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Y Physiology II > W6L3 Hormonal Regulation of Calcium and Phosphate Metabolism > Flashcards

W6L3 Hormonal Regulation of Calcium and Phosphate Metabolism Flashcards

1
Q

How many times difference is there between extracellular and intracellular calcium concentration?

A

10,000X more extracellular calcium than intracellular

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2
Q

What is the free extracellular calcium concentration? What percentage of this is of the total calcium concentration in plasma?

A

1.0-1.3 mM, which is about 45% of the total calcium concentration.

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3
Q

What are 3 hormones that play a role in regulation of calcium concentration?

A
  1. Parathyroid hormone
  2. Calcitriol
  3. Calcitonin (although this one is questionable in humans)
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4
Q

How much is the daily intake of Ca2+? How much of this is absorbed?

A

1g/day, but only 500 mg are absorbed

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5
Q

How much calcium is secreted into the GI from the ECF? How much calcium is excreted in feces? (daily)

A

325 mg / day for GI secretion, 825 mg / day is excreted in feces

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6
Q

About how much calcium is in the ECF total?

A

1000 mg (the same amount as is taken in the diet)

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7
Q

How much calcium is filtered by the kidneys? Of this amount, how much is reabsorbed? This means that how much is excreted? (daily)

A

10,000 mg / day filtered, while 9825 mg / day reabsorbed. So, 175 mg is excreted

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8
Q

How much calcium is used to form bones per day? And how much is resorbed from bones?

A

280 mg / day in BOTH directions, so equal amounts used for formation and resorption

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9
Q

How much phosphate is in the average diet per day? How much of this number is absorbed?

A

1400 mg / day in diet, while 1100 mg / day absorbed.

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10
Q

How much phosphate is in the ECF phosphate pool? How much phosphate is excreted in feces per day?

A

500 mg in ECF phosphate pool, and 500 mg / day is excreted.

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11
Q

What percentage of calcium ions are bound to proteins? What is the advantage of these protein binding?

A

45% (the same percentage as free calcium). Can be easily mobilized

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12
Q

What percentage of calcium ions are in a complex with anions (e.g. citrate)? What is the disadvantage of this?

A

10%. Cannot be easily mobilized.

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13
Q

What is the total calcium concentration in plasma?

A

2.2-2.6 mM

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14
Q

How much does the parathyroid gland weigh?

A

Less than 500 mg

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15
Q

What type of cells produce parathyroid hormone (PTH)?

A

Chief cells of the parathyroid gland

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16
Q

What is the order of how parathyroid hormone is posttranslationally modified? Which end is the biologically active sequence?

A

First pre-pro PTH (115 amino acids), then pro-PTH (90 amino acids), then final structure is PTH (84 amino acids).

The N-terminal part is the biologically active sequence (C terminal cleaved).

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17
Q

What is the free calcium concentration range for which parathyroid hormone secretion is sensitive? What happens below, during, and above this range?

A

PTH secretion below 1.0 mM [Ca2+] is 100%. Between 1.0 and 1.3 mM, PTH secretion drops steeply, reaching its minimum secretion of 5% capacity. This 5% rate continues above 1.3 mM (PTH never reaches 0% secretion!)

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18
Q

What type of GPCR is the calcium sensing receptor (CaSR) in the parathyroid gland cells?

A

Gq G protein coupled receptor

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19
Q

What is the (simple) transduction pathway of the calcium-sensing receptor (CaSR) in the parathyroid gland?

A

Extracellular [Ca2+] increase

  • > Gq activation
  • > phospholipase C pathway
  • > calcium signal in cell
  • > inhibitory effect that decreases secretion of PTH
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20
Q

What is notable about the activity and selectivity of the Calcium-sensing receptor (CaSR)?

A

Low activity (binds in mM range, while receptors usually bind in nM range), but very selective for only calcium

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21
Q

What is the cause of familial hypercalcemic hypocalcuria?

A

Mutation of CaSR, which causes even lower affinity to calcium. The parathyroid gland is then not sensitive enough to calcium, and so PTH continues to be secreted at abnormally high calcium concentration levels (i.e. 2-3 mM.

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22
Q

What is the other name for 1,25 dihydroxy vitamin D? What is its effects on PTH secretion and CaSR expression?

A

Other name = Calcitriol.

Decreases PTH secretion, increases CaSR expression

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23
Q

What is the effect of an increase in extracellular phosphate concentration on PTH secretion?

A

Increases PTH secretion

24
Q

What is the halflife of PTH?

A

~ 4 minutes (rapidly metabolized). Quickly regulates calcium concentration

25
Q

What type of GPCR are the parathyroid hormone receptors 1 and 2 (PTH1R/PTH2R)?

A

Gq and Gs, so they cause both an elevation of cAMP and a calcium signal

26
Q

What are the 3 targets of parathyroid hormone?

A
  1. Proximal tubules of kidney
  2. Thick ascending limb (TAL) + distal tubules of kidney
  3. Bones (only in osteoblasts!)
27
Q

What are the effects of PTH on the TAL and distal tubules of the kidney?

A

Stimulates calcium reabsorption

28
Q

What are the 2 effects of PTH on the proximal tubules of the kidney?

A
  1. Decrease phosphate reabsorption (so phosphate excretion is increased)
  2. Activates 1-alpha-hydroxylase, which is required to activate vitamin D to calcitriol
29
Q

What are 3 mechanisms by which PTH increases calcium reabsorption? (was drawn during lecture)

A
  1. PTH -> cAMP -> increased expression of ECaC (epithelial calcium channels)
  2. PTH -> gene expression of calcium-binding protein increased
  3. PTH -> Sodium-Calcium exchanger (NCX) expression increased
30
Q

What is the mechanism by which PTH decreases the reabsorption of phosphate? (was drawn in lecture)

A

PTH -> endocytosis of Sodium - Phosphate Cotransporter. # of these transporters decreases.

31
Q

What is the effect of PTH on bones, in regards to calcium and phosphate?

Which bone cells have receptors for PTH?

A

Both calcium and phosphate are mobilized, contributing to an increased plasma concentration of both of them

Only osteoblasts have PTH receptor.

32
Q

What is the overall effect of PTH on the plasma concentration of calcium vs phosphate?

A

PTH -> large increase in calcium concentration, but moderately decreased phosphate concentration.

The increase in phosphate that results from mobilization in bones is outmatched by the increase in phosphate excretion, so there is still a net decrease.

33
Q

What is the molecular formula for hydroxyapatite?

Why is it important that the phosphate concentration is decreased by PTH?

A

Ca5(PO4)3(OH)

(all those numbers should be subscript)

By decreasing phosphate concentration, PTH stops additional formation of hydroxyapatite

34
Q

What are 3 instances in which PTH-related peptide is produced?

A
  1. Secreted by lactating breast, provides high calcium concentration during lactation period.
  2. Secreted by various cells during development, when much calcium is needed.
  3. Appears in a lot of tumor cells, so hypercalcemia is a common side effect of tumor formation
35
Q

UV-B light is able to convert what molecule into vitamin D3?

A

7-dehydrocholesterol

36
Q

What liver enzyme acts on vitamin D3, and what is the product?

A

25 hydroxylase converts Vit D3 -> 25-hydroxyvitamin D

37
Q

What is the most important regulatory enzyme of 1,25 Dihydroxyvitamin D, and where is it located? What substrate does it convert?

A

1 α-hydroxylase (CYP1α), located in kidney.

Substrate = 25-Hydroxyvitamin D

38
Q

What are 4 things that regulate 1α-hydroxylase (CYP1α), and what are their effects (inhibition/stimulation)?

[there was a schematic drawing of this in lecture]

A

PTH, [Ca2+] decrease, and [Pi] decrease all stimulate 1α-hydroxylase.

Calcitriol (the product of the enzyme) inhibits it (neg feedback), while also stimulating 24α-hydroxylase.

39
Q

What is the inactive form of vitamin D that may be synthesized instead of calcitriol? What enzyme converts them?

A

24,25 dihydroxy or 1,24,25 trihydroxy vitamin D.

Both are synthesized from 24-hydroxylase.

40
Q

How is vitamin D transported in the blood?

A

It’s hydrophobic, so it must be transported with a Vitamin-D binding protein

41
Q

What type of receptors does vitamin D bind to? What can modify their effects?

A

Intracellular receptors that are in nuclear receptor family.

RxR (retinoid X receptor) modifies gene expression positively or negatively.

42
Q

What 3 organs are affected by active vitamin D/calcitriol?

A

Small intestine, kidney, bones

43
Q

What are the effects of calcitriol on the small intestine?

What is the mechanism of these effects?

A
  1. Increased calcium absorption from diet (most important effect of vitamin D!)
  2. Phosphate absorption is also increased

Mechanism: increased expression of transporters for both calcium and phosphate absorption

44
Q

What are the effects of calcitriol on the kidney?

A

Both Ca2+ and Pi reabsorption is increased.

1α-hydroxylase is inhibited, while 24α-hydroxylase is activated

45
Q

What are the effects of calcitriol on bones?

Both immediate effects and long term

A

Rapid effect: calcium and phosphate mobilization

Long term: normal bone development and hydroxyapatite concentration (no vitamin D -> rickets)

46
Q

What symptoms are characteristic of rickets, and why?

A

Deformation of long bones due to vitamin D deficiency during development. There is an abnormal mineralization / low hydroxyapatite concentration of bones due to poor absorption of calcium and phosphate.

Ventilation and cardiac function are also both decreased

47
Q

What cells produce calcitonin?

A

Thyroid gland C cells

48
Q

At what calcium concentrations does calcitonin secretion increase?

[graph drawn in lecture]

A

Calcitonin is not secreted until free calcium concentration is above 1.3 mM, and then it steeply increases

49
Q

What are the target cells of calcitonin? What is the effect?

A

Osteoclasts are inhibited by calcitonin, so basically -> increase bone formation.

The expected effect is decreased calcium and phosphate, but this basically doesn’t happen in humans. Removal of just the thyroid gland does not affect calcium concentration.

50
Q

What disease can be improved by using calcitonin?

A

Paget disease: overactive osteoclasts.

Therapy is calcitonin (from salmon, because it’s more active than human calcitonin, but not important to remember)

51
Q

What hormone regulates the minute-to-minute concentration of calcium ions?

A

PTH. Usually blood calcium concentration decreases, so PTH has to increase to cause Ca2+ reabsorption in the kidney

52
Q

What hormone is slower than PTH and important in long-term regulation of calcium concentration?

A

Calcitriol (active vitamin D)

53
Q

What are 3 causes of hypocalcemia?

A
  1. No PTH production
  2. No calcitriol (vitamin D deficiency in short-term)
  3. Alkalosis (less protons -> less protons bound to albumin -> more albumin available to bind to calcium -> less free calcium)
54
Q

What is the major problem with hypocalcemia?

A

Nerves are more sensitive to depolarization because the threshold potential of voltage-dependent channels is calcium-dependent.

[Ca2+] decrease -> threshold for depolarization becomes more negative.

Sensory neurons send signals for burning, tingling and numbness, while motor neurons have spontaneous contractions / tetanus, and vegetative neurons cause unwanted cardiovascular and GI effects.

55
Q

What are 2 causes of hypercalcemia?

A
  1. PTH increase (which is rare)

2. PTH-related peptide is overproduced, as in the case of a tumor

56
Q

What is the major problem from hypercalcemia?

A

Precipitation of calcium phosphate leads to stone formations, mainly in the skin, kidney, and lungs.

Y Physiology II (16 decks)

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