Calbindin, calcium transport

Turnbull Cl, Looi K, Mangum JE, Meyer M, Sayer RJ, Hubbard MJ. 2004. Calbindin independence of calcium transport in developing teeth contradicts the calcium ferry dogma. J Biol Chem. 279 55850 1. 

The circulating levels of l,25(OH)2D3 rise progressively towards the end of pregnancy, probably in response to the increased mineral demands. At the same time, an extra-renal synthesis of l,25(OH)2D3 takes place in the fetoplacental unit [4,47,48]. This synthesis is thought to occur in the decidual cells rather than in the placenta itself, although some controversy still remains upon the exact location of this process. Placental tissues have also been shown to contain specific receptors for l,25(OH)2D3 [49] as well as the faculty to synthesize the small calbindin (9 kDa) [50], However, the transplacental calcium transport is independent of the overall maternal vitamin D status [51]. The hypothesis of a differential regulation of calcium transport within the feto/placental unit may be in relation with the in situ synthesis of l,25(OH)2D3 or the fetal synthesis of this hormone. 

Calcium is absorbed in the intestine by two distinct mechanisms, an active process that is vitamin D dependent and another that is vitamin D independent. When the dietary intake of calcium is low, the intestinal uptake of calcium occurs by an active transport process that is vitamin D dependent. Active transport is most efficient in the duodenum and proximal jejunum, areas of the intestine that have a pH close to 6.0 and where calbindin, a calcium transport protein, is present. However, the amount of calcium absorbed in the ileum may be greater than that absorbed in the duodenum and jejunum... 

Both the active and passive modes of calcium transport are increased during pregnancy and lactation. This is probably due to the increase in calbindin and serum PTH and 1,25-dihydroxyvitamin D concentrations that occur during normal pregnancy. Intestinal calcium absorption is also dependent on age, with a 0.2% per year decline in absorption efficiency starting in midlife. The fractional absorption of calcium depends on the form and dietary source. Absorption rates are 29% for the calcium in cow s milk, 35% for calcium citrate, 27% for calcium carbonate, and 25% for tricalcium phosphate. Other factors that limit the bioavailability of calcium in the intestine are oxalates and phy-tates, which are found in high quantities in vegetarian diets and which chelate calcium. 

With the isolated perfused duodenum, there is a rapid increase in calcium transport in response to the addition of calcitriol to the perfusion medium. Isolated enterocytes and osteoblasts also show a rapid increase in calcium uptake in response to calcitriol. It is not associated with changes in mRNA or protein synthesis, but seems to be because of recruitment of membrane calcium transport proteins from intracellular vesicles to the cell surface. It is inhibited by the antimicrotubule compound colchicine. It can only be demonstrated in tissues from animals that are adequately supplied with vitamin D in vitamin D-deficient animals, the increase in intestinal calcium absorption occurs only more slowly, together with the induction of calbindin. 

Early studies showed that, after the administration of [ H]cholecalciferol or ergocalciferol to vitamin D-deficient animals, there is marked accumulation of [ H] 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 after the administration of calcidiol and faster stUl 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 colunmar epithelial ceils. 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. 

X 10 cmthe fact that the concentration of the latter complex may be about 10 times higher than that of free Ca " " will result in an increased net calcium transport rate. Calbindin would, in fact, act very much like myoglobin in facilitating oxygen transport through muscle tissue. 

Calbindin D28 is multimeric membrane transporter protein involved in calcium transport in the kidney (Henuningsen, 2000). It is expressed and located exclusively in the renal... 

In the rat, the dorsal tier includes cells of the dorsal parts of the VTA and SNc and cells of the RRA innervating the limbic portion of the striatum and limbic cortical fields, as well as the ventral basal forebrain structures, such as the olfactory tubercle and the amygdala. Neurons of the dorsal tier are mostly fusiform, with dendrites oriented horizontally in the mediolateral plane of the SNc. From the neurochemical point of view, neurons of the dorsal tier contain relatively low levels of TH mRNA and dopamine transporter (DAT) mRNA, and the calcium binding protein calbindin is colocalized with DA in most dorsal tier neurons (Gerfen, 1985) (Figs. 4D 13C,D). 

Although calcitriol is synthesized only in the proximal renal tubule, after the administration of pHJcalcidiol, radioactivity in the kidney accumulates only in the distal and collecting tubules. This is the region in which selective resorption of calcium from the urine occurs and, in response to calcitriol, there is induction of calbindin-D28k. As in the intestinal mucosa, calbindin in the kidney is a cytosolic protein and is presumably involved in the intracellular accumulation and transport of calcium. 

Nucleation of calcium phosphate precipitation within the matrix vesicles is mediated by phosphatidylserine, which comprises about 8% of the phospholipids of the inner cytosolic membrane surface (Fig. 9.5a). Calbindin in the vesicle (Fig. 9.5b) may also contribute. Rapid mineral growth within the vesicle keeps the concentration of dissolved calcium and inorganic phosphate ions so low that additional Ca2+ and Pi ions spontaneously enter from the extracellular fluid via their respective transporters. Attached type II and type X collagens from cartilage in the growth plate enhance calcium ion transport and calcification during endochondral ossification (Fig. 9.5b). 

Calcitriol behaves like a steroid hormone. It is transported to the nucleus of renal distal tubule cells, intestinal epithelial cells, osteoclasts, and osteoblasts where it induces calbindins, vitamin D-dependent calcium binding proteins. Calbindins mediate the intracellular movement of calcium, from diet to blood, from blood to osteoid matrix, or from bone to blood. There are two calbindin proteins, each encoded by separate genes, one of molecular weight about 9 kDa (calbindin-D. ) and one of molecular weight 28 kDa (calbindin-D28K). Each binds micromolar amounts of calcium and each disappears from animals that are... 

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. 

Candidate transmitters in AON and other olfactory cortical areas are summarized in Table 4. Aspartate has been proposed as a transmitter of AON neurons (mainly the dorsal and external divisions of AON) based on selective retrograde transport of H aspartate (Watanabe and Kawana, 1984 Fuller and Price, 1988). Fewer neurons in other subdivisions of AON contain aspartate, and no neurons in other known afferents to the bulb contain aspartate. There are a few met-enkephalin and somatostatinergic neurons in AON and some of these appear to project to the olfactory bulb (Davis et al. 1982). It appears that all neurons in AONpE contain the neuropeptide CRF (Shipley, in preparation). Besides the neurotransmitters/peptides discussed above, immunoreac-tive cells and fibers to calcium binding proteins have been described in AON. In this respect, calretinin immunoreactive fibers are found in the molecular layer of AON (Jacobowitz and Winsky, 1991), calbindin positive cells are found in all subdivisions of AON (Garcia-Ojeda et al. 1992 Celio, 1990) while parvalbumin positive cells are found in all subdivisions except for the medial one where the cells are quite sparse (Garcia-Ojeda et al. 1992 Celio, 1990). 

---