Lecture 13 ---Calcium homeostasis Flashcards by Isabella Gillett

What is the distribution of Ca2+ throughout the body?

> 99% skeleton
1% soft tissue (cells)
0.1% ECF

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Where is Ca2+ found inside cells?

MITOCHONDRIA & ER

[Ca2+] in cytoplasm = very low

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What is the distribution of Ca2+ in the ECF?

(1) IONISED CALCIUM = 50%
(2) COMPLEXED TO ANIONS = 9%
(3) BOUND TO PROTEINS (esp albumin) = 41%

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What is the BIOLOGICALLY ACTIVE form of Ca2+ in the ECF?

IONISED CALCIUM is biologically active

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What anions does Ca2+ typically complex to?

Citrate
Phosphate
Sulfate

Ca2+ complexed to anions= Biologically INACTIVE

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How much Ca2+ is in the body?

?? (male)
?? (female)

1200g (male)

1000g (female)

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What is the importance of Ca2+ in the body (7)

*(1) BONE & TEETH (increases compressible strength)
*(2) BLOOD CLOTTING (activates blood clotting factors 9/10, prothrombin, thrombin)
*(3) MUSCLE CONTRACTION (skeleton = binds to troponin, allows myosin/actin binding….smooth= binds to calmodulin = activates myosin kinase)
*(4) NERVOUS SYSTEM (Ca2+ entry at terminal causes vesicles to fuse with membrane & neurotransmitter is released)
*(5) ENDOCRINE SYSTEM (processes involving exocytosis (e.g. insulin release))
(6) CARDIOVASCULAR SYSTEM (L-type Ca2+ channels responsible for plateau phase in CV contraction)
*(7) BIOLOGICAL PROPERTIES OF MEMBRANES (makes biological membranes more IMPERMEABLE to Na+ …B/C Ca2+ binds to protein of Na+ channel on activation gate = conformational change = blocks Na+ entry…(hypercalcaemia, hypocalcaemia)

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What blood clotting factors does Ca2+ activate?

Factors 9 & 10
Thrombin
Prothrombin

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What effect does HYPERcalcaemia & HYPOcalcaemia have on neuromuscular activity?

HYPERcalcaemia (too much Ca2+): depresses NM activity

HYPOcalcaemia (too little Ca2+): makes nerves/muscle hyper excitable

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CALCIOSTAT SYSTEM

Mechanisms for maintaining plasma [Ca2+]
CALCIOSTAT SYSTEM (CaSR detect changes in ECF [Ca2+] and produce rapid response)
(1) KIDNEY–REABSORPTION
(2) INTESTINE–ABSORPTION
(3) BONES–RESORPTION

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CaSR

Calcium Sensing Receptors detect changes in ECF [Ca2+]

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KIDNEY–REABSORPTION of Ca2+

What regulates?

90% = obligate reabsorption (Proximal tubule/descending loop henley/distal tubule)

10% = SELECTIVE REABSORPTION depending on plasma [Ca2+] (distal tubule/Collecting duct)

Under control of PARATHYROID HORMONE (PTH)

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What % of the circulating calcium is filtered by the kidneys? Why not 100%?

59% is filtered

50% ==Ionised Ca2+
9% ==bound to anions

The 41% bound to proteins is NOT FILTERED

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INTESTINE–ABSORPTION of Ca2+

We absorb: 350mg/day ~30% of what we ingest, we absorb

*Vitamin D increases absorption of Ca2+ in intestine
*Ca2+ is very poorly absorbed due to it being a divalent cation

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Recommended daily intake of Ca2+

1000mg/day

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How much Ca2+ to we absorb from the diet every day?

How much Ca2+ to we excrete from the diet every day?

ABSORB: ~350mg (~30% of total absorption)

EXCRETE: ~900mg/day

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How much Ca2+ is lost in gastric juices/slough mucousal cells per day?

~250mg/day

BONES–RESORPTION of Ca2+

TWO PROCESSES:
(1) RAPID PHASE (minutes –> hours): OSTEOCYTIC OSTEOLYSIS

(2) SLOW PHASE (days–>weeks): Osteoclasts secrete H+ ions & acid phosphatase into a confined resorption bay (at the ruffled cell border)…
* *H+ combines with Cl- –> HCl which dissolves the bone tissue
* *Acid Phosphatase: hydrolyses the collagen matrix

What is OSTEOCYTIC OSTEOLYSIS

The Rapid phase of bone resorption (minutes –> horus)

Osteocytes & osteoblasts are connected by OSTEOCYSTIC MEMBRANE SYSTEM (OMS) through channels filled with BONE FLUID

(1) ==>REDUCED [Ca2+] IN BONE FLUID–> stimulates SOLUBILISATION OF BONE –> mobilisation of Ca2+ to bf
(2) ==>REDUCED [Ca2+] IN BLOOD –> stimulates parathyroid hormone (PTH) secretion –> stimulates PTH receptors on OSTEOBLASTS –> INCREASES Ca2+ MEMBRANE PERMEABILITY => Ca2+ movement from bf –> ECF

What is the SLOW PHASE of Ca2+ resorption by bones

(1) OSTEOCLASTS secrete H+ ions & Acid phosphatase

==> H+ combines with Cl- (=HCl) & dissolves the bone tissue
==> ACID PHOSPHATASE hydrolyses the collagen matrix fibres

What are the hormones that control Ca2+ Homeostasis?

What are their 1/2 lives?

(1) PARATHYROID HORMONE (PTH) -20-30min
(2) VITAMIN D-days-weeks
(3) CALCITONIN-10 min

What is the 1/2 life of Parathyroid hormone (PTH)

20-30minutes

Role of PARATHRYOID HORONE in Ca2+ homeostasis)

->1/2 life = 20-30 minutes
->Triggered by CaSR (calcium sensing receptors) on the surface of the parathyroid gland
**HIGH Ca2+ –> REDUCTION in PTH secretion/production
**LOW Ca2+ –> INCREASE in PTH secretion/production
-> Acts on KIDNEY ((1) increase reabsorption and (2) Increase activation of vitamin D3)
-> Acts on BONE (osteoblasts (CaSR)–> increases permeability to Ca2+)

How is PTH regulated?

NEGATIVE FEEDBACK (High Ca2+ act on CaSr on PT surface cells = reduce PTH production and secretion)

What is the 1/2 life of vitamin D3 (1,2 5 dihydroxycholecaliferol)

days--weeks

Source of vitamin D3?

(1) Synthesised by iradiation of 7-dehydrocholesterol to cholecalciferol in the skin (2) Diet (eggs/fish)

What step of vitamin D3 synthesis is under control of PTH?

The final hydroxylation step (in the kidney) is under PTH control: PTH increases the biosynthesis of the enzyme 1A HYDROXYLASE which converts vitamin D to the ACTIVE form in the kidneys

1A HYDROXYLASE

biosynthesis of 1A HYDROXYLASE is under control of PTH 1A HYDROXYLASE converts vitamin D to the ACTIVE FORM in the kidneys

How does vitamin D function in Ca2+ homeostasis?

(1) Increases ABSORPTION in the intestines = increase in plasma [Ca2+] (2) Increases REABSORPTION in the kidney= increase in plasma [ca2+] (3) Increases CALCIFICATION (Uses Ca2+ to lay down bone) = small reduction in plasma [Ca2+]

How is vitamin D3 regulated?

(1) 25 hydroxycholecaliferol inhibits conversion of cholecaliferol-->25hydroxycholecaliferol in the liver to consider vitamin D stores in the body

CALCITONIN

- ->Secreted by the PARAFOLLCULAR 'C' CELLS in the THYROID gland - ->1/2 life = 10 minutes - ->Stimulated by increased [Ca2+] - -> Cause Plasma [Ca2+] to decrease by (1) Inhibiting bone resorption (decrease Ca2+ release) (2) Increasing Ca2+ excretion

HYPOCALCAEMIA

too little Ca2+ | makes nerves/muscle hyperexcitable

HYPOPARATHRYOIDISM

=> Insufficient PTH secretion Leads to=> HYPOCALCAEMIA Caused by=>(1) Autoimmune disease of PT (2) Loss of PT during Thyroid removal

RICKETS & OSTEOMALACIA

=VITAMIN DEFICIENCY Rickets = condition in children =====>RICKETS TYPE 2: mutation in vitamin D receptor = activation of vitamin D doesn't work. Osteomalacia= condition in adults Causes: (1) lack of solar exposure (2) Dietary Deficiency

What causes rickets type 2?

Mutation in vitamin D receptor=activation of vitamin D doesn't work!

HYPERPARATHYROIDISM

* *Leads to HYPERCALCAEMIA (>12-15mg/dL) * *CAUSE: (1) tumour in PT gland =over secretion PTH * *Consequences: excessive demineralisation of bone

What blood Ca2+ levels are classified as HYPERcalcaemia?

>12-15mg/dL

at what [Ca2+] does plasma Ca2+ start to precipitate out as _______ in the ECF?

>70mg/dL | CaCO (Calcium carbonate)

PRIMARY (1') and SECONDARY (2') HYPERPARATHYROIDISM

1': depression of CNS/PNS, muscle weakness, constipation, kidney stones, coma 2': Increases PTH in response to hypocalcaemia (overshooting)

More Ca2+ is needed for...

(1) GROWTH (w/out Ca2+ bone density is reduced & longitudinal growth is stunted) (2) PREGNANCY/BREAST FEEDING (3) MENOPAUSE (w/out protective effects of oestrogen menopausal women are prone to fractures)

What changes are made during PREGNANCY/BREAST FEEDING to increase Ca2+ stores

Pregnancy hormones increase (1) Vitamin D levels = increase absorption of Ca2+ (2) CALCITONIN levels increase = inhibit bone resorption = pregnant women incorporate more Ca2+ into bone as a store for the growing foetus to be drawn on in the 3rd trimester)