Got Calcium? Ca 2+

Plasma Calcium Regulation Plasma calcium totals 2.4 mM (9.4 mg/dl) –Free calcium is 1.2 mM

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 Plasma Calcium Regulation

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 re- absorption 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

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 Gland –Regulates calcitonin secretion Calcium Signal Transduction in Parathyroid Gland 600 AA external domain 200 AA internal domain Phosphorylation sites

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 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) Other Effects of PTH

Hyperparathyroidism

Calcitonin Secreted by the thyroid gland Effects are much less than those of PTH

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 Effects of Calcitonin

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