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

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

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Phosphorus critical to many cellular functions:

-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 major pools of calcium in body:

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

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What is the mineral phase of bone/teeth?

Hydroxyapatitie (HA) crystals

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

HA mineralization of bone

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

Bone HA

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Normal range for total serum calcium

8.5 – 10.5mg/dL

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What are the 3 types of calcium in the blood?

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

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Normal range of ionized calcium

4.4-5.4mg/dL

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

~200mg

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

~500mg

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What are the intracellular and extracellular calcium levels?

Low intracellular calcium concentrations in cytosol
High extracellular concentration

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What regulates cell function?

Maintenance of steep gradient, intracellular calcium fluxes regulate cell function

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How is the calcium gradient achieved?

By calcium pumps in plasma membrane

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How is phosphorus present in solution?

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

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

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

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What is phosphorus absorption in gut like?

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

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What is adult serum Pi concentration?

2.5 to 4.5 mg/dL

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What is an important buffer to maintain physiological pH?

extracellular phosphate is free

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

Gut
Parathyroids
Kidney
Skeleton

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What are three process involved in calcium uptake?

Uptake
Transcellular transport of calcium
Extrusion

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How does calcium uptake occur? and where?

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

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How does transcellular transport of calcium occur?

By calcium binding proteins (calbindins)

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How does extrusion of calcium uptake occur? and where?

Basal surface of cell – by membrane transport proteins

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What isoforms are involved in calcium uptake in the gut?

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

What does TRPv6 do?

Ca 2+ uptake on apical side of intestinal epithelial cell

What does calbindin D9K do?

transcellular transport of Ca 2+ to basal side of cell

What does Ca2+ATPase1b do?

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

How is phosphate taken up into cell?

By phosphate transporter: NaPi-IIb

What happens after intestinal absorption into blood?

Ca2+ and Pi is filtered in kidney glomerulus

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

Reabsorbed in kidney tubules (REABSORPTION = very important)

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

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

What isoforms are involved in calcium uptake in the renal?

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

What main hormones are involved in calcium homeostasis?

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

What main hormones are involved in phosphate homeostasis?

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

How are Serum calcium concentrations detected?

Calcium sensing receptor (CaSR)

What expresses CaSR levels?

Parathyroid gland

What occurs in an increase of serum calcium levels?

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

What occurs in a decrease of serum calcium levels?

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

What is the receptor for the PTH?

PTH1R

What mediates the PTH actions?

via activation of adenylate cyclase/cAMP production

What is the homeostatic response to low calcium?

Increases bone resorption Increases calcium reabsorption in kidney reduces Pi reabsorption

What does the PTH stimulate in the kidney?

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

What does 1,25 dihydroxyvitamin D3 induce?

Expression of calbindins, phosphate transporters, and PTH production

What does expression of calbindings result in increased?

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

What does expression of phosphate transporters result in increased?

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

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

Increase serum calcium (and phosphate) back to normal range

When is production of PTH inhibited?

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

What is the homeostatic response to high serum calcium?

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

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

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

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

Calcitonin

What is calcitonins major effect?

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

What is calcitonins minor effect?

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

What are the main regulators of phosphate homeostasis?

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

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

PTH

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

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

What protein is important in phosphate regulation?

32kDa protein

What expression induced in bone when serum phosphate too high?

Fibroblast growth factor 23 (FGF23)

How can 32kDa protein be inactivate?

12 and 20kDa

How is expression in osteocytes inhibited by?

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

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

Osteocytes

What is FGF23 actions in the kidney?

* 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

What is the overall effect of FGF23?

Lowers serum phosphate

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

Kidney reabsorption

What phosphate co-transporters expressed in proximal tubules?

NaPiIIa, NaPiIIc

What inhibits phosphate reabsorption? and how?

PTH via inhibition of NaPiIIa and NaPiIIc

What does the absence of PTH do?

Increase phosphate reabsorption

What is produced by osteocytes when serum phosphate is high?

FGF23

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

FGF23

What are factors Regulating Calcium and Phosphate Homeostasis?

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