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Applied Biochemistry > Hormonal Control of Calcium and Phosphorus: Part 1 > Flashcards

Hormonal Control of Calcium and Phosphorus: Part 1 Flashcards

1
Q

Why are we Interested in

Calcium and Phosphorus? (3)

A

• Essential to many vital physiological processes
• Essential for proper mineralization of skeleton / dentition
• Disturbances in calcium
and phosphorus homeostasis linked to several
pathological disorders

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2
Q

Why is it Important to Maintain Extracellular Calcium (Ca2+) within a narrow range?

A 
Ca2+ ions critical to many cellular functions:
- Cell division / Cell adhesion
- Plasma membrane integrity
- 2nd messenger in signal transduction
- Muscle contractility
- Neuronal excitability
- Blood clotting
- Skeletal development
- Bone, dentin, enamel mineralization
Difficult to name a physiologic process not dependent on calcium
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3
Q

Why is it Important to Maintain Phosphorus Homeostasis?

A

Phosphorus critical to many cellular functions:

  • Membrane composition (phospholipids)
  • Intracellular signaling
  • Nucleotide structure
  • Skeletal development
  • Bone, dentin, enamel mineralization
  • Chondrocyte differentiation
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4
Q

3 major pools of calcium in body:

A

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

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5
Q

Calcium in blood & extracellular fluid and intracellular calcium accounts for –% of calcium

A

1%

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6
Q

Adult body contains ~

A

1Kg calcium – 99% in
mineral phase of bone/teeth as hydroxyapatite
(HA) crystals

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7
Q

HA mineralization of bone is important for

2

A

mechanical and weight bearing properties of bone

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8
Q

Bone HA serves as reservoir of calcium to

maintain

A

blood ionized calcium within normal

range

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9
Q

Normal range for total serum calcium =

A

8.5 – 10.5mg/dL (2.1-2.6mM)

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10
Q

ionized (biologically active fraction)=

A

45%

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11
Q

bound to albumin (pH dependent)=

A

45%

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12
Q

complexed with citrate or phosphate ions=

A

10%

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13
Q

Normal range of ionized calcium =

A

4.4-5.4mg/dL (1.1-1.35mM)

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14
Q

Ionized calcium levels relatively stable but total

calcium can vary with changes in (2)

A

amounts of albumin

or pH, etc.

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15
Q 
In a typical individual:
~---mg calcium ingested per day
~---mg absorbed by gut
~---g filtered daily through kidney - most (~99%) is
reabsorbed
~---mg excreted in urine
A

1000
200
10
200

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16
Q

—- stores about 1Kg calcium = major calcium

reservoir in the body

A

Skeleton

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17
Q

~—mg/day calcium released from bone per day due
to normal bone turnover
~—mg/day deposited in bone due to bone formation

A

500

500

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18
Q

Cells maintain — intracellular calcium concentrations in cytosol
what concentration?

A

low

~0.0001mM = 10-7M) (can increase 10-100 fold during calcium signaling, etc.

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19
Q

Extracellular concentration much —

A

higher (~ 1mM = 10-3M)

~10,000x higher

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20
Q

Maintenance of — gradient is important - intracellular calcium — regulate cell function

A

steep

fluxes

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21
Q

Gradient achieved by — — in plasma membrane

A

Ca2+ pumps

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22
Q

phosphorus is present as — — —- in solution

A

free phosphate ions

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23
Q

Present as free phosphate ions in solution =

A

inorganic

phosphate (Pi) (mixture of HPO42- and H2PO4)

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24
Q

Majority of body phosphate (~85%) in

A

hydroxyapatite

mineral phase of bone/teeth [Ca10(PO4)6(OH)2]

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25
Q

Remainder of phosphate is distributed between

A

other tissues (14%) and extracellular fluid (1%)

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26
Q

Unlike calcium, phosphorus absorption in gut =

A

quite

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

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27
Q

Dietary deficiency in phosphorus is —

A

uncommon

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28
Q

Adult serum Pi concentration ~

A
  1. 5 to 4.5 mg/dL

0. 8-1.5mM

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29
Q

Most extracellular phosphate is free in solution -

important buffer to maintain

A

physiological pH

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30
Q

Serum — levels vary more than —

as it is not as tightly regulated

A

phosphate

calcium

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31
Q

Amount of Ca2+/Pi ingested in food

= sum of amount lost in (2)

A

feces and

secrete hormones to excreted in urine

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32
Q

3 steps involved in calcium uptake

A
  1. Uptake of calcium from apical side of cell - by ion
    channels belonging to TRP superfamily (Transient
    Receptor Potential ion channels)
  2. Transcellular transport of calcium - by calcium
    binding proteins (calbindins)
  3. Extrusion of calcium on basal surface of cell – by
    membrane transport proteins (Ca2+ ATPases or Na+
    dependent Ca2+ exchangers)
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33
Q

Similar 3-step process occurs in gut, kidney,

osteoclasts, with

A

same groups of proteins but

specific isoforms are different

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34
Q

TRPV6 –

A

Ca2+ uptake on apical

side of intestinal epithelial cell

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35
Q

Calbindin D9K –

A

transcellular
transport of Ca2+ to basal side
of cell

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36
Q

Ca2+ATPase1b –

A

pumps Ca2+ out
of basal side of cell (e.g. into
capillary)

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37
Q

During high dietary calcium intake, — also occurs

A

passive calcium uptake by a diffusional paracellular (between epithelial cells) path of absorption

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38
Q

Pi taken up into cell by

A

phosphate transporter - Na+
dependent Pi co-transporter type IIb (NaPi-IIb)–
on brush border of ileum

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39
Q

Mechanism(s) for Pi — transport/extrusion into circulation not yet known

A

transcellular

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40
Q

Also some Pi uptake by — — process

A

passive diffusion

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41
Q

After intestinal absorption into blood, Ca2+ and Pi is

A

filtered

in kidney glomerulus

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42
Q

~99% of Ca2+ and ~85-95% of Pi filtered in the kidney is

A

reabsorbed in kidney tubules (REABSORPTION = very

important)

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43
Q

Ca2+ uptake in renal reabsorption = same 3 step mechanism as in gut, but different

A

isoforms of TRP and calbindin

44
Q

Ca2+ uptake in renal reabsorption 3 steps

A
  1. Uptake - TRPV5
  2. Transcellular transport – Calbindin D28K
  3. Extrusion – Ca2+ ATPase 1b (PMCa1b), Na+ dependent Ca2+exchanger (NCX1)
45
Q

Pi uptake in renal reabsorption – same mechanism as in gut

but different

A

isoforms of Na+ dependent Pi co-transporter

NaPi-IIa, NaPi-IIc

46
Q

In osteoclasts most of calcium is transported through cell by — into acidic vesicles followed by — at cell surface

A

endocytosis

exocytosis

47
Q

Many of the hormones involved in regulation of

calcium and phosphate homeostasis work by

A

altering expression of these key transporter molecules

48
Q

Main Hormones/Regulatory Factors

Involved in Ca2+I Homeostasis (3)

A

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

49
Q

Main Hormones/Regulatory Factors

Involved in Pi Homeostasis (3)

A

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

50
Q

calcium and phosphate regulation is co-ordinated to some extent because

A

some of the regulatory molecules are the same (i.e. PTH and 1,25 (OH)2 D3)
• E.g – calcium and phosphate are always released together during bone resorption

51
Q

PTH has opposite effects on Ca2+ and Pi resorption in the

A

kidney

52
Q

A couple of the hormones regulating Ca2+ and Pi homeostasis are different – for example (2)

A

calcitonin is released in response to high serum calcium and FGF23 is released in response to high serum phosphate

53
Q

— molecules responsible for Ca2+ and Pi uptake are different

A

Transport

54
Q

while the system allows for some coordination it also

allows for Ca 2+ and Pi to be regulated — if needed

A

independently

55
Q

— homeostasis more fully understood than —

homeostasis

A

Calcium

phosphate

56
Q

Serum calcium concentrations detected by

— expressed in parathyroid gland

A

Calcium Sensing Receptor (CaSR)

57
Q

increase Serum Ca2+
= — CasR signaling
= — PTH secretion

A

increase

decrease

58
Q

decrease Serum Ca2+
= — CasR signaling
= — PTH secretion

A

decrease

increase

59
Q

PTH is an 84 a.a. peptide hormone produce by

A

parathyroid glands

60
Q

Calcium regulatory activity of PTH confined to first — a.a.

A

34

61
Q

half life of PTH

A

~5 min

short half life

62
Q

PTH receptor

A

PTH1R (also binds PTHrP [parathyroid hormone related

peptide])

63
Q

Class of PTH receptor

A

B G-protein coupled receptor

64
Q

PTH actions mediated via activation of

A

adenylate

cyclase/cAMP production

65
Q

Low serum Ca2+ levels results in

A

CaSR signaling shut off which leads to

release of PTH

66
Q

PTH Actions: (3)

A

• Increases bone resorption - i.e. releases calcium and phosphate
• Increases calcium reabsorption in kidney
• Opposite effect on phosphate reabsorption in kidney (reduces Pi
reabsorption -can lead to phosphaturia)

67
Q

In kidney - PTH stimulates conversion of 25-hydroxyvitamin D3 [25(OH)D3] to

A

active form 1,25-dihydroxyvitamin D3

[1,25(OH)2D3]

68
Q

1,25 dihydroxyvitamin D3 induces expression of

A

Calbindins and other components of calcium transport system (TRPV5, TRPV6, Ca2+ ATPases,
Na+/Ca2+ exchangers) –

69
Q

1,25 dihydroxyvitamin D3 Induces expression of Calbindins and other components of calcium transport system (TRPV5, TRPV6, Ca2+ ATPases, Na+/Ca2+ exchangers) – resulting in increased: (3)

A

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

70
Q

1,25 dihydroxyvitamin D3 induces expression of phosphate transporters (NaPi-IIa,NaPi-IIb,NaPi-IIc) – resulting in increased: (3)

A

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

71
Q

1,25 dihydroxyvitamin D3 feeds back to inhibit

A

further production of PTH (negative feedback)

72
Q

Combined actions of PTH and 1,25(OH)2D3 → =

A

increase serum calcium (and phosphate) back to

normal range

73
Q

Further production of PTH inhibited when Ca2+

returns to normal and also because of inhibition by

A

1,25(OH)2D3 (NEGATIVE FEEDBACK LOOP)

74
Q

Opposite sequence of events happens when serum

calcium is —

A

HIGH

75
Q

CaSR signaling activated which reduces

A

PTH secretion

76
Q

Resultant reduction in — production in kidney

A

1,25(OH)2D3

77
Q

Leads to — release of calcium and phosphate from
skeleton, — intestinal calcium and phosphate
absorption/renal calcium reabsorption

A

reduced

reduced

78
Q

Many of effects mediated through modulation of

expression of

A

calcium transporter proteins

79
Q

Calcitonin = hormone released by — gland in

response to — serum calcium

A

thyroid

elevated

80
Q

Calcitonin generally opposed — actions

A

PTH

81
Q

Major effect of calcitonin-

A

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

82
Q

Minor effect of calcitonin

A

inhibits renal reabsorption of Ca2+ and phosphate allowing them to be excreted in the urine

83
Q

Calcitonin role now thought to play a more minor role because

A

thyroid tumors that secrete excessive amounts of calcitonin have normal serum calcium (probably kidneys become resistant)

84
Q

Removal of thyroid has only a small effect on

A

calcium homeostasis

85
Q

Main regulators of phosphate homeostasis: (4)

A

Parathyroid hormone (PTH)
1,25-dihydroxyvitamin-D3 [1,25(OH2)D3]
Fibroblast growth factor 23 (FGF23)
(Dentin matrix protein-1/PHEX)

86
Q

Parathyroid hormone (PTH)

  • – phosphate release from bone
  • – renal phosphate reabsorbtion
  • – 1,25 D3 production by kidney
A

increases
decreases
increases

87
Q

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

increases (3)

A

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

88
Q

Regulation overlaps with regulation of Ca2+ but also

—

A

independent

89
Q

Phosphate regulation not as well understood as calcium –

— evolving field

A

rapidly

90
Q

— sensing mechanism not yet determined

A

Phosphate

91
Q

FGF23 – kDa protein – important in — regulation

A

32

phosphate

92
Q

Expression induced in bone when — — too
high (esp. osteoblasts, osteocytes, lining cells/
osteoprogenitors)

A

serum phosphate

93
Q

FGF23 can be cleaved into smaller fragments of 12 and 20kDa to

A

inactivate the protein

94
Q

Expression of FGF23 in osteocytes inhibited by two key proteins:

A

Dentin matrix protein-1 (DMP1)

Phosphate regulating endopeptidase homolog, X-linked (PHEX)

95
Q

major source of endocrine FGF23 and now known to

be major players in regulation of phosphate homeostasis

A

osteocytes

96
Q

FGF23 Actions in the Kidney: (2)

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

97
Q

Overall effect of FGF23 –

A

lowers serum phosphate

98
Q

Although gut and skeleton contribute to phosphate
regulation, main mechanism for (rapid) regulation of
phosphate –

A

KIDNEY reabsorption

99
Q

Type II Na2+-dependent phosphate co-transporters

expressed in proximal tubules = (2)

A

NaPiIIa, NaPiIIc

100
Q

PTH inhibits

A 
phosphate reabsorption (via inhibition of
NaPiIIa and NaPiIIc expression)
101
Q

Absence of PTH increases

A

phosphate reabsorption

102
Q

FGF23 produced by osteocytes when serum phosphate is

high -

A

downregulates NaPiIIa and NaPiIIc (reduces Pi

reabsorption in kidney)

103
Q

Factors Regulating Calcium and Phosphate Homeostasis (4)

A

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

104
Q

System has some overlap - especially bone resorptive component, because

A

Ca and Pi are simultaneously released during resorption

105
Q

Because the renal reabsorption of Ca and Pi are regulated

differently by PTH, and because FGF23 regulates phosphate separately, this allows some degree of

A

independent regulation

Applied Biochemistry (52 decks)

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