Lecture 46- Calcium and Phosphate Homeostasis Flashcards
what cellular functions are calcium ions critical in
-cell division/ cell adhesion
-plasma membrane integrity
- 2nd messenger in signal transduction
- muscle contractility
- neuronal excitability
- blood clotting
-skeletal development
- bone, dentin, enamel mineralization
what cellular functions is phosphorus critical in
-membrane composition
- intracellular signaling
- nucleotide structure
- skeletal development
- bone, dentin, enamel mineralization
- chondrocyte differentiation
what are the 3 major pools of calcium in the body
-bone calcium
-calcium in blood and extracellular fluid
- intracellular calcium
what is the hydroxyapatite mineralization of bone important for
mechanical and weight bearing properties of bone
what does bone hydroxyapatite serve as a reservoir for
calcium to maintain blood ionized calcium within normal range
what is the normal range for total serum calcium in the blood
8.5-10.5 mg/dL
what is the biologically active fraction of calcium
the ionized form
what are the forms of calcium in the blood
-ionized
- bound to albumin
- complexed with citrate or phosphate ions
what is the normal range of ionized calcium
4.4-5.4 mg/dL
describe the concentration of ionized calcium and total calcium
ionized calcium levels are relatively stable but total calcium can vary with changes in amounts of albumin or pH
how much calcium is ingested per day
1000mg
how much calcium is absorbed by the gut per day
200mg
how much calcium is filtered through the kidney daily
10g
how much calcium is excreted in urine daily
200 mg
how much calcium does the skeleton store
1Kg
how much calcium is released from bone per day due to normal bone turnover
500mg/day
how much calcium is deposited in bone due to bone formation
500mg/day
what is the concentration of extracellular calcium
1-2 mM
what is the concentration of intracellular calcium
0.0001 mM
what is phosphorus present as
free phosphate ions in solution - inorganic phosphate
where is the majority of body phosphate
in hydrozyapatite mineral phase of bone/teeth
where is the remainder of body phosphate
distributed between other tissues and extracellular fluid
where is phsophorus absorbed
in the gut
what is the adult serum phosphorus concentration
2.5-4.5 mg/dL
what is the function of the extracellular phosphate free in solution
buffer to maintain physiological pH
which serum level varies more: phosphate or calcium?
phosphate as it is not as tightly regulated
what organs are involved in calcium and phosphate homeostasis
gut, skeleton, kidney, and parathyroids
how are calcium and phosphate concentrations regulated in the gut
through absorption
how are calcium and phosphate concentrations regulated in the skeleton
bone turnover
how are calcium and phosphate concentrations regulated in the kidney
filtration and reabsorption
what are calcium and phosphate concentrations regulated in parathyroids
hormone secretion
what are the 3 steps in calcium uptake
-uptake of calcium from apical side of cell by ion channels belonging to TRP superfamily (transient receptor potential ion channels)
- transcellular transport of calcium - by calcium binding proteins (calbindins)
- extrustion of calcium on basal surface of cell by membrane transport proteins (Ca2_ ATPases or Na+ dependent Ca2+ exchangers)
what does the TRPV6 channel do
Ca2+ uptake on apical side of intestinal epithelial cell
what does calbindin D9K do
transcellular transport of Ca2+ to basal side of cell
what does Ca2+ ATPase1b do
pumps Ca2+ out of basal side of cell
what happens during high dietary calcium intake
passive calcium uptake by a diffusional paracellular path of absorption occurs
how is phosphate taken up into the cell
by phosphate transporter Na+ dependent Pi co-transporter type 2b on brush border of ileum
what happens after intestinal absorption of calcium and phospate into blood
filtered in kidney glomerulus
how much calcium and phosphate are reabsorbed in kidney tubules
99% of Ca2+ and 85-95% of Pi
what are the 3 steps in Ca2+ uptake in renal reabsorption
-uptake
- transcellular transport
- extrusion
what does Pi uptake look like in renal absorption
same mechanism as in gut but different isoforms of Na+ depended Pi co-transporter
what hormones are involved in calcium homeostasis
-PTH
-calcitriol
- calcitonin
what hormones are involved in phosphate homeostasis
PTH, calcitriol, FGF23, and DMP1/PHEX
when is PTH released
when serum calcium is low
how does the body increase calcium in the blood
increase calcium release from bone, increase calcium uptake in gut, increase calcium reabsorption in kidney
what are serum calcium concentrations detected by
calcium sensing receptor expressed in the parathyroid gland
what does high serum calcium do to CasR signaling
increases it
describe PTH
84 amino acid peptide hormone produced by parathyroid glands
what is the PTH receptor called
PTH1R
what type of receptor is PTH1R
GPCR
what are PTH actions mediated via
activation of adenylate cyclase/cAMP production
what does CaSR signaling shut off do to PTH
leads to release of PTH
what does PTH do
-increases bone resorption (releases Ca and Pi)
- increases calcium reabsorption in kidney
- opposite effect on phosphate reabsorption in kidney
what does PTH stimulate in kidney
conversion of 25(OH)D3 to active form 1,25(OH)2D3
what are the actions of 1,25(OH)2D3
-induces expression of calbindins and other components of calcium transport system
-induces expression of phosphate transporters
what does the expression of calbindins and other components of calcium transport system result in
INCREASED:
-Ca2+ uptake in intestine
-Ca2+ reabsorption in the kidney tubules
- Ca2+ release into circulation from bone
what does the expression of phsophate transporters result in
INCREASED:
- Pi uptake in the intestine
- Pi reabsorption in they kidney tubules
- Pi release into circulation from bone
what do the combined actions of PTH and 1,25(OH)2D3 result in
increase serum calcium and phosphate back to normal range
what happens when Ca2+ returns to normal
further production of PTH inhibited and inhibition by active Vit D3
what is the homeostatic response to high serum calcium mediated through
modulation of expression of calcium transporter proteins
when is calcitonin released and by what
released by thyroid gland in response to elevated serum calcium
what does calcitonin oppose
PTH actions
what is the major effect of calcitonin
inhibits osteoclast resorption in bone by causing retraction of osteoclast ruffled border
what is the minor effect of calcitonin
inhibits renal reabsorption of Ca2+ and phosphate allowing them to be excreted in the urin
why calcitonin NOW though to play a more minor role
thyroid tumors that secrete excessive amounts of calcitonin have normal serum calcium
does the removal of the thyroid have a large affect on calcium homeostasis
NO
what are the main regulators of phosphate homeostasis
-PTH,
active vitamin D 3
- FGF 23
when is expression of FGF23 induced
when serum phosphate is too high
what does PTH do w phosphate
- increases phosphate relase from bone
- decreases renal phosphate reabsorption
- increases active vitamin D3 production by kidney
what does 1,25(OH)2D3 do
- increases phosphate release from bone
- increases renal phosphate reabsorption
- increases phosphate uptake in gut
what is FGF 23 expression in osteocytes inhibited by
DMP-1 and PHEX
what is a major source of endocrine FGF23 and regulate phosphate homeostasis
osteocytes
what are FGF23 actions in the kidney
-decreases reabsorption of phosphate
- decreases production of active vit D3
what is the overall effect of FGF23
lowers serum phosphate
what is the main mechanism for rapid regulation of phosphate
kidney reabsorption
where are NaPi2a and NaPi2c expressed
in proximal tubules
how does PTH inhibit phosphate reabsorption
via inhibition of NaPi2a and Napi2c expression
what results in the absence of PTH
increases phosphate reabsoprtion
what produces FGF23 and when
osteocytes when serum phosphate is high
what does FGF23 downregulate
NaPi2a and NaPi2c
