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Twenty-four lactating cows were fed a normal-calcium (.75% of dry matter) diet plus free-choice dicalcium phosphate supplement for 8 wk, a low-calcium (.25% of dry matter) diet for 9 wk, and a low-calcium (.25% of dry matter) diet plus free-choice supplement for 4 wk. The low-calcium diet did not appear to affect adversely feed intake, milk production, or plasma ions. Depression of plasma calcium by sequestration with a chelating agent was less following low intake of calcium than following adequate calcium intake. Presumably, lower calcium intake increased parathyroid hormone which resulted in a larger and more responsive calcium pool immediately mobilizable. Changes in plasma phosphorus and magnesium were similar among treatments. Low calcium intake for short times apparently will not affect intake or production and may increase resistance to calcium stress such as hypocalcemia and parturient paresis.
The total membrane fraction of a chick embryo fibroblast (CEF) homogenate accumulates calcium in an energy-dependent manner. This activity can be dissociated into azide-sensitive and azide-insensitive components. The azide-sensitive component of calcium uptake is believed to represent mitochondrial calcium uptake. The azide-insensitive component of calcium uptake is enhanced by the presence of a calcium trapping agent such as oxalate, and cannot utilize, ADP, inorganic phosphate and a Krebs cycle substrate to support uptake. The distribution of the azide-insensitive calcium uptake in subcellular fractions suggests that this uptake occurs in other than mitochondrial membranes. The membranes most likely to contribute to the azide-insensitive component of calcium uptake are the endoplasmic reticulum and plasma membrane. A microsomal preparation from CEF cells is essentially devoid of the azide-sensitive calcium uptake activity. This microsomal activity is similar in characteristics to the sarcoplasmic reticulum of skeletal muscle. However the specific activity of CEF microsomal calcium uptake system is much less than that found in the skeletal muscle system. The transport of calcium by these membranes provide a mechanism for the regulation of cytosol calcium levels and may play a role in the control of movement and growth of cultured cells.
Mitochondrial and heavy microsomal fractions were isolated from rat hearts perfused for different intervals with Ca2+-free medium, as well as from hearts reperfused with control medium after perfusion with Ca2+-free medium. Contractile failure due to intracellular calcium deficiency produced by perfusing the isolated rat hearts with Ca2+-free medium resulted in a marked decline of calcium binding and uptake activities of the mitochondrial fraction without any effect on the microsomal fraction. On the other hand, inability of the rat hearts to recover their contractile force due to intracellular calcium overload produced by reperfusion for 10 min with control medium after 5-20 min of perfusion with Ca2+-free medium was associated with decreased microsomal calcium-binding and uptake activities and increased mitochondrial calcium-binding and uptake activities. When the hearts perfused with Ca2+-free medium in the presence of low sodium (35 mM) for 5 min were reperfused with control medium, the contractile force recovered completely, and appreciable augmentation in mitochondrial calcium transport or depression in microsomal calcium transport as seen in conditions of intracellular calcium overload did not occur. These results suggest dramatic alterations in calcium-transporting properties of mitochondria and sarcoplasmic reticulum in hearts failing due to intracellular calcium deficiency and calcium overload, respectively.
This study was designed to investigate the roles of bone and kidney in the acute regulation of plasma calcium by parathyroid hormone (PTH) during prolonged calcium deprivation. The effect of PTH was assessed by gland ablation. Animals were thyroparathyroidectomized or sham-operated and their urine was collected for 3 h. Subsequently they were anaesthetized and bled from the abdominal aorta. In rats fed on a low calcium diet, urinary hydroxyproline excretion was enhanced and, unlike animals fed on a normal diet, decreased 3 h after thyroparathyroidectomy (TPTX). In addition TPTX decreased plasma calcium by 0-45 mg/100 ml in normal rats compared with 1-94 mg/100 ml in animals fed on a calcium-deficient diet. Urinary calcium increased by 161 and 12 mug and accounted for 82 and 1-4 % of the fall in plasma calcium in normal and calcium-deprived animals respectively. The corresponding contributions of bone were 18 and 98-6%. These findings support the view that with prolonged calcium deprivation in adult rats, the relative contributions of bone and kidney to the acute regulation of the plasma calcium level by PTH are reversed. As a result, bone rather than kidney becomes the more important organ. At the same time non-PTH-mediated kidney reabsorption of calcium is increased.
We studied 25 borderline-hyperparathyroidism patients whose total serum calcium concentration was within normal limits (reference range: 2.25--2.75 mmol/liter) but whose concentrations of serum ionized calcium were above normal (reference range: 1.03--1.23 mmol/liter). Their hyperparathyroidism was histopathologically verified. To compare the discriminating value of corrected serum calcium with ionized calcium, we studied the serum calcium and albumin concentrations in a reference group of 2098 patients. After patients from endocrine and dialysis departments were excluded from the reference group, we obtained the range (mean +/- 2 SD) 2.05--2.71 mmol/liter for uncorrected serum calcium and 2.11--2.63 mmol/liter for corrected serum calcium. The correction factor for calcium on albumin was 20 mumol/g. Even with this limit for corrected serum calcium, 13 of 25 borderline hyperparathyroidism patients had values that fell within the reference range. We conclude that correcting total serum calcium values for serum albumin concentration improves discrimination of borderline hyperparathyroid patients, but that measurement of ionized calcium in serum discriminates better.
To study the reported decline in intestinal calcium absorption with age, calcium active transport, immunoreactive calcium protein (CaBP) content, and alkaline phosphatase activity were measured in the intestine of two strains of rats aged 3-wk--20 mo. Calcium active transport, as measured by everted gut sacs from Sprague-Dawley rats, was greatest at 3 wk, but it declined rapidly with no active transport demonstrable at 3 mo or thereafter. CaBP content closely paralleled the decline in active transport, but alkaline phosphatase activity increased as active transport decreased. Intestinal adaptation to dietary calcium was studied by feeding high- and low-calcium diets to Fischer 344 rats aged 1.5--12 mo. In 1.5-mo-old rats fed a low-calcium diet, there was an increase in calcium active transport, CaBP content, and alkaline phosphatase activity relative to animals fed a high-calcium diet. However, the magnitude of this intestinal adaptation decreased with age until there was only marginal adaptation by 12 mo. The observed changes in calcium active transport with age and diet may be explained by the parallel changes in the vitamin D-dependent CaBP content of the intestine.
Marked lowering of plasma ionized calcium concentrations [Ca++] occurred in eight patients (2 days to 54 years old) who required extensive pharmacologic support of the circulation. [Ca++]'s ranged from 0.21 to 0.53 mM. Only one patient survived. The hypocalcemia occurred in the absence of massive transfusion of citrated whole blood or well after such transfusions had been discontinued. These abnormally low concentrations of ionized calcium were not readily corrected by intravenous administration of calcium salts in doses generally recommended. The process responsible for inadequate hemodynamic function appeared to be associated with a severe disturbance in calcium metabolism. Contribution of the latter to the severity of hemodynamic deterioration is unclear, and little benefit from intravenous calcium therapy was found. In two patients, normal [Ca++] could not be restored by administration of CaCl2 alone, but [Ca++] rose to normal following continued calcium replacement therapy in conjunction with increased isoproterenol infusion. There was no predictable relationship between total and ionized plasma calcium concentrations. Thus, measurement of total calcium provided no indication of the level of the biologically active moiety. [Ca++] was low with both normal and low plasma pH values. The data suggest that a very high infusion rate of CaCl2 may required to restore [Ca++] to normal and that hypocalcemia occurring during low-flow states often cannot be corrected by calcium therapy alone. It is recommended that calcium replacement therapy be undertaken only with close monitoring of [Ca++].
Oral calcium carbonate (0-5 g, pH 9-4) increased serum gastrin and gastric acid output with slight but insignificant change in serum calcium. A similar rise in serum calcium during an intravenous infusion of calcium gluconate failed to increase serum gastrin and gastric acid output. Both intragastric calcium actions were abolished by acidification of the calcium carbonate solution (pH 1-0). The increase in serum gastrin and gastric acid output after intragastric calcium carbonate was not affected, however, by a simultaneous intraduodenal acid load. Equivalent neutralising doses of magnesium hydroxide (pH 9-4) did not increase serum gastrin and gastric acid output above basal levels, whereas antral acidification with 20 ml 0-1 N HCl resulted in a slight decrease in serum gastrin. Intraduodenal calcium carbonate (pH 3-0) also increased serum gastrin and gastric acid output, whereas an equivalent volume of intraduodenal saline (pH 3-0) had no effect. These findings indicate that calcium increases serum gastrin by local stimulation of antral and duodenal mucosa. They also suggest that the action of calcium on gastric secretion is partly mediated by gastrin.
Intestinal 47Ca absorption was determined from blood and stool radioactivity after oral administration of 150 ml saline containing the isotope (as 47CaCl2) and 500 mg of elementary calcium in the form of one of three commercial calcium preparations from "NAF" or "Collett" (containing calcium carbonate) or from "Sandoz" (containing mainly calcium lactogluconate). 51CrEDTA was used as unabsorbable marker to allow corrections for incomplete faecal collection. The calcium carbonate preparations were only partially dissolved when administered, but the calcium absorption from these preparations was found to be no less than that from the completely soluble calcium "Sandoz" preparation. The calculated minimal absorption of calcium was, on an average, about 100 mg from all three calcium preparations in subjects without known intestinal calcium absorption defects.
1. A study has been made of the calcium movements in isolated acinar cells of rabbit pancreas in relation to the process of enzyme secretion. 2. After 90 min, the 45Ca2+ uptake level of the acinar cells reaches a steady state level which depends on the extracellular calcium concentration: it increases with increasing calcium concentration. 3. Carbachol, in addition to stimulating enzyme secretion, causes a decrease in the 45Ca2+ content of pre-loaded acinar cells. This decrease is virtually independent of the extracellular calcium concentration. It is followed by an uptake of 45Ca2+ which only in a medium with 2.5 mM Ca2+ leads to a significantly higher 45Ca2+ level than the steady state level. 4. Carbachol, added to acinar cells not preloaded with 45Ca2+, increases the 45Ca2+ uptake in medium with 2.5 mM and in that with 0.1 mM Ca2+. 5. The amount of enzyme released by carbachol depends on the extracellular calcium concentration: it is larger in media with higher calcium concentration. 6. It is concluded that the increase in cytoplasmic calcium concentration which takes place immediately upon addition of a stimulus and which is necessary for the stimulation of the enzyme secretion, is caused by a release of calcium from an intracellular pool and not by an influx of calcium from the extracellular medium. 7. The results suggest that there are at least three different calcium pools in the pancreatic acinar cells.
1. The rapid stimulation of intestinal Ca(2+) transport observed in vitamin D-deficient chicks after receiving 1,25-dihydroxycholecalciferol has necessitated a re-evaluation of the correlation hitherto observed between this stimulation and the induction of calcium-binding protein synthesis. By 1h after a dose of 125ng of 1,25-dihydroxycholecalciferol, Ca(2+) transport is increased. This is at least 2h before calcium-binding protein can be detected immunologically and 1h before synthesis of the protein begins on polyribosomes, and thus the hormone stimulates Ca(2+) transport before calcium-binding-protein biosynthesis is induced. 2. The maximum increase in Ca(2+) transport observed after this dose of 1,25-dihydroxycholecalciferol (attained by 8h) is similar to that observed after 1.25-25mug of cholecalciferol, but the stimulation is only short-lived, in contrast with the effect observed after the vitamin. At later times after the hormone, however, when Ca(2+) transport has declined to its basal rate, the cellular content of calcium-binding protein remains elevated. 3. Calcium-binding protein is synthesized on free rather than membrane-bound polyribosomes, which implies that it is an intracellular protein. 4. Rachitic chicks require the presence of dietary calcium for maximum stimulation of calcium-binding protein production by cholecalciferol. 5. These results suggest that calcium-binding protein is an intracellular protein, and that its synthesis may be a consequence of the raised intracellular calcium content of the intestinal epithelial cells resulting from 1,25-dihydroxycholecalciferol-stimulated Ca(2+) transport. We propose that calcium-binding-protein synthesis is necessary for maintaining the stimulated rate of Ca(2+) transport, which is initiated by other factors.
The response of hyperparathyroidism and skeletal calcium loss in haemodialysis patients to treatment with 1alpha-hydroxyvitamin D3 and a dialysate calcium concentration of 1.375 mmol/l was compared with the response to treatment with a dialysate calcium concentration of 1.375 or 1.75 mmol/l alone over a 6 month period. In patients treated with 1alpha-hydroxyvitamin D3 there was a significant rise in plasma calcium associated with a significant fall in plasma alkaline phosphatase and plasma parathyroid hormone as well as resolution of sub-periosteal erosions. In these patients there was a significant rise in the calcium content of the forearm assessed by neutron activation analysis in comparison to patients treated with a dialysate calcium concentration of 1.75 or 1.375 mmol/l alone. In patients treated with a dialysate calcium concentration of 1.375 or 1.75 mmol/l alone there was no significant change in the plasma calcium, alkaline phosphatase or parathyroid hormone after 6 months and in these patients subperiosteal erosions either did not change or became worse. No significant difference in the response in these two groups was observed. This study indicates that treatment of haemodialysis patients with 1alpha-hydroxyvitamin D3 is significantly more effective than treatment with a dialysate calcium concentration of 1.375 or 1.75 mmol/l alone in preventing progression of hyperparathyroidism and skeletal calcium loss.
Proteins' flexibility is a feature in communicating changes in cell signaling instigated by binding with secondary messengers, such as calcium ions, associated with the coordination of muscle contraction, neurotransmitter release, and gene expression. When binding with the disordered parts of a protein, calcium ions must balance their charge states with the shape of calcium-binding proteins and their versatile pool of partners depending on the circumstances they transmit. Accurately determining the ionic charges of those ions is essential for understanding their role in such processes. However, it is unclear whether the limited experimental data available can be effectively used to train models to accurately predict the charges of calcium-binding protein variants. Here, we developed a chemistry-informed, machine-learning algorithm that implements a game theoretic approach to explain the output of a machine-learning model without the prerequisite of an excessively large database for high-performance prediction of atomic charges. We used the ab initio electronic structure data representing calcium ions and the structures of the disordered segments of calcium-binding peptides with surrounding water molecules to train several explainable models. Network theory was used to extract the topological features of atomic interactions in the structurally complex data dictated by the coordination chemistry of a calcium ion, a potent indicator of its charge state in protein. Our design created a computational tool of CaXML, which provided a framework of explainable machine learning model to annotate ionic charges of calcium ions in calcium-binding proteins in response to the chemical changes in an environment. Our framework will provide new insights into protein design for engineering functionality based on the limited size of scientific data in a genome space.
1. The dependence of reproductive activity in the laying hen upon adequate calcium intake has been investigated. 2. The response of plasma luteinising hormone concentration in calcium-deficient, as compared with calcium-replete hens, to injections of luteinising hormone releasing hormone and progesterone suggested that the primary site of reproductive dysfunction is the hypothalamus rather than the pituitary gland. 3. Laying hens, when presented with a calcium-deficient diet, ceased to lay as the plasma ionised calcium concentration decreased to less than 1.0 mM, supporting the view that there is a threshold of blood calcium activity below which reproductive activity ceases. 4. Supplementation of the diet with calcium produced an immediate restoration of plasma ionised calcium concentration to normal, despite an interval of a few days before the plasma total calcium returned to normal and egg laying resumed.
Dependence of large intestinal calcium transport on vitamin D has been examined in vitro in colon only. The authors studied calcium fluxes in cecum and colon in vivo by perfusion with 1.6 mM calcium chloride in saline. Tracer 45Ca either was injected parenterally 24 hr before study or was added to the perfusates. For 8--10 wk after weaning, rats had been fed a rachitogenic diet; 48 and 24 hr before study, 50% of the animals were treated with 20,000 IU vitamin E2. In a separate set of animals, mucosal calcium binding protein was analyzed by the Chelex assay method. In comparison with vitamin D-deficient rats, the colon of vitamin D-treated rats showed higher lumen-to-plasma flux and lower plasma-to-lumen flux and net absorption instead of net secretion. In cecum, calcium transport was not significantly altered by vitamin D treatment. Mucosal calcium binding protein was higher in cecum than in colon in both groups and was higher in vitamin-D-treated than in vitamin D-deficient animals in both segments. The current study shows that in the rat colon calcium fluxes both into and out of the lumen as well as net transport are significantly by vitamin D treatment, but that cecal transport rates are not affected. In both cecum and colon, mucosal calcium binding protein increases with vitamin D treatment.
Sections of neurosecretory cells fixed in glutaraldehyde and osmium tetroxide were studied by means of an EMMA-4 analytical microscope. Secretory granules in neurosecretory cells of the corpus cardiacum and of the brain, both in the desert locust Schistocerca and in the blowfly Calliphora, as well as neurosecretory granules in posterior pituitaries of the frog Rana and of the albino rat all contain a high concentration of calcium. A distinct sulphur peak was also a constant feature. In neurosecretory cells of the corpus cardiacum of Schistocerca the chromatin contained a high concentration of calcium. The mitochondria also contained much calcium, but part of this disappeared during preparation except when fixative and wash contained calcium chloride. By block staining with uranyl acetate most calcium is displaced from the mitochondria, whereas most of the calcium remains in the neurosecretory granules. Since the calcium peaks in spectra from neurosecretory granules appear of similar size, regardless of variations in the preparative procedure, this calcium must be firmly bound. The possible role of the calcium bound to the neurosecretory substance is discussed. The presence of sulphur in insect neurosecretory granules indicated the presence of a protein besides the hormone, i.e., an insect neurophysin.