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Biochemistry (Cole) > Lecture 45 Hormonal Control of Calcium and Phosphorus > Flashcards

Lecture 45 Hormonal Control of Calcium and Phosphorus Flashcards

1
Q

Why are we interested in calcium and phosphorus?

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

What cellular functions is Calcium critical in?

A
  • cell division
  • plasma membrane integrity
  • 2nd messenger in signal transduction
  • muscle contractility
  • neuronal excitability
  • blood clotting
  • skeletal development
  • bone, dentin, enamel mineralization
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3
Q

What are the 3 major calcium stores in the body?

A
  • bone (99% of calcium)
  • calcium in blood and extracellular fluid
  • intracellular calcium
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4
Q

How much calcium does the adult body contain?

A
  • 1Kg of calicum

99% in mineral phase of bone/teeth as hydroxyapatite crystals

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5
Q

What is the normal range for total serum calcium?

A
  • 8.5-10.5 mg/dL (2.1-2.6mM)
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6
Q

How much of the calcium is ionized or biologically active?

A
  • 45%
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7
Q

What % of calcium is bound to albumin and what % is complexed with cirtrate or phosphate ions?

A
  • 45% bound to albumin (pH dependent)

- 10% complexed with citrate or phosphate ions

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8
Q

What is the range of ionized calcium?

A
  • 4.4-5.4 mg/dL (1.1-1.35 mM)
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9
Q

Are ionized calcium levels stable?

A
  • yes relatively stable but total calcium can vary with changes in amounts of albumin or pH
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10
Q

Why do you need more calcium when youre older?

A
  • your gut cant resorb it as well
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11
Q

What are the daily calcium numbers in a typical individual?

A
  • 1000mg calcium ingested per day
  • 200 mg absorbed by guy
  • 10 g filtered daily through kidney (most is 99% reabsorbed so we dont lose CA)
  • 200 mg excreted in urine
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12
Q

What is the major calcium store reservoir in the body?

A
  • skeleton (stores about 1Kg calcium)
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13
Q

How much calcium is released form bone per day due to normal bone turnover?

A
  • 500 mg/day
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14
Q

How much calcium is deposited in bone due to bone formation daily?

A
  • 500 mg/day
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15
Q

Why is important that calcium has a low intracellular concentration?

A
  • intracellular calcium fluxes regulate cell function
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16
Q

What is the intracellular calcium concentration?

A
  • .0001 mM = 10^-7 M

can increase 10-100 fold during calcium signaling

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17
Q

What is the extracellular calcium concentration?

A
  • 1-2 mM
  • 10^-3M
    (10,000 x higher than inside the cell)
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18
Q

How is the calcium gradient achieved?

A
  • Ca2+ pumps in plasma membrane
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19
Q

What are the cellular functions phosphate has a role in?

A
  • membrane composition (phospholipids)
  • intracellular signaling
  • nucleotide structure
  • skeletal development
  • bone, dentin, enamel mineralization
  • chondrocyte differentiation
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20
Q

How is phosphorus present in solution?

A
  • as free phosphate ions (inorganic phosphate Pi)
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21
Q

where is majority of body phosphate?

A
  • 85% in hydroxyapatite mineral of bone/teeth
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22
Q

Is phosphorus absorption in gut efficient?

A
  • Yes unlike calcium

80-90 % of dietary phosphorus absorbed

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23
Q

Is dietary deficiency in phosphorus common?

A
  • no its uncommon
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24
Q

What is the adult serum Pi concentration?

A
  • 2.5 to 4.5 mg/dL (.8 - 1.5 mM)
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25
Q

Serum phosphate levels vary _____ than calcium as it is not as tightly regulated

A
  • more
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26
Q

Most ______ phosphate is free in solution - important buffer to maintain physiological PH

A
  • extracellular
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27
Q

What does a net zero calcium/phosphate balance mean?

A
  • amount ingested in food is = to sum of amount lost in feces and excreted in urine
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28
Q

what are the 3 steps of calicum uptake?

A
  • uptake of calcium from apical side of cell by ion channels belonging to TRP supefamily
  • transcellular transport of calcium by calbindins
  • extrusion of calcium on basal surface of cell by membrane transport proteins (Ca2+ ATPases or Na+/ dependent Ca2+ exchangers)
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29
Q

What type of up take happens during high dietary calcium intake?

A
  • passive calcium uptake by a diffusional paracellular (between epithelial cells) path of absorption
30
Q

What takes up Phosphate?

A
  • Pi taken up into cell by phosphate transporter (Na dependent Pi co transporter type IIb) NaPi-IIb
  • on brush border of ileum
31
Q

99% of Ca2+ and 85-95% of Pi filtered in the kidney is reabsorbed in kidney tubultes T/F

A
  • T

- reabsorption is very important

32
Q

What does the uptake of calcium in kidney?

A
  • TRPV5
33
Q

What does the transcellular transport in kidney?

A
  • calbindin D28K
34
Q

What does extrustion of calcium in kidney?

A
  • Ca2+ ATPase 1b, Na Dependent Ca2+ exchanger NCX1
35
Q

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

A
  • endocytosis

- exocytosis

36
Q

How do many of the hormones involved in regulation of calcium and phosphate homeostasis work?

A
  • by altering expression of these key transporter molecules
37
Q

What are the main hormones involved in calcium homestasis?

A
  • PTH
  • 1,25 Dihydroxyvitamin D3
  • Calcitonin
38
Q

What produced calcitonin?

A
  • thyroid glands
39
Q

What are the main hormones involved in phosphate homeostasis?

A
  • PTH
  • 1.25 Dihydroxyvitamin D3
  • FGF23 (expressed by osteocytes)
40
Q

When is FGF23 released?

A
  • when serum phosphate is too high
41
Q

What effect does PTH have on calcium levels

A
  • increases Ca2+ release from bone
  • increases uptake in gut
  • increases absorption
  • overall this will increase blood calcium levels
42
Q

When is PTH released?

A
  • when Ca blood levels are too low
43
Q

How does the parathyroid gland know when to release PTH?

A
  • it has calcium sensing receptor (CaSR) that senses serum calcium concentrations
44
Q

When serum calcium levels are high this increaes CaSR signaling which does what?

A
  • decreases PTH secretion (secretes calcitonin instead)
45
Q

When serum Ca levels are low this decreaes CasR signaling which in turn?

A
  • increases PTH secretion
46
Q

What is PTH?

A
  • 84 a.a peptide hormone produced by parathyroid glands
  • calcium regulatory activity confined to first 34 a.a
  • short half-life = ~ 5 minutes
47
Q

PTH1R (receptor for PTH)

A
  • class B G-protein coupled receptor

- PTH actions mediated via activation of adenylate cyclase/cAMP production

48
Q

Homeostatic response to Low Calcium?

A
  • Low serum Ca2+ levels –> CaSR signaling shut off –> leads to increase PTH secretion
49
Q

PTH actions

A
  • increases bone resorption i.e releases calcium and phosphate
  • increases calcium resorption in kidney
  • has opposite effect on phosphate reabsorption
50
Q

What action does PTH have on phosphate reabsorption in kidney?

A
  • it decreases it which can lead tp phosphaturia (excess phosphate in urine)
51
Q

What does PTH do in the kidney?

A
  • it stimulates conversion of 25-hydroxyvitamin D3 to active form 1,25 dihydroxyvitamin D3
52
Q

What are the actions of 1,25 dihydroxyvitamin D3 for calcium?

A
  • Ca2+ uptake in intestine
  • ca 2+ resorption in the kidney tubules
  • Ca2+ release into circulation from bone
53
Q

How does 1,25 increase calcium blood serum levels?

A
  • induces expression of calbindins and other components of calcium transport system
54
Q

what does 1,25 do to phosphate levels?

A
  • induces expression of phosphate transporters which results in increased:
    • Pi uptake in the intestine
    • Pi reabsorption in the kidney tubules
    • Pi release into circulation from bone
55
Q

What happens when serum calcium levels are high?

A
  • CaSR signaling acrivated- reduces PTH secretion
  • reduction of 1,25(OH)2D3 production in kidney
  • leads to REDUCED release of calcium from skeleton REDUCED intestinal calcium absorption/renal calcium absorption
  • many of effects mediated through modulation of expression of calcium transporter proteins
56
Q

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

A
  • calcitonin
57
Q

What does calcitonin do?

A
  • opposes PTH actions
  • effects mediated by calcitonin receptor in osteoclasts- activation causes retraction of osteoclast ruffled border
  • in kidney, gut- calcitonin opposes effects of PTH
58
Q

Why is calcitonin role now thought to be minor?

A
  • because thyroid tumors or removal of thyroid have a small effect on calcium homeostasis
59
Q

What are the main regulators of phosphate homeostasis?

A
  • parathyroid hormone (PTH)
  • 1,25 dihydroxy vitamin D3
  • FGF23
  • regulation overlaps with regulation of Ca2+ but also independent
60
Q

Is phosphate regulation as well understood as calcium?

A
  • no
61
Q

When is FGF23 expressed?

A
  • when serum phosphate too high
62
Q

What expresses FGF23?

A
  • osteocytes primarily

- osteoblasts, lining cells/osteoprogenitors

63
Q

What inhibits expression of FGF23 in osteocytes?

A
  • DMP1

- PHEX

64
Q

_______ are major source of endocrine FGF23 and now know to be major players in regulation of phosphate homeostasis

A
  • Osteocytes
65
Q

What is the action of FGF23 in the kidney?

A
  • decreases reabsorption of phosphate ( by down regulating expression of Na+ dependent phosphate transporters) means that more phosphate is excreted in urine
  • decreases production of 1,25 OH2D3
  • overall lowers serum phosphate
66
Q

What is the main mechanism for regualtion of phosphate?

A
  • kidney reabsorption
67
Q

How does PTH inhibit phosphate reabsorption?

A
  • inhibition of NaPiIIa and NaPiIIc expression
68
Q

What type II Na2+ dependent phosphate co transporters are expressed in the proximal tubules of kidney?

A
  • NaPiIIa and NaPiIIc
69
Q

Absence of PTH does what to phosphate reabsorption?

A
  • increases phosphate reabsorption
70
Q

Why is FGF23 produced by osteocytes when serum phosphate is high?

A
  • because it downregulates NaPiIIa and NaPiIIc which reduces Pi reabsorption in kidney

Biochemistry (Cole) (25 decks)

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