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Biochem Exam 5 > 11/14: Hormonal Control of Calcium and Phosphorus I > Flashcards

11/14: Hormonal Control of Calcium and Phosphorus I Flashcards

1
Q

Ca2+ ions critical to many cellular functions:

A
  • Cell division / Cell adhesion
  • Plasma membrane integrity
  • 2nd messenger in signal transduction
  • Muscle contractility
  • Neuronal excitability
  • Blood clotting
  • Skeletal development
  • Bone, dentin, enamel mineralization
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2
Q

Phosphorus critical to many cellular functions:

A

-Membrane composition (phospholipids)
-Intracellular signaling
-Nucleotide structure
-Skeletal development
-Bone, dentin, enamel mineralization
-Chondrocyte differentiation
- Phosphorus critical to many cellular functions:

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3
Q

3 major pools of calcium in body:

A

Bone calcium – 99%
Calcium in blood & extracellular fluid 1%
Intracellular calcium 1%

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4
Q

What is the mineral phase of bone/teeth?

A

Hydroxyapatitie (HA) crystals

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5
Q

What is important for mechanical and weight bearing properties of bone?

A

HA mineralization of bone

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6
Q

What serves as reservoir of calcium to
maintain blood ionized calcium within normal
range?

A

Bone HA

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7
Q

Normal range for total serum calcium

A

8.5 – 10.5mg/dL

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8
Q

What are the 3 types of calcium in the blood?

A

45% = ionized (biologically active fraction)
45% = bound to albumin (pH dependent)
10% = complexed with citrate or phosphate ions

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9
Q

Normal range of ionized calcium

A

4.4-5.4mg/dL

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10
Q

What are the calcium intake in a typical individual absorbed by gut and excreted in urine?

A

~200mg

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11
Q

What are the calcium intake in a person with a major calcium reservoir absorbed by gut and excreted in urine?

A

~500mg

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12
Q

What are the intracellular and extracellular calcium levels?

A

Low intracellular calcium concentrations in cytosol
High extracellular concentration

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13
Q

What regulates cell function?

A

Maintenance of steep gradient, intracellular calcium fluxes regulate cell function

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14
Q

How is the calcium gradient achieved?

A

By calcium pumps in plasma membrane

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15
Q

How is phosphorus present in solution?

A

As free phosphate = inorganic phosphate (mix of HPO42- and H2PO4-)

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16
Q

What is the majority of body phosphate present as in bone/ teeth?

A

Hydroxyapatitie mineral (Ca10(PO4)6(OH)2)

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17
Q

What is phosphorus absorption in gut like?

A

Efficient (~80-90% of dietary phosphorus absorbed)

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18
Q

What is adult serum Pi concentration?

A

2.5 to 4.5 mg/dL

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19
Q

What is an important buffer to maintain physiological pH?

A

extracellular phosphate is free

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20
Q

What are the main organ systems involved in Calcium and phosphate homeostasis?

A

Gut
Parathyroids
Kidney
Skeleton

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21
Q

What are three process involved in calcium uptake?

A
  1. Uptake
  2. Transcellular transport of calcium
  3. Extrusion
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22
Q

How does calcium uptake occur? and where?

A

Apical side of cell - by ion channels belonging to TRP superfamily

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23
Q

How does transcellular transport of calcium occur?

A

By calcium binding proteins (calbindins)

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24
Q

How does extrusion of calcium uptake occur? and where?

A

Basal surface of cell – by membrane transport proteins

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25
Q

What isoforms are involved in calcium uptake in the gut?

A

Uptake: TRPV6
Transcellular transport: Calbindin D9K
Extrusion: Ca2+ATPase1b

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26
Q

What does TRPv6 do?

A

Ca 2+ uptake on apical
side of intestinal epithelial cell

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27
Q

What does calbindin D9K do?

A

transcellular transport of Ca 2+ to basal side
of cell

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28
Q

What does Ca2+ATPase1b do?

A

Pumps Ca2+ out of basal side (e.g., into capillary)

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29
Q

How is phosphate taken up into cell?

A

By phosphate transporter: NaPi-IIb

30
Q

What happens after intestinal absorption into blood?

A

Ca2+ and Pi is filtered in kidney glomerulus

31
Q

What happens to ~99% of Ca 2+ and ~85-95% of Pi filtered in the kidney?

A

Reabsorbed in kidney tubules (REABSORPTION = very important)

32
Q

What are the 3 steps of calcium uptake in renal reabsorption?

A
  1. Uptake
  2. transcellular transport
  3. extrusion
    **same as in the gut, but different isoforms of TRP and calbindin
33
Q

What isoforms are involved in calcium uptake in the renal?

A

Uptake: TRPV5
Transcellular transport: Calbindin D28k
Extrusion: Ca2+ATPase1b (PMCa1b), Na dependent Ca exchanger (NCX1)

34
Q

What main hormones are involved in calcium homeostasis?

A

Parathyroid Hormone (PTH)
1,25 dihydroxyvitamin D3 [1,25(OH)2D3] (calcitriol)
Calcitonin (may play a more minor role)

35
Q

What main hormones are involved in phosphate homeostasis?

A

Parathyroid Hormone (PTH)
1,25 dihydroxyvitamin D3 [1,25(OH)2D3] (calcitriol)
Fibroblast growth factor-23 (FGF23)

36
Q

How are Serum calcium concentrations detected?

A

Calcium sensing receptor (CaSR)

37
Q

What expresses CaSR levels?

A

Parathyroid gland

38
Q

What occurs in an increase of serum calcium levels?

A

↑Serum Ca2+ –> CasR signals via PLC/IP3 –> ↓PTH secretion

39
Q

What occurs in a decrease of serum calcium levels?

A

↓Serum Ca2+ –> CasR signals via adenylate cyclase/cAMP –> ↑PTH secretion

40
Q

What is the receptor for the PTH?

A

PTH1R

41
Q

What mediates the PTH actions?

A

via activation of adenylate cyclase/cAMP production

42
Q

What is the homeostatic response to low calcium?

A

Increases bone resorption
Increases calcium reabsorption in kidney
reduces Pi reabsorption

43
Q

What does the PTH stimulate in the kidney?

A

Conversion of 25-hydroxyvitamin D3[25(OH)D3] to active form 1,25-dihydroxyvitamin D3[1,25(OH)2D3]

44
Q

What does 1,25 dihydroxyvitamin D3 induce?

A

Expression of calbindins, phosphate transporters, and PTH production

45
Q

What does expression of calbindings result in increased?

A

Ca2+ uptake in the intestine
Ca2+ reabsorption in the kidney tubules
Ca2+ release into circulation from bone

46
Q

What does expression of phosphate transporters result in increased?

A

Pi uptake in the intestine
Pi reabsorption in the kidney tubules
Pi release into circulation from bone

47
Q

What does combined actions of PTH and 1,25(OH)2D3 do?

A

Increase serum calcium (and phosphate) back to normal range

48
Q

When is production of PTH inhibited?

A

when Ca2+ returns to normal and also because of inhibition by 1,25(OH)2D3 (NEGATIVE FEEDBACK LOOP)

49
Q

What is the homeostatic response to high serum calcium?

A

High serum calcium → CaSR signals via PLC/IP3 →
reduces PTH (1,25(OH)2D3) secretion

50
Q

What does a reduction in 1,25(OH)2D3 production in kidney lead to?

A

reduced release of calcium and phosphate from
skeleton
reduced intestinal calcium and phosphate
absorption/renal calcium reabsorption

51
Q

What is a hormone released by thyroid gland in
response to elevated serum calcium?

A

Calcitonin

52
Q

What is calcitonins major effect?

A

Inhibits osteoclast resorption in bone by
causing retraction of osteoclast ruffled border

53
Q

What is calcitonins minor effect?

A

Inhibits renal reabsorption of Ca 2+ and phosphate allowing them to be excreted in the urine

54
Q

What are the main regulators of phosphate homeostasis?

A

Parathyroid hormone (PTH)
1,25-dihydroxyvitamin-D3 [1,25(OH2)D3]
Fibroblast growth factor 23 (FGF23)

55
Q

What increases phosphate release from bone, decreases renal phosphate reabsorption, increases 1,25D3 production by kidney?

A

PTH

56
Q

What increases phosphate release from bone, increases renal phosphate reabsorption, increases phosphate uptake in gut?

A

1,25-dihydroxyvitamin-D3 [1,25(OH2)D3]

57
Q

What protein is important in phosphate regulation?

A

32kDa protein

58
Q

What expression induced in bone when serum phosphate too high?

A

Fibroblast growth factor 23 (FGF23)

59
Q

How can 32kDa protein be inactivate?

A

12 and 20kDa

60
Q

How is expression in osteocytes inhibited by?

A

2 proteins:
Dentin matrix protein-1 (DMP1)
Phosphate regulating endopeptidase homolog, X-linked (PHEX)

61
Q

What is the major source of endocrine FGF23 and now known to be major players in regulation of phosphate homeostasis?

A

Osteocytes

62
Q

What is FGF23 actions in the kidney?

A
  • Decreases reabsorption of phosphate (by downregulating expression of Na + dependent phosphate transporters) – means that more phosphate is excreted in urine.
  • Decreases production of 1,25(OH)2D3
63
Q

What is the overall effect of FGF23?

A

Lowers serum phosphate

64
Q

What is the main mechanism for (rapid) regulation of phosphate?

A

Kidney reabsorption

65
Q

What phosphate co-transporters expressed in proximal tubules?

A

NaPiIIa, NaPiIIc

66
Q

What inhibits phosphate reabsorption? and how?

A

PTH via inhibition of NaPiIIa and NaPiIIc

67
Q

What does the absence of PTH do?

A

Increase phosphate reabsorption

68
Q

What is produced by osteocytes when serum phosphate is high?

A

FGF23

69
Q

What downregulates NaPiIIa and NaPiIIc (reduces Pi
reabsorption in kidney)?

A

FGF23

70
Q

What are factors Regulating Calcium and Phosphate Homeostasis?

A

PTH
1,25(OH)2D3 (calcitriol)
Calcitonin
FGF23

Biochem Exam 5 (11 decks)

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