Physiology of Calcium Metabolism

Nicolaysen, R; Eeg-Larsen, N; Malm, Ole J.

doi:10.1152/physrev.1953.33.3.424

Cited by 297 publications

(56 citation statements)

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“…In view of the strong evidence that 1,25-(OH)2D3 is the metabolically active form of vitamin D in the intestine (9)(10)(11), and that its concentration is regulated by the dietary calcium concentration, we suggest that 1,25-(OH)2D3 is the "endogenous factor" of Nicolaysen et al (22). The presence of 1,25-(OH)2D3 is obviously vitamin D-dependent and even slight hypocalcemia stimulates its synthesis.…”

Section: Deluca Manuscript In Preparation)mentioning

confidence: 73%

Regulation by Calcium of In Vivo Synthesis of 1,25-Dihydroxycholecalciferol and 21,25-Dihydroxycholecalciferol

Boyle

Gray

DeLuca

1971

Proc. Natl. Acad. Sci. U.S.A.

426

113

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A metabolite of vitamin D believed to be the metabolically active form in the intestine has recently been isolated in pure form from intestine and unequivocally identified in this laboratory as 1,25-dihydroxycholecalciferol (1,25-(OH)2D3)(1, 2). Simultaneously, Lawson et al. provided evidence for this structure with a partially purified material from kidney homogenates (3). This metabolite acts more rapidly than 25-(OH)D3 to initiate intestinal calcium transport (4-6). The kidney is the site of synthesis of 1,25-(OH)2D3 from 25-(OH)D3 (7); this observation was confirmed by Gray et al. (8). Other experiments have provided strong evidence that 1,25-(0H2)D3 is the metabolically active form of vitamin D in the intestine (9-11). It, therefore, seemed possible that the concentration of 1,25-(OH)2D3 in the serum and intestinal mucosa plays an important role in the adaptation of calcium absorption to the concentration of calcium in the diet (12).This report demonstrates that dietary calcium concentration has a profound effect on the in vivo production of 1,25-(OH)2D3 and 21,25-(OH)2D3. Furthermore, these alterations in metabolite balance correlate with changes in serum calcium, but not serum phosphate concentration. An independent study has also shown that dietary strontium has an equally marked effect on the production of 1, 325 pmoles of tritiated 25-(OH)D3 was administered intrajugularly in 0.05 ml of 95% ethanol with mild ether anethesia. The rats were fasted at this time, but water continued to be available ad libitum. 12 hr later the rats were killed by decapitation and blood serum was collected. The upper 50 cm of small intestine was quickly removed, flushed with ice-cold saline, slit open, and the mucosa was scraped off with a glass slide. The kidneys and livers were removed. The fore-and hind-limbs were stripped of muscle, the long bones were split, and the marrow was discarded. All tissues were stored at -16'C until they were extracted with chloroform and methanol (14). In early experiments, the tissue from 3 to 4 animals fed the same diet was combined before extraction, while in later experiments the serum calcium concentrations of the rats were analyzed for similarity before pooling of tissues. In other cases, the tissues from each animal were analyzed individually.Radioactive metabolites were separated on a 2 X 15 cm column containing 10 g of Sephadex LH-20 equilibrated with 35% Skellysolve B (petroleum ether, b.p. 67-680C) in 65% chloroform (15). The tissue extracts were applied to the column in 1 ml of the same solvent mixture and eluted with a further 190 ml. Recovery of radioactivity from the columns varied from 90 to 105%.The elution position of 1,25-(OH)2D3 on this column has been established (2, 8). The less-polar metabolite was identified as 21,25-(OH)2D3 by cochromatography. A sample of the 2131

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Section: Deluca Manuscript In Preparation)mentioning

confidence: 73%

Regulation by Calcium of In Vivo Synthesis of 1,25-Dihydroxycholecalciferol and 21,25-Dihydroxycholecalciferol

Boyle

Gray

DeLuca

1971

Proc. Natl. Acad. Sci. U.S.A.

426

113

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“…The effects of valinomycin and carbonyl cyanide p-trifluoromethoxyphenylhydrazone on Ca2+ uptake (Table 2) were consistent with the observed effects of the above anions, conditions that enhanced intravesicular negativity stimulated uptake. Since the uptake values obtained in the presence of the ionophores and anion gradients differed significantly from the respective control values even after 90min of incubation at 250C, and EGTA in the stop and wash solution would be expected to remove Ca2+ that was reversibly bound to the outer membrane surface, the (Nicolaysen et al, 1953), for the active transport of Ca2+ by gut sacs in vitro (Schachter & Rosen, 1959;Dowdle et al, 1960) and for Ca2+ uptake by isolated cells in vitro (Freund & Bronner, 1975).…”

Section: Discussionmentioning

confidence: 97%

Calcium uptake in isolated brush-border vesicles from rat small intestine

Miller¹,

Bronner²

1981

Biochemical Journal

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Ca2+ uptake in brush-border vesicles isolated from rat duodena was studied by a rapid-filtration technique. Ca2+ uptake showed saturation kinetics, was dependent on the pH and ionic strength of the medium and was independent of metabolic energy. Uptake activity was readily inhibited by Ruthenium Red, La3+, tetracaine, EGTA, choline chloride and Na+ or K+. The effect of variations in medium osmolarity on Ca2+ uptake and the ionophore A23 187-induced efflux of the cation from preloaded vesicles indicated that the Ca2+-uptake process involved binding to membrane components, as well as transport into an osmotically active space. Scatchard-plot analyses of the binding data suggested at least two classes of Ca2+-binding sites. The high-affinity sites, Ka = (2.7 + 1.1) x 104M-1 (mean + S.D.) bound 3.2 + 0.8 nmol of Ca2+/mg of protein, whereas the low-affinity sites (Ka = 60 ± 6 mF1) bound 1 10 + 17 nmol of Ca2+/mg of protein. In the presence of l10mM-NaCl, 1.7 and 53nmol of Ca2+/mg of protein were bound to the high-and low-affinity sites respectively. Decreased Ca2+-uptake activity was observed in vesicles isolated from vitamin D-deficient as compared with vitamin D-replete animals and intraperitoneal administration of 1,25-dihydroxycholecalciferol to vitamin D-deficient rats 16h before membrane isolation stimulated the initial rate of Ca2+ uptake significantly. The data indicated that Ca2+ entry and/or binding was passive and may involve a carrier-mediated Ca2+-uptake component that is associated with the brush-border membrane. Altering the electrochemical potential difference across the membrane by using anions of various permeability and selected ionophores appeared to increase primarily binding to the membrane rather than transport into the intravesicular space. Since there is considerable binding of Ca2+ to the vesicle interior, a comprehensive analysis of the transport remains difficult at present.

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“…With the discovery of the vitamin D endocrine system came the understanding that this process was directly stimulated by the hormonal form of vitamin D, 1␣,25-dihydroxyvitamin D 3 (1,25-(OH) 2 D 3 ) (4). Because this hormonal form of vitamin D is regulated in response to the need for calcium, it became clear that the endogenous factor discovered by Nicolaysen and Egg-Larsen is the vitamin D endocrine system producing the final vitamin D hormone, 1,25-(OH) 2 D 3 (4,5). There is still debate whether vitamin D further influences the diffusional component of calcium absorption, taking place at high intestinal levels of calcium (6,7).…”

Section: Microarrays ͉ Trpv6 Ko Mice ͉ Vitamin D ͉ Vitamin D Mechanismentioning

confidence: 99%

TRPV6 is not required for 1α,25-dihydroxyvitamin D ₃ -induced intestinal calcium absorption in vivo

Kutuzova

Sundersingh

Vaughan

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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The requirement for TRPV6 for vitamin D-dependent intestinal calcium absorption in vivo has been examined by using vitamin D-deficient TRPV6 null mice and littermate wild-type mice. Each of the vitamin D-deficient animals received each day for 4 days 50 ng of 1,25-dihydroyvitamin D 3 in 0.1 ml of 95% propylene glycol:5% ethanol vehicle or vehicle only. Both the wild-type and TRPV6 null mice responded equally well to 1,25-dihydroxyvitamin D 3 in increasing intestinal calcium absorption. These results, along with our microarray data, demonstrate that TRPV6 is not required for vitamin D-induced intestinal calcium absorption and may not carry out a significant role in this process. These and previous results using calbindin D9k null mutant mice illustrate that molecular events in the intestinal calcium absorption process in response to the active form of vitamin D remain to be defined.A primary function of vitamin D is to markedly increase intestinal absorption of calcium and phosphate (1). During the 1950s, this absorption was shown to be primarily an active calcium transport process and an independent active phosphate transport process (2, 3). With the discovery of the vitamin D endocrine system came the understanding that this process was directly stimulated by the hormonal form of vitamin D, 1␣,25-dihydroxyvitamin D 3 (1,25-(OH) 2 D 3 ) (4). Because this hormonal form of vitamin D is regulated in response to the need for calcium, it became clear that the endogenous factor discovered by Nicolaysen and Egg-Larsen is the vitamin D endocrine system producing the final vitamin D hormone, 1,25-(OH) 2 D 3 (4, 5). There is still debate whether vitamin D further influences the diffusional component of calcium absorption, taking place at high intestinal levels of calcium (6, 7).The molecular mechanism underlying active calcium transport in response to vitamin D began unraveling with the discovery of calbindin D 9k by Wasserman and colleagues (8). Schachter and colleagues (9) also found a transporter responsive to vitamin D. Others have reported that vitamin D stimulates the basal lateral membrane calcium ATPase believed to be a calcium transporter (10, 11). These components have been put together in a diagrammatic fashion to present the current hypothesis of how 1,25-(OH) 2 D 3 stimulates active intestinal calcium absorption. TRPV6 is a calcium channel protein clearly induced by 1,25-(OH) 2 D 3 (12). Calcium entering through this channel is believed to associate with calbindin D 9k , which serves as a shuttle for calcium, presenting it to the basal lateral membrane calcium ATPase. This step provides the energy input for the transfer of calcium against a concentration gradient. All three of these genes are clearly under the influence of the active form of vitamin D (13). Unfortunately not all evidence is currently in support of this hypothesis. Transgenic mice in which calbindin D 9k has been eliminated have shown that calbindin D 9k is not required for 1,25-(OH) 2 D 3 -stimulated intestinal calcium absorption (14, 15). Fo...

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Physiology of Calcium Metabolism

Cited by 297 publications

References 0 publications

Regulation by Calcium of In Vivo Synthesis of 1,25-Dihydroxycholecalciferol and 21,25-Dihydroxycholecalciferol

Regulation by Calcium of In Vivo Synthesis of 1,25-Dihydroxycholecalciferol and 21,25-Dihydroxycholecalciferol

Calcium uptake in isolated brush-border vesicles from rat small intestine

TRPV6 is not required for 1α,25-dihydroxyvitamin D ₃ -induced intestinal calcium absorption in vivo

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Physiology of Calcium Metabolism

Cited by 297 publications

References 0 publications

Regulation by Calcium of In Vivo Synthesis of 1,25-Dihydroxycholecalciferol and 21,25-Dihydroxycholecalciferol

Regulation by Calcium of In Vivo Synthesis of 1,25-Dihydroxycholecalciferol and 21,25-Dihydroxycholecalciferol

Calcium uptake in isolated brush-border vesicles from rat small intestine

TRPV6 is not required for 1α,25-dihydroxyvitamin D 3 -induced intestinal calcium absorption in vivo

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TRPV6 is not required for 1α,25-dihydroxyvitamin D ₃ -induced intestinal calcium absorption in vivo