Mineralization calcium transporter proteins

The mechanism of action of the vitamin D metabolites remains under active investigation. However, calcitriol is well established as the most potent agent with respect to stimulation of intestinal calcium and phosphate transport and bone resorption. Calcitriol appears to act on the intestine both by induction of new protein synthesis (eg, calcium-binding protein and TRPV6, an intestinal calcium channel) and by modulation of calcium flux across the brush border and basolateral membranes by a means that does not require new protein synthesis. The molecular action of calcitriol on bone has received less attention. However, like PTH, calcitriol can induce RANK ligand in osteoblasts and proteins such as osteocalcin, which may regulate the mineralization process. The metabolites 25(OH)D and 24,25(OH)2D are far less... 

The Isolated, vascularly perfused rat intestine system has been used to investigate the influence of various zinc-binding ligands on zinc absorption. With this approach the functional integrity of the intestine with respect to several minerals, including calcium, iron and zinc uptake, and subsequent transfer of these minerals to their respective serum transport proteins is maintained (32,33). The intestinal perfusion system allows the simultaneous measurement of both mucosal zinc uptake (retention) and transfer to the portal circulation (absorption), and thus provides detailed information on the nature of the mechanisms of both uptake from the lumen and transfer to albumin in the portal circulation. 

Vitamin D is a fat soluble vitamin related to cholesterol. In the skin, sunlight spontaneously oxidizes cholesterol to 7-dehydrocholesterol. 7-Dehydrocholesterol spontaneously isomerizes to cholecalciferol (vitamin D3), which is oxidized in the liver to 25-hydroxy cholecalciferol and, under the influence of PTH in the kidney, to 1,25-dihy-droxy cholecalciferol (calcitriol), the active form of vitamin D. Vitamin D induces the expression of calcium ion transport proteins (calbindins) in intestinal epithelium, osteoclasts, and osteoblasts. Calbindins and transient receptor potential channels (TRPV) are responsible for the uptake of calcium from the diet. In children, the absence of sunlight provokes a deficiency of vitamin D, causing an absence of calbindins and inadequate blood calcium levels. Osteoid tissue cannot calcify, causing skeletal deformities (rickets). In the elderly, there is a loss of intestinal TRPV receptors and decreased calbindin expression by vitamin D. In both cases, the resultant low blood calcium levels cause poor mineralization during bone remodeling (osteomalacia). Rickets is the childhood expression of osteomalacia. Osteoclast activity is normal but the bone does not properly mineralize. In osteoporosis, the bone is properly mineralized but osteoclasts are overly active. 

In summary, one might expect to find calcium-binding proteins playing six distinct roles in living systems 1. binding sites on the outer surface of plasma membranes, 2. transport carriers in cell membranes, 3. intracellular storage reservoirs of calcium, 4. intracellular receptors linked to calcium function (i.e., in contractile systems), 5. as part of matrix of mineralized tissues and, 6. as a co-factor in calcium-activated enzymes. 

In addition to its effects on bone and kidney cells, PTH affects the transport of calcium in the cells of the intestine and the lactating mammary gland. The hormone increases the absorption of calcium from the gut and its secretion in milk. Thus parathormone resembles vitamin D in regulating calcium transport in various kinds of cell. It too may act by regulating the biosynthesis of a specific protein, since actinomycin D prevents the action of PTH on osteoclasts which results in mobilization of bone mineral. Actinomycin D, however, does not affect the increased phosphate excretion by the kidney caused by PTH, so presumably a different mechanism is involved. 

This would extend our model of balanced HC1 transport for mineral dissolution, but additional studies are required to understand the integration of this model (Blair et al., 2002), Figure 2. There is a pervasive cytoskeletal-src dependence of proper targeting for the ion transporters of osteoclasts (Zuo et al., 2006 Tehrani et al., 2006 Abu-Amer et al., 1997 Soriano et al., 1991). The actin-directed disposition of CLIC protein has also been observed in microvilli of placental cells (Berryman et al., 2004). In osteoclasts the coordinated disposition of V-ATPase and CLIC required for full expression of the bone resorption phenotype (Edwards et al., 2006). It is clear that much of the osteoclasts organization exists to support the massive acid secretion for bone calcium solubilization. 

For instance, urea, the product of protein digestion from which the term urine is derived, must be removed. Other waste products of metabolism must be removed. Any toxins produced by bacteria must be removed. Any drug residue or other unusable material must be removed. Any excess hormone must be removed. Glucose, on the other hand, should not be eliminated and proteins should not be secreted. Vitamins need to be saved, as does calcium and a certain amount of sodium and other minerals. However, water must be regulated. Too much water in the blood would be bad because if blood were too dilute, then not enough nutrients would be transported to the cell. If blood had too little water, then the physical process of pumping the blood around would be... 

Mineralization is the precipitation of calcium phosphate, but biochemical mediation of this process is not fully understood. In this chapter, the chemistry underlying mineralization (Sect. 1) and the structures ofbones and teeth (Sect. 2) are described. Osteoblasts secrete osteoid matrix and matrix vesicles that transport type I collagen and calcium phosphate, respectively, to the matrix where they will mineralize. Secreted matrix vesicles take up calcium and phosphate until they burst and release the calcium phosphate, which then redissolves and remineralizes around the type I collagen (Sect. 3). Glycoproteins involved in correctly modeling bone and dentin, and the role of osteocalcin in limiting excessive bone growth is then discussed (Sect. 4). There follows a detailed description of enamel (E) mineralization and of the major proteins involved (Sect. 5) followed by two summaries the difference between enamel and bone mineralization, and the vitamins required for mineralization (Sect. 6). 

Figure 9.8 outlines how matrix vesicles increase and decrease the concentration of pyrophosphate. NTP-PPi hydrolase synthesizes pyrophosphate from stromal fluid nucleotides, mostly ATP (ATP —> AMP + PPi). Many cells secrete ATP into the extracellular fluid and it passes into the blood plasma where it affects a variety of cells independently of its function in intracellular energy metabolism. In mice, a nonfunctional ANK protein or a deletion of NTP-PPi hydrolase decreases the extracellular pyrophosphate concentration and the phenotype exhibits extensive mineralization. Thus, the hydrolysis of pyrophosphate appears to be a major function of alkaline phosphatase (TNAP) after the calcium phosphate precipitate has raptured the matrix vesicles. Rapid mineralization of collagen and the rest of the osteoid matrix ensue without a need to transport any more Ca2+ or Pi to the region. 

Phosphorus has more known functions in the animal body than any other mineral element. Together with calcium, phosphorus plays a major role in the formation of bones and teeth, as well as eggshells. It is a component of nucleic acids, which control cell multiplication, growth and differentiation. In combination with other elements, phosphorus has a role in the maintenance of cellular osmotic pressure and the acid-base balance. Energy transfer processes in all living cells involve interconversion of the phosphate-containing nucleotides, adenosine diphosphate (ADP) and ATP, and thus phosphorus participates in all biological events. Other roles include its presence in phospholipids, where it functions in cell-wall structure, fatty acid transport and protein as well as amino acid formation. 

Some elements, for example calcium and molybdenum, may interfere with the absorption, transport, function, storage or excretion of other elements. There are many ways in which minerals may interact, but the three major ways involve the formation of unabsorbable compounds, competition for metabolic pathways and the induction of metal-binding proteins. The interaction of minerals with each other is an important factor in animal nutrition, and an imbalance of mineral elements -as distinct from a simple deficiency - is important in the aetiology of certain nutritional disorders of farm animals. The use of radioactive isotopes in recent years has advanced our knowledge of mineral nutrition, although there are many nutritional diseases associated with minerals whose exact causes are still unknown. 

Minerals and Vitamins. Mineral absorption occurs throughout the small and laige intestines, with the rate of absorption depending on a number of factors—pH, carriers, diet composition, etc. Numerous mechanisms of mineral absorption have been elucidated. Many minerals, for example, iron and sodium, require active transport systems. Others, such as calcium, utilize both carrier proteins and diffusion mechanisms. Moreover, vitamin D is required for calcium absorption, and vitamins C and E favor the absorption of iron. 

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