Lecture 11 Flashcards
What are the physiological roles of calcium?
Bone growth and remodelling, Muscle contraction and neurotransmitter release, Enzyme co-factor, Membrane potential regulation, Essential housekeeping ion
Where is the majority of the calcium found within the body?
99% found in skeleton –> not free
Where are calcium levels regulated?
Kidney, Bone, GIT
What are calcium levels detected by? What effect does it have on PTH?
Calcium sensing receptors (CaSR), Found in parathyroid gland, Stimulates low release of parathyroid hormone (PTH)
Where are the parathyroid glands located?
4 parathyroid glands situated in the posterior surfaces of the thyroid gland
Where is PTH produced and secreted from?
Chief cells in the parathyroid gland
What do chief cells do?
Synthesise pre-prohormone (115AA) for parathyroid hormone (PTH), Pre-prohormone is then cleaved to give a biologically active 84AA peptide
What are the short and long term effects of PTH?
Secretion of PTH (seconds to minutes), Increased gene expression (hours to days), Increased proliferative activity of PT cells (days to weeks/longer), Eventually get an increase in gland size and unregulated production of PTH
What are the primary, direct effects of PTH?
PTH acts on kidney to: Increase Ca2+ reabsorption, Promotes PO4 excretion (inhibits reabsorption), Increase production of active vitamin D, PTH acts on bone to: Mobilise calcium
What are the secondary, indirect effects of PTH?
All due to increased vitamin D production
What does PTH do overall?
Increases plasma calcium, Decreases PO4
What does vitamin D do? What is it required for?
Ca2+ uptake from gut, Cartilage production (chondrocytes), Mineralisation (indirect): Ca2+ and PO4 reabsorption/excretion kidney, Required for osteoblast and osteoclast differentiation, Increased osteoclast action (direct on bone) but via osteoclasts
How is active vitamin D synthesised?
Absorb vitamin D3 or D2, Vitamin D3 gets hydrolysed in liver –> Produces 25-hydroxy vitamin D3 called calcidiol –> This is the inactive form, Calcidiol needs to go through another hydrolysis reaction –> Carried out by 1 alpha-hydroxylase in response to PTH in the kidney –> Forms active form of vitamin D3 (1,25(OH)2D3) or calcitriol
Describe the role of PTH and vitamin D in calcium homeostasis
Low calcium is detected by parathyroids and leads to secretion of higher levels of PTH, PTH activates 1-alpha hydroxylase which converts calcidiol to calcitriol in the kidney, Calcitriol then acts to: Increase calcium absorption in the GI tract, Increase calcium reabsorption in the kidney, Increase bone resorption calcium release in the bone (bone mineralisation), PTH also acts to stimulate calcium reabsorption in the kidney and increase bone resorption calcium release in the bones
What is phosphate required for?
Important in intracellular metabolism (e.g ATP synthesis), Needed for phosphorylation to occur (enzymes) –> Causes conformational changes that expose/shield active sites, Needed for phospholipids in membranes
What regulates phosphate levels?
Calcium tightly regulates it
What does a balance of phosphate depend on?
Diet and uptake from gut –> Absorption from gut is 80-90% efficient; Ca2+ ~20%, Intracellular:extracellular movement, Urinary excretion: Actively reabsorbed by PCT, Only place excreted is the kidney, 84% ionised (compare with Ca2+)
Describe phosphate homeostasis
Low phosphate levels leads to upregulation of 1-alpha hydroxylase, Leads to formation of calcitriol from calcidiol –> Calcitriol upregulates PO4 (phosphate) reabsorption –> Calcitriol upregulates reabsorption of phosphate in the kidneys –> Calcitriol upregulates phosphate release from bone, If this happens for too long, get excessive activation of osteoclasts and get release FGF-23 –> FGF-23 inhibits PTH –> FGF-23 inhibits 1-alpha hydroxylase –> FGF-23 STOPS ALL OF THE ABOVE
What are the differences in the actions of PTH and calcitriol regarding calcium and phosphate?
PTH activates pumps that pump calcium back into the blood and phosphate out of the blood, Calcitriol activates pumps that pump both calcium AND phosphate ions into the blood, Have very different functions
What is fibroblast growth factor (FGF)-23?
Made predominantly by osteoclasts (osteocytes), Regulates PTH and phosphate levels, Stimulated by prolonged activation of osteoclasts, Counteracts actions of vitamin D induced phosphate changes –> Prevents vitamin D mediated hyperphosphatemia
Why do we FGF-23? How does it work?
If PTH/vitamin D3 have activated your osteoclasts (bone mineralisation —> release of calcium and phosphate from bone), can be bad –> Need to regulate this –> If you don’t, get osteoporosis from unchecked activation/mineralisation of bones –> get bone lesions, To prevent this unchecked mineralisation of bone, fibroblast growth factor (FGF-23) inhibits calcitriol (vitamin D3) –> Negative feedback loop to silence function of calcitriol –> Prevents activation and production of 1-alpha hydroxylase –> inhibits formation of new calcitriol –> Also inhibits type II sodium-phosphate co-transporters
What is klotho?
Klotho –> obligate receptor partner for FGF-23 –> Originally cloned as an age controlling gene –> Mutation leads to a syndrome resembling aging
What are the 3 mechanisms of calcium absorption in the intestine?
Transcellular transport, Endosomal pathway, Non-endosomal pathway
What is the transcellular transport mechanism of calcium absorption?
Calcium = associated with calcium binding protein (e.g albumen) and passes between cells –> Calcium binding proteins are upregulated by calcitriol –> Need to break tight/gap junctions between epithelial cells –> Called transcellular transport –> Rare
