Transcript Lecture 23
Got Calcium? Ca2+ Plasma Calcium Regulation • Plasma calcium totals 2.4 mM (9.4 mg/dl) – Free calcium is 1.2 mM Plasma Calcium Regulation • Free calcium is tightly regulated (5%) – Too low = neuronal hyper-excitability – Too high = neuronal depression • Control points for calcium – Absorption – Via intestines – Excretion – Via urine – Temporary storage – Via bones Active Control of Calcium • Vitamin D3 – Diet and sun • Parathyroid hormone – Parathyroid gland • Calcitonin – Thyroid gland • Skeletal loading – Osteoblasts and osteoclasts Vitamin D3 and Calcium Control • Vitamin D3 (Cholecalciferol) – Converted to precursor in liver • Initially stored • Converted to 25-Hydroxycholecalciferol • Feedback control limits concentration – Converted to active form in kidney • 1,25-Dihydroxycholecalciferol • Under the feedback control of parathyroid hormone (PTH) Effects of Active Form of Vit D3 • Promotes intestinal absorption of calcium • Causes synthesis of calcium-binding protein and related facilitated transport • Takes a couple of days to fully develop response • Has slight effect to increase calcium reabsorption in kidneys • Works with PTH to cause calcium absorption from bone Parathyroid Hormone • Secreted by parathyroid glands – Rapid response to reduced calcium (minutes) • Polypeptide – 84 amino acid residues – 9,500 daltons M.W. • Peptide fragments can be active for periods measured in hours • Operates in tissues via cAMP second messenger Parathyroid Hormone Calcium Signal Transduction in Parathyroid Gland 600 AA external domain • G-Protein Coupled Receptor • Activates Phospholipase C – Leads to increased Diacylglycerol (DG) and Inositol trisphosphate (IP3) as secondary messengers – Inhibits adenylate cyclase to reduce cAMP • Present in C cells of Thyroid Phosphorylation Gland sites 200 AA internal domain – Regulates calcitonin secretion Effects of PTH • Increases calcium absorption from bone – Existing osteocytes stimulated (minutes to hours) to transport calcium – calcium pumps – Existing osteoclasts activated and new osteoclasts formed (days to weeks) to digest bone and release calcium • Stimulated indirectly by osteoblasts Other Effects of PTH • Decreases excretion of calcium by kidneys – Important to prevent bone deterioration • Increases calcium absorption – Effect manifested via Vitamin D3 • Produces most active form of D3 in the kidney (1,25-dihydroxy-cholecalciferol) Hyperparathyroidism Calcitonin • Secreted by the thyroid gland • Effects are much less than those of PTH Effects of Calcitonin • Attenuates absorptive ability of osteoclasts • Inhibits formation of new osteoclasts – Osteoclast decrease causes osteoblast decrease – Effect to decrease calcium is transitory – Causes reduced bone turnover • Has weak effect in kidney and intestines Non-Hormonal Control of Plasma Calcium • Changes in calcium intake can be rapidly accommodated – Buffer capacity of amorphous calcium in bone – Calcium is sequestered in intracellular spaces – Can help restore plasma calcium in tens of minutes