Homeostasis calcium

Increased levels of cytosolic calcium could potentiate ischaemia-reperfusion injury in several ways. For example, conversion of xanthine dehydrogenase to xanthine oxidase may be catalysed by a calcium-dependent protease (McCord, 1985). However, because it has been so difficult to demonstrate the presence of xanthine 

Phosphorus homeostasis (see Section 5.2.1) is intimately involved with that of calcium. The most important reservoir of calcium and phosphorus within the mammalian body is in bone—85% of the body s calcium and 85-90% of phosphorus is found there. Ninety-nine percent of bone calcium remains in the mineral phase as Ca3(P04)2, and so on, but the other 1% can rapidly exchange with extracellular calcium. 

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Factors controlling calcium homeostasis are calcitonin, parathyroid hormone(PTH), and a vitamin D metabolite. Calcitonin, a polypeptide of 32 amino acid residues, mol wt - SGOO, is synthesized by the thyroid gland. Release is stimulated by small increases in blood Ca " concentration. The sites of action of calcitonin are the bones and kidneys. Calcitonin increases bone calcification, thereby inhibiting resorption. In the kidney, it inhibits Ca " reabsorption and increases Ca " excretion in urine. Calcitonin operates via a cyclic adenosine monophosphate (cAMP) mechanism. 

Stimulation of the neuron lea ding to electrical activation of the nerve terminal in a physiologically relevant manner should eUcit a calcium-dependent release of the neurotransmitter. Although release is dependent on extracellular calcium, intracellular calcium homeostasis may also modulate the process. Neurotransmitter release that is independent of extracellular calcium is usually artifactual, or in some cases may represent release from a non-neuronal sources such as gha (3). 

Vitamin D [1406-12-2] is a material that is formed ia the skin of animals upon kradiation by sunlight and serves as a precursor for metaboUtes that control the animal s calcium homeostasis and act ki other hormonal functions. A deficiency of vitamin D can cause rickets, as weU as other disease states. This tendency can be a problem wherever animals, including humans, especially kifants and children, receive an kiadequate amount of sunshine. The latter phenomenon became prevalent with the advent of the kidustrial revolution, and efforts to cute rickets resulted ki the development of commercial sources of vitamin D for supplementation of the diet of Hvestock, pets, and humans. 

The discovery that vitamin D metaboUtes play a much larger biochemical role than just maintaining calcium homeostasis has stimulated a number of groups around the world to develop more economical chemical syntheses for the vitamin D metaboUtes and analogues, which might be useful ki studykig and treating D -related diseases and conditions. Many of these methods are reviewed ki References 139 and 140. 

Although it is being found that vitamin D metaboUtes play a role ia many different biological functions, metaboHsm primarily occurs to maintain the calcium homeostasis of the body. When calcium semm levels fall below the normal range, 1 a,25-dihydroxy-vitainin is made when calcium levels are at or above this level, 24,25-dihydroxycholecalciferol is made, and 1 a-hydroxylase activity is discontiaued. The calcium homeostasis mechanism iavolves a hypocalcemic stimulus, which iaduces the secretion of parathyroid hormone. This causes phosphate diuresis ia the kidney, which stimulates the 1 a-hydroxylase activity and causes the hydroxylation of 25-hydroxy-vitamin D to 1 a,25-dihydroxycholecalciferol. Parathyroid hormone and 1,25-dihydroxycholecalciferol act at the bone site cooperatively to stimulate calcium mobilization from the bone (see Hormones). Calcium blood levels are also iafluenced by the effects of the metaboUte on intestinal absorption and renal resorption. 

Calcium plays a vital role ia excitation—contraction coupling, and failure to maintain iatraceUular calcium homeostasis results ia ceU death. The avaUabUity of the calcium antagonists also provides a powerful tool for basic studies of excitation—contraction coupling, stimulus—excretion coupling, and other specific physiological functions. 

PTH is the most important regulator of bone remodelling and calcium homeostasis. PTH is an 84-amino acid polypeptide and is secreted by the parathyroid glands in response to reductions in blood levels of ionised calcium. The primary physiological effect of PTH is to increase serum calcium. To this aim, PTH acts on the kidney to decrease urine calcium, increase mine phosphate, and increase the conversion of 25-OH-vitamin D to l,25-(OH)2-vitamin D. PTH acts on bone acutely to increase bone resorption and thus release skeletal calcium into the circulation. However, due to the coupling of bone resorption and bone formation, the longer-term effect of increased PTH secretion is to increase both bone resorption and bone formation. 

The steroid hormone 1,25-dihydroxy vitamin D3 (calcitriol) slowly increases both intestinal calcium absorption and bone resorption, and is also stimulated through low calcium levels. In contrast, calcitonin rapidly inhibits osteoclast activity and thus decreases serum calcium levels. Calcitonin is secreted by the clear cells of the thyroid and inhibits osteoclast activity by increasing the intracellular cyclic AMP content via binding to a specific cell surface receptor, thus causing a contraction of the resorbing cell membrane. The biological relevance of calcitonin in human calcium homeostasis is not well established. 

A peptide hormone rapidly inhibiting osteoclast activity. The relevance of calcitonin in human calcium homeostasis is not well understood. Calcitonin has been used for the treatment of osteoporosis, although due to the availability of more potent drugs with less side effects, and the lack of clear data on the anti-fracture efficacy of calcitonin, its clinical use has been steadily declining. 

In addition to its classical role as regulator of calcium homeostasis, 1,25-dihydroxy vitamin D3 (calcitriol) displays immunosuppressive properties. Inhibition of T-lymphocyte proliferation seems to be mediated via regulation of CD80/86 costimulatory molecule expression on APCs. For clinical use as immunosuppressant, however, analogues of vitamin D3 that do not influence calcium metabolism are needed. 

A major regulator of bone metabolism and calcium homeostasis, parathyroid hormone (PTH) is stimulated through a decrease in plasma ionised calcium and increases plasma calcium by activating osteoclasts. PTH also increases renal tubular calcium re-absorption as well as intestinal calcium absorption. Synthetic PTH (1-34) has been successfully used for the treatment of osteoporosis, where it leads to substantial increases in bone density and a 60-70% reduction in vertebral fractures. 

There is evidence for immunosuppressive effects of PAHs in rodents (Davila et al. 1997). For example, strong immunosuppressive effects were reported in mice that had been dosed with benzo[fl]pyrene and 3-methyl cholanthrene, effects that persisted for up to 18 months (Environmental Health Criteria 202). Multiple immu-notoxic effects have been reported in rodents, and there is evidence that these result from disturbance of calcium homeostasis (Davila et al. 1997). PAHs can activate protein tyrosine kinases in T cells that initiate the activation of a form of phospholipase C. Consequently, release of inositol triphosphate—a molecule that immobilizes Ca + from storage pools in the endoplasmic reticulum—is enhanced. 

In addition to its role in regulating calcium homeostasis, vitamin D is required for the intestinal absorption of calcium. Synthesis of the intracellular calciumbinding protein, calbindin, required for calcium absorption, is induced by vitamin D, which also affects the permeability of the mucosal cells to calcium, an effect that is rapid and independent of protein synthesis. 

Vitamin D Metabolism Both Regulates Is Regulated by Calcium Homeostasis... 

The main function of vitamin D is in the control of calcium homeostasis, and in mrn vitamin D metabolism is... 

Ubogu EE, Cossoy MB, Ransohoff RM (2006) The expression and function of chemokines involved in CNS inflammation. Trends Pharmacol Sci 27 48-55 Verkhratsky A, Orkand RK, Kettenmann H (1998) GUal calcium homeostasis and signaling function. Physiol Rev 78 99-141... 

Bonavia R, Bajetto A, Barbero S, Albini A, Noonan DM, Schettini G (2001) HlV-1 Tat causes apoptotic death and calcium homeostasis alterations in rat neurons. Biochem Biophys Res Commun 288 301-308... 

Na/K Pump Activity and its Role in Cellular Calcium Homeostasis... 

The sarcolemmal Na/K pump plays an imp>ortant, although indirect role in the regulation of cellular calcium homeostasis. The transmembrane Na gradient is maintained by the activity of the Na/K pump and the thermodynamic energy of this gradient in turn drives the Na/Ca exchange mechanism (Sheu and Fozzard, 1982 Barry and Bridge, 1993). Thus, the intracellular Ca concentration is closely related to intracellular Na and the activity of the Na/K pump (Bers and Ellis, 1982). 

Barry, W.H. and Bridge, J.H.B. (1993). Intracellular calcium homeostasis in cardiac myocytes. Circulation 87, 1806-1815. 

Tirmenstein, M.A. and Nelson, S.D. (1989). Subcellular binding and effects on calcium homeostasis produced by acetaminophen and a nonhepatotoxic regioisomer, 3 -hydroxyacetanilide, in mouse liver. J. Biol. Chem. 264, 9814-9819. 

McArdle, A., Edwards, R.H.T. and Jackson, M.J. (1993). Calcium homeostasis during contractile activity of vitamin E deficient skeletal muscle. Proc. Nutr. Soc. 52, 83A. 

Organic peroxides such as cumene hydroperoxide and t-butyl hydroperoxide have extensively been used as experimental agents. They provoke lipid peroxidation in hepatocytes, probably by the generation of alkoxyl and peroxyl radical intermediates after reaction with cytochrome P450. Other cytotoxic mechanisms are probably involved including protein thiol and non-protein thiol oxidation and deranged calcium homeostasis (Jewell et al., 1986). In fact, the addition of cumene hydroperoxide to isolated bUe duct cells, devoid of cytochrome P450 activity, still results in cell death but lipid peroxidation is not detectable (Parola et al., 1990). 

The above studies have generated a huge body of invaluable data concerning the effects of oxidative stress on cells. In particular the importance of GSH in cell protection and the role of disturbed calcium homeostasis in cell killing have been greatly illuminated. 

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