (brady/tachycardia, BP
changes) + GI-system
II. HORMONES - Clinical importance
7D5-1. What are the characteristics of Hypercalcemia?
- Hypercalcemia: [Ca2+]EC/plasma > 1,3mM
- It also effects the threshold potential of VG-Ca2+channels, but will not cause a problem since the local depolarization is (always) big enough to evoke an AP
II. HORMONES - Clinical importance
7D5-2. What are the causes of Hypercalcemia?
- ↑PTH (ex: PTH-producing tumor)
- ↑PTH-related peptide (produced by tumor cells etc.)
II. HORMONES - Clinical importance
7D5-3. What happens in hypercalcemia?
↑[Ca2+]EC/plasma will generate the precipitation of CaPi salt
-> stone formation in kidney, interstitial space of lung and skin
