Stimulation of Intestinal Calcium and Phosphate Absorption

Early studies showed that, after the administration of [3H]cholecalciferol or ergocalciferol to vitamin D-deficient animals, there is marked accumulation of [3H]calcitriol in the nuclei of intestinal mucosal cells. Physiological doses of vitamin D cause an increase in the intestinal absorption of calcium in deficient animals; the response is faster alter the administration of calcidiol and faster still after calcitriol. There are two separate responses of intestinal mucosal cells to calcitriol: a rapid increase in calcium uptake that is due to recruitment of calcium transporters to the cell surface (Section 3.3.2) and a later response from the induction of a calcium binding protein, calbindin-D. Induction of Calbindin-D In response to calcitriol administration, there is an increase in mRNA synthesis and then in the synthesis of calbindin-D in intestinal mucosal cells, which is correlated with the later and more sustained increase in calcium absorption. In vitamin D-deficient animals, there is no detectable calbindin in the intestinal mucosa, whereas in animals adequately provided with vitamin D, it may account for 1% to 3% of soluble protein in the cytosol of the columnar epithelial cells. Although the rapid response to calcitriol is an increase in the permeability of the brush border membrane to calcium, the induction of calbindin permits intracellular accumulation and transport of calcium. The rapid increase in net calcium transport in tissue from vitamin D-replete animals is presumably dependent on the calbindin that is already present; in deficient animals, there can be no increase in calcium transport until sufficient calbindin has accumulated to permit intracellular accumulation, despite the increased permeability of the brush border.

Calbindin is a relatively small protein (the chick protein has an Mr of28,000, whereas those from mammalian intestinal mucosa have Mr between 8,000 to 11,000) and binds calcium with high affinity (Kd[ss 1 - 10 x 10-7 M). The mammalian intestinal protein (calbindin-D9k) has two calcium binding domains, whereas the chick protein (calbindin-D28k) has four. As well as being the intestinal calcium binding protein in birds, calbindin-D28k is also found in mammalian kidneys, liver, and pancreas. There is little sequence homology between calbindin-D9k and calbindin-D28k, despite the fact that there is considerable interspecies homology in calbindin-D28k. The calcium binding domain of calbindin-D is distinct from the lower affinity calcium binding domains of the y-carboxyglutamate-containing calcium binding proteins (Section 5.3) and is similar to that of other high-affinity calcium binding proteins, such as calmodulin, parvalbumin, troponin C, and brain S-100 protein, none of which is calcitriol dependent. It consists of an octahedral calcium binding region formed from a helix-loop-helix structure; the loop region has side-chain oxygen atoms that chelate calcium. Other metal ions are also bound, with lower affinity: cadmium > strontium > manganese > zinc > barium > cobalt > magnesium.

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