Lecture 13 ---Calcium homeostasis Flashcards
What is the distribution of Ca2+ throughout the body?
> 99% skeleton
1% soft tissue (cells)
0.1% ECF
Where is Ca2+ found inside cells?
MITOCHONDRIA & ER
[Ca2+] in cytoplasm = very low
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%
What is the BIOLOGICALLY ACTIVE form of Ca2+ in the ECF?
IONISED CALCIUM is biologically active
What anions does Ca2+ typically complex to?
Citrate
Phosphate
Sulfate
Ca2+ complexed to anions= Biologically INACTIVE
How much Ca2+ is in the body?
?? (male)
?? (female)
1200g (male)
1000g (female)
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)
What blood clotting factors does Ca2+ activate?
Factors 9 & 10
Thrombin
Prothrombin
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
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
CaSR
Calcium Sensing Receptors detect changes in ECF [Ca2+]
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)
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
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
Recommended daily intake of Ca2+
1000mg/day
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
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)
