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6-Ca%20homeostasis[1] - Bioregulation of Calcium and...

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Unformatted text preview: Bioregulation of Calcium and Phosphate Homeostasis I. Importance of Calcium and Phosphate 1 Role of calcium • Bone & tooth formation tooth formation • Muscle contraction • Release of secretory granules in neurons and glandular cells • Second messenger • Cofactor in blood clotting • High levels in mammalian milk & avian egg shells 2 Role of phosphate • Essential component of bones & teeth component of bones teeth • Many essential molecules contain phosphate: phospholipids in cell membrane, nucleic acids, nucleotides, etc. • Energy storage as ATP, creatine phosphate • Second messengers: cAMP, cGMP • Activation of many enzymes via protein kinases • Major buffer system in urine Interrelationship between Ca2+ and HPO42• Product of free plasma concentrations of of free plasma concentrations of 2+ and HPO 2- is constant for a given Ca 4 physiological state if [Ca2+] [HPO42-] and vice versa 3 Bone formation and resorption • Calcium phosphate is present as small phosphate is present as small crystals: hydroxyapatite crystals • Osteoblasts are responsible for bone formation • Osteocytes (derived from osteoblasts) are completely surrounded by bone completely surrounded by bone • Osteoclasts are responsible for bone resorption 4 II Endocrine Regulation of Calcium II. Endocrine Regulation of Calcium and and Phosphate Homeostasis in Mammals Hormones involved in Ca homeostasis • Parathyroid hormone (PTH) secreted by the hormone (PTH) secreted by the parathyroid glands • Calcitonin (CT) secreted by parafollicular cells = C-cells in the thyroid • 1,25-dihydroxycholecalciferol (1,25-DHC) = calcitriol = derivative of vitamin D3 secreted by the combined activities of skin, liver & kidney • PTH & CT signal via GPCRs, calcitriol signals via a nuclear vitD receptor 5 Parathyroid glands and PTH • Embedded within the thyroid glands in some within the thyroid glands in some mammals including man and dogs • Separate glands located near the thyroid in other mammals including rat • Glands arise from pharyngeal endoderm but chief cells that produce PTH have a neuroectodermal origin • PTH is a 84 AA polypeptide • Hypercalcemic, increases plasma [Ca2+] 6 Regulation of PTH secretion 7 C-cells and CT • C-cells or parafollicular cells (origin neural or parafollicular cells (origin neural crest cells in ultimobranchial bodies) lay between the thyroid follicles in the thyroid gland • CT is a 32 AA peptide • Hypocalcemic, reduces plasma [Ca2+] reduces plasma [Ca colloid in lumen thyroid gland gland follicular cell capillary parafollicular cell blood vessel nerve 8 1,251,25-DHC = calcitriol • Derivative of vitamin D3, produced by of vitamin produced by combined action of skin, liver and kidney • Vitamin D3 is produced in the skin or taken up from the intestine • Essential role in Ca2+ absorption = calcitriol 9 III. Interactions of PTH, CT, and 1,251,25-DHC 10 Ca2+ and HPO42- regulation in bone • Minute-to-minute regulation of plasma Ca2+ and regulation of plasma Ca 2- levels: HPO4 osteocytic osteolysis caused by PTH • Major changes (growth, pregnancy, lactation): interaction of PTH, calcitriol, and CT on osteoclasts and osteoblasts osteoclasts and osteoblasts • CT mainly inhibits osteoclasts, PTH stimulates both osteoblasts and osteoclasts (depending on dose) Regulation of Ca2+ uptake in intestine • Calcitriol stimulates synthesis of calcium-binding stimulates synthesis of calcium proteins such as calbindin • Calbindin facilitates uptake of Ca2+ at the mucosal surface of epithelial cells • It binds Ca2+ intracellularly during the transport to the serosal border (protection) • At the serosal border Ca2+ is transported into the interstitial fluid and then diffuses into the blood capillaries • HPO42- follows passively 11 Ca2+ and HPO42- regulation in kidney • PTH increases HPO42- excretion and hence Ca2+ increases HPO and hence Ca reabsorption • PTH stimulates production of calcitriol in the kidney 12 13 Rachitis = rickets Other Other hormones and Ca homeostasis • Thyroid hormones & glucocorticoids influence hormones glucocorticoids influence mineral homeostasis • GH has indirect effects via IGFs • Estrogens and androgens have important stimulatory effects on osteoblast activity increased risk of osteoporosis in menopause risk of osteoporosis in menopause and andropause 14 15 ...
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