Unformatted text preview: PSL302Y: Lecture 06, by Prof. Lam! Fri., Sept. 24, 2010 Calcium (Ca2+) Balance Why regulate [Ca2+]blood? Where is most of your Ca2+ found? How do hormones regulate [Ca2+]? - Parathyroid hormone - Vitamin D3 How are Ca2+ and phosphate linked?
Calcium Balance Why is calcium critical for normal physiology? - Intracellular signaling: i.e. G protein-coupled receptors, 2ndary messengers up [Ca2+] - Hormone secretion: i.e. rise in intracellular [Ca2+] cause beta cells to secrete insulin - Blood clotting - Neural excitability - Muscle contraction: influx of Ca2+ causes muscle contraction - Building & maintaining bone: made of crystallized Ca2+ Ex. Burdyga. Nature, 436:559, 2005: "calcium spark" is a spike in intracellular [Ca2+] in a secretory cell, causing release of hormones How is the total calcium in your body maintained?
Intake diet, small intestine lumen Output kidney Na +/Ca2+ exchanger Calcium Balance calbindin September 24, 2010 How is the total calcium in your body maintained? Regulated by intake from diet, i.e. milk, and absorbed by small intestine
September How excreted from bloodstream: 24, 2010 2+ enters via channels, binds Ca to calbindin and enters kidneys via Na+/Ca2+ exchanger OR via Ca2+ ATPase Recommended eco e ded ~ 1,000 mg/day Ca2+channel Ca2+ATPase
Hoenderop 2000 Am J Physiol Renal Physiol 278 pF352 Total body Ca2+ = intracellular + extracellular (ECF/plasma + bone) - 99% of calcium found in body exists in the bone, whereas 0.1% in the ECF and 0.9% inside cell - Input by small intestine and output by kidneys keeps [Ca2+] at 2.5mM. Total body Ca2+ = intracellular + extracellular (ECF/plasma + bone)
small intestine ECF (extracellular fluid) 0.1%
3 bone 99% kidney [Ca2+] 2.5 mM urine cell 0.9% [free Ca 2+] 0.001 mM 1 of 4 PSL302Y: Lecture 06, by Prof. Lam! Fri., Sept. 24, 2010 Bone is constantly being formed and Bone is constantly being formed and resorbed resorbed
blood vessel and nerve osteon Calcium in bone is mainly in crystals (hydroxyapatite = Ca10(PO4)6(OH2)). A small fraction is ionized and readily exchangeable. spongy bone
Calcium Balance -Bone is made up of crystalline Ca2+ -Small fraction exists in ionized fluid form -Fluid is readily exchangeable if acute rise in [Ca2+] is required, i.e. In bloodstream September 24, 2010 compact bone Bone dynamics (cycle is ~100 days): 1. Resting phase - Osteoclasts resorb, osteoblasts lining cells form, osteocytes (retired osteoblasts) bone b 1. Resting phase 2. Resorption: recruitment of 3. Calcium Balance September 24, 2010 5 osteoclasts to resolve (chew) bone cavity made by osteoclasts 3. Cavity formed w/i bone bone 4. Osteoblasts can start bone remodelling and/or repair Bone dynamics (~100 days): osteoclasts resorb, osteoblasts form, osteocytes (retired osteoblasts)
2. Resorption osteoclasts bone b 4. Formation/repair osteoblasts new bone bone "About 5% of your bone mass is being remodeled by ~2 mil bone-remodeling units" Calcium Balance - Bone remodeling is complex procedure! How does the endocrine system control [Ca2+]? [ ] How does the endocrine system control [Ca2+]?
thyroid September 24, 2010 Multiple hormones parathyroid hormone vitamin D3 p parathyroids y calcitonin l it i (essential for life) -Multiple targets for hormones to regulate [Ca2+], which has diverse fxns throughout body -Thus multiple hormones fxn to regulate [Ca2+] 6 PTH increases plasma [Ca2+] by acting directly on bone and kidney g y y
blood small instestine PTH plasma [Ca2+] by acting directly on bone and kidney - PTH has direct impact to favour efflux of Ca2+ from bone to blood - When [Ca2+]blood, PTH release stimulated - Other routes to up [Ca2+]blood
8 [Ca [C 2+]
vitamin D bone parathyroid hormone kidney 2 of 4 PSL302Y: Lecture 06, by Prof. Lam! Fri., Sept. 24, 2010 How does PTH use bone as a bank 2+ How does PTH use withdraws bank? from which it bone as a Ca2+ from which it withdraws Ca ?
Calcium Balance "quick-cash" = fast exchange of Ca2+ from bone fluid (labile pool), -This September 24, 2010 procedure pumped out by osteoblasts and osteocytes "loan" = slow exchange of Ca2+ from bone itself (stable pool), by locally dissolving bone is tightly regulated by osteoclasts and osteocytes -Rapid exchange occurs w/ bone fluid -Slow exchange occurs btwn crystal bone -How does PTH directly affect bone structure and osteoclast activity? bone osteoblast, mineralized fluid: osteocyte bone: b labile pool fast stable pool of Ca2+ 2+ of Ca slow plasma Ca2+ Ca2+ In osteoblasts PTH, altering gene expression of RANKL and OPG, In osteoblasts, PTH alters expression of RANKL & OPG to control osteoclast activity controls osteoclast activity
-PTH directly affects osteoclasts via indirect mech -Bind to G protein-coupled receptor cAMP 10 expressed at surface of osteoblast (not osteoclast osteoblast RANKL RANK osteoclast) -> triggers cAMP Calcium Balance September 24, 2010 intracellular signaling pathway -> OPG altered expression of RANKL OPG = osteoprotegerin (RANKL inhibitor) -RANKL binds to RANK, which then RANKL = receptor activator of nuclear factor kappa B ligand regulate osteoclasts Gensure 2005 Biochem Biophys Res Commun 328, p. 666 -Also: endogenous inhibitor OPG regulates (-ve feedback) RANKL activity Calcium Balance September 24, 2010
"Parathyroid cells are exquisitely calcium concentration" concentration
PTH, PTH/PTHr receptor "Parathyroid cells are exquisitely sensitive to changes in sensitive to changes] in extracellular extracellular [Ca2+ - When blood has low [free have relatively high [PTH] - When blood has high [free Ca2+], have relatively 11 low [PTH] Ca2+], [PTH]serum (% maximum) What type of feedback regulates PTH release? What type of feedback regulates PTH release? [free Ca2+]blood (mM)
Chen 2004 Am J Physiol Renal Physiol 286 p1005 parathyroid PTH chief cell PLC + [Ca2+]
blood calcium-sensing receptor t -When [Ca2+] rises, can bind to Ca2+ -sensing (G protein-coupled receptor) receptor, found on parathyroid cells -Triggers downstream PTH signaling cascade (involves Ca2+) -Inhibits PTH release 12 3 of 4 PSL302Y: Lecture 06, by Prof. Lam!
Calcium Balance September 24, 2010 Fri., Sept. 24, 2010 What is Vitamin D's is vitamin D's mech What mechanism of action? of action? vitamin D3, calcitriol, , 1,25-dihydrocholecalciferol Vitamin D3, Vitamin D3, formed by 3. 25-hydroxycholecalciferol formed by sunlight sunlight
1. 7-dehydrocholesterol 2. cholecalciferol -Sunlight required to stimulate synthesis of vit. D -In skin, precursor is 7-dehydrocholesterol -> cholecalciferol September 24, 2010 -Cholecalciferol converted in liver -> 25-hydroxycholecalciferol Calcium Balance September 24, 2010 -25-hydroxycholecalciferol converted in kidney -> 1,254. 1,25-dihydrocholecalciferol dihydrocholecalciferol = ACTIVE FORM OF vit. D -Why not synthesize vit. D in one organ? Bc/ so vital in Ca2+ Vitamin D3 signaling, must require redundant mechs to synthesize it.
14 arbl.cvmbs.colostate.edu in D3, d by sunlight 3. 25-hydroxycholecalciferol How do hormonescorrect a a calcium deficit? How do hormones correct calcium deficit?
Low [Ca 2+]blood Increased parathyroid hormone release drocholesterol
Calcium Balance September 24, 2010 vitamin D 4. 1,25-dihydrocholecalciferol
efflux of Ca2+ from bone f b
arbl.cvmbs.colostate.edu alciferol 15 decreased loss of 2 Ca2+ in urine increased [Ca 2+]blood increased absorption of Ca2+ from intestine -PTH targets bone or kidney to up [Ca2+ -Favours, depending on signaling mech, cause efflux of Ca2+ or decreased loss from urine -Also kidneys responsible for secreting vit. D Phosphate metabolism, controlled by the same mechanisms that regulate Phosphate metabolism, controlled by same mechs that regulate Ca2+, but not as tightly Ca2+ metabolism but not as tightly metabolism,
bone hydroxyapatite crystals (Ca10(PO4)6(OH2))
15 ATP increases phosphate release from bone decreases phosphate reabsorption in kidney Vitamin D increases phosphate absorption by intestine and reabsorption by kidney PTH -Phosphate linked to Ca2+ via bone hydroapatite (bone crystals) 16 -Equally important to regulate phosphate homeostasis for bone maintenance & ATP production -PTH and vit. D play role in regulating [phosphate] using similar mechs for Ca2+; although some diffces in directional flow of phosphate and Ca2+ 4 of 4 ...
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- Calcium Balance