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Control of plasma calcium Regulation of calcium Systems of the body: Integrative aspects Helen Christian normal concentration of plasma calcium what h t are the th effects ff t off calcium l i deficiency d fi i & excess? what disturbs plasma calcium? how is calcium ‘sensed’? the hormones that control the intake and loss of calcium consequences of too much/too little endocrine control Any questions email: [email protected] Extracellular calcium Is tightly controlled within narrow range to allow proper functioning of tissues excitation-contraction coupling synaptic transmission platelet aggregation and coaggulation Total plasma calcium concentration 2.4 mM Intracellular calcium Is tightly controlled at levels 10,000 fold lower than extracellular calcium Intracellular second messenger in regulation of cell division muscle contraction cell ll motility tilit membrane trafficking secretion 1 Hypocalcaemia Intracellular calcium Total plasma calcium concn 2.4 mM <1.2 mM total plasma Ca2+ is very dangerous 10-3M 10-7M causes nerve hyperexcitability and muscle tetany CaBPs CaBPs IP3, IP3 ryanodine Capacitative (store-activated) calcium entry increases low sensitivity to Na+ Ca2+ The majority of non-bone calcium is EXTRACELLULAR Hypercalcaemia Calcium concentrations decreased excitability of nerves Control of plasma & extracellular Ca2+ 1.2 1 2 mM urinary stones > 3mM renal failure, 4mM cardiac failure dangerous in the long term Total plasma calcium 2.4 mM 50% ionised 45% bound to protein 5% bound to citrate, phosphate 2 Effect of protein concentration on plasma calcium Loss of protein in nephrotic syndrome i increases free f Ca2+ 45% of ‘normal’ total plasma calcium is bound to protein Excess protein in multiple myeloma, reduces free Ca2+ Effect of phosphate and citrate on plasma ionised calcium Effect of pH on plasma ionised calcium 5% of ‘normal’ total plasma calcium is bound to phophate and citrate increases the negative charge on plasma proteins Phosphate: rapid movement of phosphate into blood, e.g. as a result of crush injury to muscle, reduces free Ca2+ Alkalosis more calcium binds to protein, ionised Ca2+ falls results in hypocalcaemic tetany Acidosis decreases negative charge on plasma proteins Citrate: e.g. from massive blood transfusion reduces free Ca2+ less calcium binds to protein, ionised Ca2+ rises results in hypercalcemia 3 Total body calcium 99% is stored in skeleton 25 Moles, 1kg 1% iin ti tissues, circulation Plasma and bone calcium homeostasis Bone • Bone contains the major store of body calcium as hydroxyapatite Ca10(PO4)6 OH2 • Dynamic D i ti tissue • The bone cells - osteoblasts, osteocytes, osteoclasts -all play a role in forming, maintaining and remodelling bone. • Mechanical stress stimulates bone formation, disuse (eg illness; space flight) causes loss of bone. Osteoblasts (blue) and osteocytes (green) maintain bone; Osteoclasts secrete acid and proteolytic enzymes responsible for breaking down bone Homeostasis of bone calcium is essential for bone strength Homeostasis of plasma ionised calcium (1.2 mM Ca2+) is essential for many vital functions In normal physiology the demands of plasma calcium are stronger, bones contain huge reserves of calcium (approx 1kg) 4 Exercise - physical stress on bones Sensed by osteocytes, bone-lining cells. Daily requirements for calcium Transmit stimulus to osteoblasts via gap junctions Dietary intake varies enormously, so fluxes vary to stimulate new bone synthesis. •Children, pregnant / lactating women net accumulation of Ca2+ 3 mmoles/day •Pubertal growth spurt accumulate 5-7 mmoles/day •Post-menopausal women and ageing males Ca2+ loss, osteoporosis Calcium fluxes Hormones influencing calcium Parathyroid hormone PRINCIPAL CONTROL Vitamin D and its metabolites ileum C l it i Calcitonin mmoles 5 How and where is Ca2+ sensed? Parathyroid hormone (PTH) The calcium sensor/receptor Principal control of plasma calcium Secreted in response to fall in serum Ca2+ Restores lo low plasma Ca2+ to normal Located in parathyroid gland, kidney distal tubule gut enterocytes, tubule, enterocytes osteoblasts PTH increases calcium reabsorption in distal tubule of kidney Calcium receptor signalling activated by plasma ionised calcium Æinhibits adenylate cyclase and stimulates phospholipase C. a fall in plasma Ca2+ causes secretion of PTH Glomerulus filters ionised and complexed: 250 mmoles/day with Na+ + H20 60% PCT 9% mainly passive paracellular reabsorption of 60% with Na (hormone-insensitive); some active DCT & collecting duct active reabsorption of 9% via luminal membrane epithelial Ca channel Only 1% lost in urine 30% increases cAMP in distal tubule epithelia and increases calcium absorption but not clear which transporter is affected; stimulates 1α-hydroxylase activity 1% 6 Actions of PTH in bone PTH PTH long term actions on bone acts on osteoblasts in bone intermittent PTH necessary for normal bone turnover rapid: stimulates release of Ca2+ (alters osteoblasts allowing osteoclast access to osteoid) long-term: osteoclasts stimulated via osteoblasts Æbreaking down of bone Parathyroid hormone summary released by parathyroid glands when plasma calcium low increases Ca2+ reabsorption in kidney increases synthesis of 1,25 vitamin D3 in y kidney in bone increases osteoclast activity via actions on osteoblasts NFkB OPGligand = RANK c-fos OPG is osteoprotegerin Pathology of PTH Deficiency (eg damage in thyroid g y) or receptor p defect (‘PTH ( surgery) resistance’) low plasma Ca2+ - tetany Excess from parathyroid tumours b bone destruction d i high plasma Ca2+ , urinary stones sluggish CNS 7 Production of Vitamin D and its active metabolite ‘calcitriol’ 1,25(OH)2 vitamin D3 Vitamin 1,25 D3 Diet acetate synthesized y in kidney y in response p to PTH when plasma calcium falls restores total body calcium and phosphate to normal acts to increase: gut g 7-dehydrocholesterol sunlight, skin Pre-vitamin D3 calcium uptake from gut vitamin D3 liver vitamin D 25-hydroxylase 25 (OH) vitamin D3 calcium reuptake in kidneys vitamin D3 calcium mobilisation from bone circulation Vitamin D Receptor action VitD R in i the th nucleus bind DNA and activate transcription kidney PCT 25 vitamin D 1α-hydroxylase PTH stimulates 1,25 (OH)2 vitamin D3 increases total body calcium Dietary intake of calcium is primarily controlled by Vitamin 1,25D3 small intestine absorption controlled by Vitamin 1,25D3 Acts in enterocytes to increase synthesis of : Calbindin (calcium shuttling protein) Ca2+ ATPase (basolateral) Na+-Ca2+ exchanger (basolateral) Timescale - hours Epithelial Ca2+ channels (apical) Similar mechanism increases calcium reabsorption in the kidney 8 Vitamin 1,25 D3 stimulates synthesis of calcium transport proteins Effects of Vitamin 1,25D3 on bone Bone synergises with PTH actions induces differentiation of osteoclasts inhibits osteoblast collagen g synthesis Small intestine, distal tubules kidney Vitamin 1,25 D3 pathology Rickets -lack of Vit D3 Vitamin D-resistant rickets Calcitonin peptide hormone from C cells in thyroid Renal rickets lack of Vit 1,25D3 in renal failure Adult - osteomalacia general loss of minerals Excess 1,25D3 Vitamin D poisoning - renal stones prevention of hypercalcaemia; excess bone breakdown no long term effect on serum Ca2+ effects are over-ridden by PTH if in excess; CT receptor downregulation 9 Raised plasma calcium stimulates calcitonin release Calcitonin Bone inhibits osteoclast breakdown of bone greatest effect when resorption rapid when young Gut helps control rise in Ca2+ due to meals inhibits absorption Calcitonin pathology Pathology: no effects Deficiency: compensated by reduction in PTH Sex steroids Oestrogen and testosterone act on osteoblasts and precursors. Deficits lead to osteoporosis osteoporosis, especially post postmenopausal. Excess: secretion by carcinomas 10 Osteoporosis Other hormones Glucocorticoids excess causes osteoporosis by reducing bone protein formation Thyroid hormone (T3) excess causes osteoporosis Insulin, Growth G hormone and Insulin-like growth factors PTH-related protein Summary uncontrolled secretion from some tumours (e.g. breast, lung, prostate) acts via PTH receptors on bone and kidney to increase plasma calcium above normal levels, known as ‘hypercalcaemia of malignancy’ 11