Maintaining Calcium Homeostasis

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. 

Phospholamban (PLB or PLN) is a single-pass, 52-residue integral membrane protein that regulates myocardial contractility by direct physical interaction with sarco(endo)plasmic reticulum Ca-ATPase (SERCA), a 110-kDa enzyme that maintains calcium homeostasis in the sarcoplasmic... 

Vitamin Dj, through its active metabolite, 1,25-(0H)2D3, also plays an important role in maintaining calcium homeostasis by enhancing intestinal calcium absorption, PTH-induced mobilization of calcium from bone, and calcium reabsorption in the kidney. 

The physiological role of vitamin D is to maintain calcium homeostasis. Phosphate metabolism is also affected. Vitamin D accomplishes its role by enhancing the absorption of calcium and phosphate from tte small intestines, promoting their mobilization from bone, and decreasing their excretion by the kidney. Also involved are parathyroid hormone and edeitonin. 

Vitamin D is responsible for maintaining calcium homeostasis. Low calcium concentrations lead to hyperparathyroidism and bone resorption. Vitamin D insufficiency (11 to 20 ng/mL) and deficiency (<10 ng/mL) [25(OH) vitamin D measurement, 10 ng/mL = 25 mcmol/L] is becoming more commonly recognized in all age groups, ° especially malnourished individuals, northerners, women wearing veiled dresses, African-Americans, seniors, and long-term care residents. Low vitamin D concentrations resnlt from insufficient intake, decreased sun exposure, decreased skin production, decreased liver and renal metabolism, and winter residence in northern climates. 

Premature infants develop rachitic lesions more readily than term infants. An oral dose of vitamin D as small as 100 International units per day has prevented the development of rickets in term infants and active rickets has been cured with 300 Int. units per day. The recent observations indicating that parathyroid hormone is the trophic hormone necessary for the manufacture of the metabolically active form of vitamin D thereby maintaining calcium homeostasis would suggest that this vitamin should be employed relatively early during total parenteral alimentation in the infant. 

Figure 7 Photoproduction and sources of vitamin D. Vitamin D is metabolized in the liver to 25-hydroxyvitamin D [25(OH)D], which is responsible for maintaining calcium homeostasis. 25(OH)D is also converted to 1,25(OH>2 D in a variety of other cells and tissues for the purpose of regulating cell growth, immune function, as well as a variety of other physiologic processes that are important for the prevention of many chronic diseases. MS, multiple sclerosis RA, rheumatoid arthritis. (Copyright Michael F Holick (2004) Vitamin D Importance in the prevention of cancers, type 1 diabetes, heart disease, and osteoporosis. American Journal of Clinical Nutrition 79 362-371, used with permission.)...

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. 

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). 

The GP made a provisional diagnosis of osteomalacia and prescribed vitamin D supplements. Vitamin D measurements are not performed routinely, but the assumption is that a low result would have been obtained on the blood sample. Most of the vitamin D necessary to maintain normal calcium homeostasis is derived from endogenous synthesis by reactions in the skin (which require UV radiation from sunlight), liver and kidney. The cultural habits of Mrs Al-Ameri required her to dress in a burqah and niqab whenever she left the home, meaning that very little of her skin was exposed to daylight. 

It plays an important role in calcium metabolism. It regulates calcium homeostasis and maintains normal levels of plasma calcium and phosphate. 

When calcium homeostasis cannot be maintained, the resulting hypocalcemia can have serious consequences (SEDA-18, 388) (207,208). This so-called glucocorticoid hyperparathyroidism was the explanation traditionally most prominently advanced for glucocorticoid osteoporosis, but it is not the only one and may not be the most central. Other biochemical effects include ... 

Fundamentally, calcium homeostasis is a result of coordinated transportation of Ca2+ ions through several sets of membranes, which delineate distinct cellular compartments these compartments maintain very different Ca2+ concentrations, and have a specific role in both physiological and pathological Ca2+ signalling (Petersen et al., 1994 Berridge et al., 2003 Carafoli 2004 Verkhratsky 2005). 

There is a delicate balance between cellular membrane permeability and intracellular calcium homeostasis during CVB3 infection. It has been well-documented that sustained elevation of calcium levels in the cytosol precedes Cyt c release from the mitochondria, and that the small amount of released Cyt c interacts with the inositol triphosphate receptor (IP3R) on the endoplasmic reticulum (ER) and prevents inhibition of ER calcium release. The overall increase of calcium leads to a massive release of Cyt c to maintain ER calcium release through interaction with the IP3Rs in a positive feedback loop, and to activate downstream caspases to execute apoptosis of damaged cells. 

The mitochondrial Ca2+ pool plays a second role in cellular Ca2+ homeostasis by serving as a sink for Ca2+ during times of excessive Ca2+ uptake by the cell. Under this circumstance, the non-ionic calcium pool in the matrix space can increase 10-fold or more, thereby protecting the cell from Ca2+ intoxication. This mechanism provides a temporary device by which the cell can protect itself, but in the long term only by regulating Ca2+ fluxes across the plasma membrane can the cell maintain Ca2+ homeostasis [14]. 

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