7.6A. Calcium metabolism. Flashcards by Aurora H

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%)

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I. Background
2. What are the important values of PHOSPHATE concentration?

PO43-: Extracellular [Pi] = 0,8 – 1,5mM

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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

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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

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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)

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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%

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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

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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

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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

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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

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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)

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II. HORMONES
2D. Make a schematic diagram to demonstrate the relationship between Plasma/EC [Ca2+] and PTH secretion?

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II. HORMONES
2E. Make a schematic diagram to demonstrate the relationship between Ca2+-sensor and PTH secretion?

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II. HORMONES
2F. How does Calcitriol (Vitamin D) affect PTH regulation?

Calcitriol (Vitamin D) will decrease PTH gene expression by increasing the CaSR expression

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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+)

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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)

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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.

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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

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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↑

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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

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II. HORMONES
3C3. Make a schematic diagram that demonstrate the operation of PTH1R in TAL + distal convoluted tubules of kidney

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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)?

1. Ca2+-absorption↑ (ECaC, binding proteins, all proteins – expression↑) 2. Pi-absorption↑ (transporter expression↑=)

II. HORMONES 4E3. What are the Active vitamin D effects in Kidney?

1. Ca2+ and Pi reabsorption↑ 2. 1α-hydroxylase activity↑ 3. 24α-hydroxylase activity↑

II. HORMONES 4E4. What are the Active vitamin D effects in Bone (osteoblast)?

1. Short effect: Ca2+, Pi mobilization (decreases mass of bone) 2. 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?

1. Paget’s disease 2. Salmon-calcitonin 3. 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?

1. No PTH 2. No vitamin D (calcitriol) 3. 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?

1. Hypercalcemia: [Ca2+]EC/plasma > 1,3mM 2. 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