Got Calcium? Ca2+

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 externaldomain

200 AA internaldomain

Phosphorylationsites

• 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