Discuss the regulation of extracellular calcium homeostasis in man.

Outline:

·        Role of calcium in body

·        Importance of calcium homeostasis

·        Key hormones:

- PTH: detects fall in plasma calcium

- cholecalciferol: negative feedback on PTH

- calcitonin: lower plasma calcium (not significant)

·        Regulatory mechanisms in kidneys, intestines and bone

Essay:

            The calcium ion is fundamentally important to all biological systems and it plays many regulatory roles in humans. Ca²⁺ is needed in blood coagulation, transmission of nervous impulses, muscle contraction and intracellular signal transduction. In both the extrinsic and intrinsic pathways of blood coagulation, Ca²⁺ is required in the activation of Factor X, formation of prothrombin activator and the conversion of prothrombin to thrombin. The coming of a nerve impulse opens Ca²⁺ channels; the influx of Ca²⁺ causes the exocytosis of neurotransmitters such as acetylcholine into the synapse. In muscle contraction, Ca²⁺ binds to troponin I and removes tropomyosin, revealing the actin binding sites for the myosin head to bind to, facilitating the completion of the power stroke. Ca²⁺ is an important second messenger by itself or it can be coupled with a protein calmodulin. The calcium-calmodulin complex activates myosin light chain kinase in smooth muscle contraction.

            As a result of its actions on many cellular mechanisms, the concentration of calcium is maintained within specific limits of physiological tolerance in several compartments. The resting intracellular cytosolic concentration of free Ca²⁺ is only 10^-7M.

Hypocalcemia increases neuronal permeability to Na⁺ and hence neuronal excitability. This results in seizures and muscle spasm. Hypercalcemia decreases neuronal excitability and leads to muscle weakness, but its more prominent effect is in the formation of renal stones that cause urinary tract infection.

            Plasma Ca²⁺ is approximately 2.5 mmol/L of which 45% is free Ca²⁺, 50% is protein bound and 5% is complexed with citrate, oxalate etc. Daily dietary intake of calcium is about 1000 mg and they are absorbed in the intestines by active transport. Large amounts of Ca²⁺ is filtered at the kidneys; 98 to 99% of it is reabsorbed, 60% at the proximal tubules and the rest at the distal tubules. Most of the Ca²⁺ is stored in the bone, 99% of it in a slow turnover pool involved in the bone remodeling via the processes of bone formation and resorption. About 1% of Ca²⁺ in bone is found in the bone canalicular fluid where it serves as a readily exchangeable pool to defend any perturbations in plasma Ca²⁺.

Parathyroid hormone (PTH) is the primary regulator of plasma Ca²⁺ levels. Hypocalcemia (a plasma Ca²⁺ levels of below 1.3 mmol/L) stimulates PTH secretion. The paramount effect of PTH is to increase plasma calcium levels by stimulation of bone resorption, renal tubular calcium reabsorption, and cholecalciferol synthesis, thereby preventing any drastic drop in plasma Ca²⁺ to the extent of affecting normal body function. At the same time, PTH decreases plasma phosphate concentration by inhibition of renal phosphate reabsorption.

            PTH receptors are present in both osteoblasts and osteoclasts. The overall effect of PTH on bone is to stimulate bone resorption and enhances the release of calcium (and phosphate) into the extracellular fluid (ECF). There are two phases of PTH action: a rapid and a late phase. During the rapid phase, PTH stimulates osteolysis by transferring calcium from the bone canalicular fluid into the osteocyte and hence out of the opposite side of the ECF. It increases the activity of the calcium pump, facilitating the outflow of Ca²⁺ from the bone and inhibits synthesis of collagen by osteoblasts, thus suppressing bone formation. During the late phase of PTH action, PTH stimulates the osteoclasts to resorb completely mineralized bone, releasing both calcium and phosphate into the ECF. The organic bone matrix is hydrolyzed by increased activity of collagenase and lysosomal enzymes. PTH also stimulates in acid phosphatase and carbonic anhydrase activity which increase formation of lactic and citric acid – the resultant decrease in pH contributes to the absorptive process.

            In the kidneys, PTH increases the reabsorption of calcium from the ascending loop of Henle and the distal tubule via the production of cAMP as a second messenger. PTH inhibits the reabsorption of phosphate in the proximal tubule and thereby increase urinary phosphate excretion, allowing deposition of the extra phosphate released by PTH-stimulated bone resorption without which dangerous precipitation of calcium-phosphate complexes might occur. PTH also inhibits the reabsorption of sodium and bicarbonate in the proximal tubule which prevents the occurrence of metabolic alkaosis due to the release of bicarbonate during the dissolution of hydroxyapatite crystals in bone. An important action of PTH is to stimulate the synthesis of cholecalciferol by inducing the key enzyme 1a-hydroxylase.

            Hypocalcemia, PTH itself and hypophosphatemia as a result of PTH action all act to stimulate the production of cholecalciferol. The increase in cholecalciferol stimulates calcium absorption in the intestines by increasing the number of calcium pumps in the apical membrane and the inducing the synthesis of calcium carriers called calbindins to ferry calcium across the intestinal cell. Cholecalciferol binds to receptors in osteoblasts, generating a paracrine signal that increases the recruitment, differentiation and fusion of precursors into active osteoclasts, thereby stimulating bone resorption and increasing the flux of calcium into the ECF.

            The combined actions of PTH and cholecalciferol increase plasma Ca²⁺ levels back to normal, which suppresses PTH secretion. This is augmented by the inhibitory effect of cholecalciferol on PTH synthesis.

            While the secretion of PTH and cholecalciferol are increased in response to a falling plasma Ca²⁺, the hormone calcitonin is released from the parafollicular C cells in the thyroid in response to increased Ca²⁺ levels. Calcitonin acts on the bone to decrease Ca²⁺ permeability of the osteoclasts and osteoblsts, inhibiting osteoclastic activity and decreasing osteolytic activity of osteocytes and osteoclasts. It decreases intestinal absorption of calcium and phosphate, increase renal excretion of calcium and phosphate and inhibits 1a-hydroxylase activity. The end result of all these actions is to decrease plasma Ca²⁺ levels back to normal. However, excessive or deficient secretion of calcitonin has no discernible abnormalities and therefore its role in calcium homeostasis is not well established.