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
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
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
4
Q
How much calcium does the adult body contain?
A
- 1Kg of calicum
99% in mineral phase of bone/teeth as hydroxyapatite crystals
5
Q
What is the normal range for total serum calcium?
A
- 8.5-10.5 mg/dL (2.1-2.6mM)
6
Q
How much of the calcium is ionized or biologically active?
A
- 45%
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
8
Q
What is the range of ionized calcium?
A
- 4.4-5.4 mg/dL (1.1-1.35 mM)
9
Q
Are ionized calcium levels stable?
A
- yes relatively stable but total calcium can vary with changes in amounts of albumin or pH
10
Q
Why do you need more calcium when youre older?
A
- your gut cant resorb it as well
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
12
Q
What is the major calcium store reservoir in the body?
A
- skeleton (stores about 1Kg calcium)
13
Q
How much calcium is released form bone per day due to normal bone turnover?
A
- 500 mg/day
14
Q
How much calcium is deposited in bone due to bone formation daily?
A
- 500 mg/day
15
Q
Why is important that calcium has a low intracellular concentration?
A
- intracellular calcium fluxes regulate cell function
16
Q
What is the intracellular calcium concentration?
A
- .0001 mM = 10^-7 M
can increase 10-100 fold during calcium signaling
17
Q
What is the extracellular calcium concentration?
A
- 1-2 mM
- 10^-3M
(10,000 x higher than inside the cell)
18
Q
How is the calcium gradient achieved?
A
- Ca2+ pumps in plasma membrane
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
20
Q
How is phosphorus present in solution?
A
- as free phosphate ions (inorganic phosphate Pi)
21
Q
where is majority of body phosphate?
A
- 85% in hydroxyapatite mineral of bone/teeth
22
Q
Is phosphorus absorption in gut efficient?
A
- Yes unlike calcium
80-90 % of dietary phosphorus absorbed
23
Q
Is dietary deficiency in phosphorus common?
A
- no its uncommon
24
Q
What is the adult serum Pi concentration?
A
- 2.5 to 4.5 mg/dL (.8 - 1.5 mM)
25
Serum phosphate levels vary _____ than calcium as it is not as tightly regulated
- more
26
Most ______ phosphate is free in solution - important buffer to maintain physiological PH
- extracellular
27
What does a net zero calcium/phosphate balance mean?
- amount ingested in food is = to sum of amount lost in feces and excreted in urine
28
what are the 3 steps of calicum uptake?
- 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)
29
What type of up take happens during high dietary calcium intake?
- passive calcium uptake by a diffusional paracellular (between epithelial cells) path of absorption
30
What takes up Phosphate?
- Pi taken up into cell by phosphate transporter (Na dependent Pi co transporter type IIb) NaPi-IIb
- on brush border of ileum
31
99% of Ca2+ and 85-95% of Pi filtered in the kidney is reabsorbed in kidney tubultes T/F
- T
| - reabsorption is very important
32
What does the uptake of calcium in kidney?
- TRPV5
33
What does the transcellular transport in kidney?
- calbindin D28K
34
What does extrustion of calcium in kidney?
- Ca2+ ATPase 1b, Na Dependent Ca2+ exchanger NCX1
35
In osteoclasts most of calcium is transported through cell by ________ into acidic vesicles followed by ______ at cell surface
- endocytosis
| - exocytosis
36
How do many of the hormones involved in regulation of calcium and phosphate homeostasis work?
- by altering expression of these key transporter molecules
37
What are the main hormones involved in calcium homestasis?
- PTH
- 1,25 Dihydroxyvitamin D3
- Calcitonin
38
What produced calcitonin?
- thyroid glands
39
What are the main hormones involved in phosphate homeostasis?
- PTH
- 1.25 Dihydroxyvitamin D3
- FGF23 (expressed by osteocytes)
40
When is FGF23 released?
- when serum phosphate is too high
41
What effect does PTH have on calcium levels
- increases Ca2+ release from bone
- increases uptake in gut
- increases absorption
- overall this will increase blood calcium levels
42
When is PTH released?
- when Ca blood levels are too low
43
How does the parathyroid gland know when to release PTH?
- it has calcium sensing receptor (CaSR) that senses serum calcium concentrations
44
When serum calcium levels are high this increaes CaSR signaling which does what?
- decreases PTH secretion (secretes calcitonin instead)
45
When serum Ca levels are low this decreaes CasR signaling which in turn?
- increases PTH secretion
46
What is PTH?
- 84 a.a peptide hormone produced by parathyroid glands
- calcium regulatory activity confined to first 34 a.a
- short half-life = ~ 5 minutes
47
PTH1R (receptor for PTH)
- class B G-protein coupled receptor
| - PTH actions mediated via activation of adenylate cyclase/cAMP production
48
Homeostatic response to Low Calcium?
- Low serum Ca2+ levels --> CaSR signaling shut off --> leads to increase PTH secretion
49
PTH actions
- increases bone resorption i.e releases calcium and phosphate
- increases calcium resorption in kidney
- has opposite effect on phosphate reabsorption
50
What action does PTH have on phosphate reabsorption in kidney?
- it decreases it which can lead tp phosphaturia (excess phosphate in urine)
51
What does PTH do in the kidney?
- it stimulates conversion of 25-hydroxyvitamin D3 to active form 1,25 dihydroxyvitamin D3
52
What are the actions of 1,25 dihydroxyvitamin D3 for calcium?
- Ca2+ uptake in intestine
- ca 2+ resorption in the kidney tubules
- Ca2+ release into circulation from bone
53
How does 1,25 increase calcium blood serum levels?
- induces expression of calbindins and other components of calcium transport system
54
what does 1,25 do to phosphate levels?
- 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
What happens when serum calcium levels are high?
- 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
what hormone is released by thyroid gland in response to elevated serum calcium?
- calcitonin
57
What does calcitonin do?
- 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
Why is calcitonin role now thought to be minor?
- because thyroid tumors or removal of thyroid have a small effect on calcium homeostasis
59
What are the main regulators of phosphate homeostasis?
- parathyroid hormone (PTH)
- 1,25 dihydroxy vitamin D3
- FGF23
- regulation overlaps with regulation of Ca2+ but also independent
60
Is phosphate regulation as well understood as calcium?
- no
61
When is FGF23 expressed?
- when serum phosphate too high
62
What expresses FGF23?
- osteocytes primarily
| - osteoblasts, lining cells/osteoprogenitors
63
What inhibits expression of FGF23 in osteocytes?
- DMP1
| - PHEX
64
_______ are major source of endocrine FGF23 and now know to be major players in regulation of phosphate homeostasis
- Osteocytes
65
What is the action of FGF23 in the kidney?
- 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
What is the main mechanism for regualtion of phosphate?
- kidney reabsorption
67
How does PTH inhibit phosphate reabsorption?
- inhibition of NaPiIIa and NaPiIIc expression
68
What type II Na2+ dependent phosphate co transporters are expressed in the proximal tubules of kidney?
- NaPiIIa and NaPiIIc
69
Absence of PTH does what to phosphate reabsorption?
- increases phosphate reabsorption
70
Why is FGF23 produced by osteocytes when serum phosphate is high?
- because it downregulates NaPiIIa and NaPiIIc which reduces Pi reabsorption in kidney
