Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.4.3 (phospholipase C)
18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1,25-dihydroxycholecalciferol (1,25(OH)2D3) rapidly affects calcium (Ca2+) transport in several cell systems, suggesting physiological actions independent of genomic activation. To test this hypothesis, we studied immediate to early effects (0.5-300 sec) of 1,25(OH)2D3 on cytosolic Ca2+ [Ca2+]i in single osteogenic sarcoma ROS 17/2.8 cells loaded with fura-2. An acute rise in [Ca2+]i was observed in 40% of the cells following addition of 1,25(OH)2D3, with a threshold concentration of 10(-11) M. In most cases, the [Ca2+]i rise was transient, with return to baseline within 1 min; less frequently a more prolonged effect was observed, with variable recovery times. 25-hydroxycholecalciferol (25(OH)D3) reproduced the effect of 1,25(OH)2D3 on [Ca2+]i, with equal potency and similar responses, whereas 24,25-dihydroxycholecalciferol, 1 alpha-hydroxycholecalciferol, and 22 oxa-1,25(OH)2D3 were not effective. 1,25(OH)2D3 also increased [Ca2+]i in ROS 24/1 cells, which are defective of receptors for the vitamin D metabolites. At high doses (10(-8)-10(-7) M) of 1,25(OH)2D3 the [Ca2+]i rise in ROS 17/2.8 cells was due to both influx of extracellular Ca2+ and release of Ca2+ from intracellular stores, as the effect was only partially inhibited by Ca2(+)-channel blockade by nifedipine. At low doses (10(-9)-10(-10) M), the effect was entirely dependent on extracellular Ca2+. 1,25(OH)2D3 also increased the production of inositol 1,4,5 trisphosphate (Ins(1, 4, 5)P3) and diacylglycerol, at a threshold dose of 10(-9) M, indicating activation of phospholipase C (PLC). In two thirds of the cells studied, a second addition of 1,25(OH)2D3 within 5 min to cells prestimulated with equimolar doses of the vitamin D metabolite resulted in a [Ca2+]i transient of higher amplitude than the first, a phenomenon occurring at all doses of the hormone, and associated with production of Ins(1, 4, 5)P3. This response amplification was not produced by 25(OH)D3, and pretreatment with 1 alpha(OH)D3 did not significantly enhance 1,25(OH)2D3-induced production of Ins(1, 4, 5)P3. In conclusion, activation of the Ca2+ message system by vitamin D metabolites is a rapid, nongenomic effect; 1,25(OH)2D3 specifically activates both PLC and dihydropyridine-sensitive Ca2+ channels, and "primes" the cells to respond with an enhanced [Ca2+]i rise to a subsequent homologous stimulation; the presence of both the 1 alpha and 25 hydroxyl groups is necessary to express the full hormonal action of vitamin D on [Ca2+]i.
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PMID:Nongenomic activation of the calcium message system by vitamin D metabolites in osteoblast-like cells. 222 14

In the submitted review the author pays attention to mechanisms of control of insulin secretion and the mutual interaction of other messengers (cAMP, calcium and inisitol triphosphate) with special attention to the calcium signal which plays a most important role in the stimulation of the excitable B cell. The trigger of the two-stage insulin secretion is cyclic accumulation of calcium in the cytosol of the B cell and the mutual harmony between calcium of the intra- and extracellular compartment. In the early stage of insulin secretion in particular the intracellular compartment is the source of calcium; from there the ion is released due to the action of inositol triphosphate (IP3) activated by phospholipase C. Calcium of the extracellular compartment is mobilized also in the early secretory stage by opening of the depolarization-dependent calcium channels, it plays, however, a more important part during the second stage. Activation of the other messengers, incl. the calcium signal, depends on the type of secretagogue stimulus. During systemic changes of calcium homeostasis in vivo the calcium signal of the B cell is activated or inhibited in different ways. In the course of hypercalcaemia, in particular if acute, the direct influence of calcium ions on insulin secretion is modulated by further factors, e.g. somatostatin, calcitonin, cholecystokinin, glucagon, adrenocortical hormones, opioids and other substances released into the blood stream. In chronic hypercalcaemia which is the result of primary hyperparathyroidism or vitamin D intoxication the action of calcium on the metabolic and hormonal response is enhanced by the ionophoretic action of parathormone or active vitamin D metabolites.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[The calcium signal in the regulation of insulin secretion]. 269 62

The steroid hormone 1,25(OH)2-vitamin D-3 [1,25(OH)2D3] stimulated phospholipase A2 (PLA2) activity in embryonic chick myoblasts releasing [3H]arachidonic acid from the sn-2 position of phospholipids. GTP-binding protein mediation of 1,25(OH)2D3-dependent PLA2 activity was investigated in cells prelabeled with [3H]arachidonic acid. AIF4-, a G-protein activator, mimicked 1,25(OH)2D3-stimulated arachidonic acid release from myoblasts in a dose-dependent manner. Consistent with the involvement of a G-protein in the activation of PLA2 by the hormone, guanosine 5'-O-(3-thiotriphosphate) (GTP gamma S), a stable GTP analogue which activates G-protein mediated signals, strongly enhanced arachidonic acid release in myoblasts. Guanosine 5'-O-(2-thiodiphosphate) (GDP beta S), which competitively inhibits G-protein activation by GTP and its analogues, abolished 1,25(OH)2D3-dependent arachidonic acid release. Bordetella pertussis toxin pretreatment significantly suppressed the hormone action whereas cholera toxin had minor effects on 1,25(OH)2D3 action. Hormone-induced activation of PLA2 was mimicked by the Ca2+ ionophore A23187 and blocked by nifedipine, but was unaffected by neomycin, a phospholipase C inhibitor, ruling out the contribution of phosphoinositide metabolism to arachidonic acid release. These results suggest that 1,25(OH)2D3-stimulation of PLA2 activity in embryonic chick myoblasts is mediated by a pertussis toxin-sensitive GTP-binding protein coupled to influx of extracellular calcium.
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PMID:1,25(OH)2-vitamin D-3 stimulates phospholipase A2 activity via a guanine nucleotide-binding protein in chick myoblasts. 764 3

Recent studies indicate that the vitamin D hormone, 1 alpha,25-dihydroxyvitamin D3 exerts rapid effects (seconds to minutes) in a variety of cell types. These rapid nongenomic actions in osteoblasts include effects on membrane voltage-gated calcium channels, phospholipase C activity, and the sodium/hydrogen antiport. Since the rapid effects occur in osteoblasts that lack the nuclear vitamin D receptor, it is postulated that the nongenomic responses to the hormone reflect interaction with a separate, membrane localized signalling system. Preliminary studies demonstrate the presence of a receptor on the membranes of osteoblasts that lack the nuclear vitamin D receptor. This membrane receptor recognizes 1 alpha,25-dihydroxyvitamin D3 and its inaction 1 beta epimer, but not 25-hydroxyvitamin D3. These rapid nongenomic actions generated by interaction with the membrane receptor modulate the effects of the hormone on gene transcription. Thus, the rapid nongenomic pathway may play a regulatory function in modulating the genomic pathways affected by 1 alpha,25-dihydroxyvitamin D3.
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PMID:Nongenomic actions of the steroid hormone 1 alpha,25-dihydroxyvitamin D3. 787 22

The steroid hormone 1 alpha,25-dihydroxyvitamin D3 has been shown to exert rapid effects (15 s to 5 min) in osteoblasts. These effects occur in osteoblast-like cells lacking the nuclear vitamin D receptor, ROS 24/1, suggesting that a separate signalling system mediates the rapid actions. These non-genomic actions include rapid activation of phospholipase C and opening of calcium channels, pointing to a membrane localization of this signalling system. Previous studies have shown that the 1 beta epimer of 1 alpha,25-dihydroxyvitamin D3 can block these rapid actions, indicating that the 1 beta epimer may bind to the receptor responsible for the rapid actions in a competitive manner. We have assessed the displacement of 3H-1 alpha,25-dihydroxyvitamin D3 by vitamin D compounds, as well as the apparent dissociation constant of 1 alpha,25-dihydroxyvitamin D3 and its 1 beta epimer for the membrane receptor in membrane preparations from ROS 24/1 cells. Increasing concentrations of 1 alpha,25-dihydroxyvitamin D3, 7.25 nM to 725 nM, displaced 3H-1 alpha,25-dihydroxyvitamin D3 from the membranes with 725 nM of the hormone displacing 40-49% of the radioactivity. Similarly, 1 beta,25-dihydroxyvitamin D3, 7.25 nM and 72.5 nM, displaced 1 alpha,25-dihydroxyvitamin D3 binding while 25-hydroxyvitamin D3, 72.5 nM and 725 nM, did not. The apparent dissociation constant (KD) for 1 alpha,25-dihydroxyvitamin D3 was determined from displacement of 3H-1 alpha,25-dihydroxyvitamin D3 yielding a value of 8.1 x 10(-7) M by Scatchard analysis. The KD for the 1 beta epimer determined from displacement of 3H-1 beta,25-dihydroxyvitamin D3 was 4.8 x 10(-7) M.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Binding characteristics of a membrane receptor that recognizes 1 alpha,25-dihydroxyvitamin D3 and its epimer, 1 beta,25-dihydroxyvitamin D3. 789 Aug 9

Vitamin D3 metabolites regulate the differentiation of chondrocytes isolated from the growth zone or resting zone of rat costochondral cartilage. Since some of the direct membrane effects of vitamin D metabolites are nongenomic, we hypothesized that protein kinase C (PKC) plays a role in signal transduction for these chondrocyte differentiation factors and that the regulation of PKC by the vitamin D metabolites is cell maturation dependent. Confluent, fourth passage cultures of growth zone and resting zone chondrocytes were treated with vitamin D3 metabolites for up to 24 h, lysed, and cell extracts assayed for kinase activity using a specific PKC substrate peptide. The addition of 1,25-(OH)2D3 to growth zone cell cultures resulted in a rapid dose-dependent stimulation of PKC, significant at 10(-9)-10(-7) M, beginning at 3 min and sustained until 90 min; 1,25-(OH)2D3 had no effect on PKC activity in resting zone chondrocyte cultures. The addition of 24,25-(OH)2D3 to resting zone cultures showed a slower PKC activation, with significant stimulation seen at 90-360 min for 10(-8)-10(-7) M 24,25-(OH)2D3. However, 24,25-(OH)2D3 had no effect on PKC activity in growth zone cell cultures at all times and concentrations examined. The specificity of PKC stimulation by the vitamin D3 metabolites was verified using a specific pseudosubstrate region peptide inhibitor, which reduced PKC activity when included in the reaction mixture. Pretreatment of the cultures with U73, 122, a phospholipase C inhibitor, decreased 1,25-(OH)2D3-stimulated PKC activity but had no effect upon 24,25-(OH)2D3-induced activity. The tyrosine kinase inhibitor, genistein, did not inhibit the PKC response in either vitamin D3 metabolites-treated culture. Neither actinomycin D nor cycloheximide affected 1,25-(OH)2D3-induced PKC activity in growth zone chondrocyte cultures, while both compounds inhibited 24,25-(OH)2D3-induced activity in resting zone chondrocyte cultures. The results of this study indicate that vitamin D metabolites stimulate PKC activity in a metabolite- and cell-maturation-specific manner. Effects of 1,25-(OH)2D3 appear to be nongenomic, whereas the effects of 24,25-(OH)2D3 probably involve a genomic mechanism.
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PMID:Maturation-dependent regulation of protein kinase C activity by vitamin D3 metabolites in chondrocyte cultures. 822 60

For the last 5 years, attention has focused on the nongenomic effects of 1,25-(OH)2D3, but considerably less is known about the mechanisms of the nonnuclear actions of 24,25-(OH)2D3. The present study examines and compares the rapid (5-90 s) effects of 100 pM to 10 nM 24,25-(OH)2D3, 10 pM to 1 nM 1,25-(OH)2D3, and 1-100 nM 25-OHD3 on the formation of inositol phosphates and lipids in confluent mouse osteoblasts. 24,25-(OH)2D3 and 25-OHD3 effects were dose dependent; those of 1,25-(OH)2D3 were dose dependent in a bell-shaped manner. The two dihydroxylated metabolites induced a multiphasic response in inositol 1,4,5-trisphosphate (IP3) formation with three stimulation peaks; the IP3 response to 25-OHD3 was monophasic. The amplitude of the IP3 response to 24,25-(OH)2D3 was greater and its oscillation period was slower than that induced by 1,25-(OH)2D3. The diacylglycerol (DAG) responses to secosteroids showed two stimulation peaks that appeared at different times depending on the secosteroid used. Pretreatment with neomycin totally inhibited the first DAG response; neomycin had no effect on the second peak of DAG induced by 25-OHD3, whereas it partially blocked the second response of DAG to 24,25-(OH)2D3 and 1,25-(OH)2D3. These data show for the first time that 24,25-(OH)2D3 can modulate phospholipid metabolism in confluent mouse osteoblasts as early as 5-10 s. The first pathway used by all three secosteroids is that of the hydrolysis of phosphatidylinositol 4,5-bisphosphate via phospholipase C activation, leading to the formation of the two second messengers, IP3 and DAG, since neomycin totally blocked the response. Thus, the action of these secosteroids on the osteoblast membrane may also implicate several steps of the phosphatidylcholine cycle, according to the metabolite tested. Finally, these data point to a direct interaction of vitamin D metabolites with specific membrane recognition moieties.
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PMID:Oscillations in inositol 1,4,5-trisphosphate and diacyglycerol induced by vitamin D3 metabolites in confluent mouse osteoblasts. 823 75

The role of the vitamin D-induced calcium binding protein termed calbindin-D (CaBP) in the biological response to 1,25-dihydroxyvitamin D3 was assessed by photoaffinity labeling techniques. The heterobifunctional cross-linking reagent methyl-4-azidobenzoimidate was employed for studies with the 28 KD chick intestinal calbindin-D28K. Calcium-dependent interactions were evident with purified chick intestinal CaBP-immunoglobulins and bovine intestinal alkaline phosphatase; in the absence of Ca2+ there was a greatly diminished crosslinking process. There were also at least two membrane components of chick intestinal brush border membranes, with M(R) = 60,000 and 130,000, which were photoaffinity cross-linked with CaBP in a calcium-dependent manner. Similar interactions were demonstrated following incubations of CaBP with phosphatidylinositol-specific phospholipase C (PI-PLC)-treated supernatant fractions from chick intestinal brush borders. PI-PLC was shown to release 14% of the alkaline phosphatase from chick intestinal brush borders compared to greater than 80% for rabbit and chick kidney BBM preparations. Specific interactions between CaBP and brush border membrane proteins could also be demonstrated in the absence of photoaffinity labeling by Sephadex G-150 chromatography of Triton X-100 solubilized incubations between calbindin-D28K and chick intestinal BBMS, with 17% of the radiolabelled CaBP comigrating with alkaline phosphatase activity. These studies collectively demonstrate that calbindin-D28K undergoes calcium-dependent conformational changes which alter its subsequent interactions with cellular proteins in a way consistent with other calcium-binding proteins such as calmodulin or troponin C.
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PMID:Evidence for calcium mediated conformational changes in calbindin-D28K (the vitamin D-induced calcium binding protein) interactions with chick intestinal brush border membrane alkaline phosphatase as studied via photoaffinity labeling techniques. 836 39

We have previously established an uremic rat model which is suitable for investigating the effect of various treatment modalities on the progression of renal osteodystrophy [1]. Four months subsequent to 5/6 nephrectomy, animals were treated three times a week for 3 months with either vehicle, 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], 1,25(OH)2D3 + 24,25-dihydroxyvitamin D3 [24,25(OH)2D3], 1,25(OH)2D3 + calcitonin (CT), or 1,25(OH)2D3 + 24,25(OH)2D3 + CT. At termination of the study, clinical chemistry, chemical composition, and mechanical properties of femurs, calvarial parathyroid hormone (PTH)-elicited adenylate cyclase (AC), and phospholipase C (PL-C) activities, femoral cross-sectional area, and bone histomorphometry were analyzed. The main findings were that 1,25(OH)2D3 +/- 24,25(OH)2D3 treatment enhanced elasticity as well as time to fracture at the femoral metaphysis. CT potentiated the increase in elasticity obtained by 1,25(OH)2D3 +/- 24,25(OH)2D3 treatment. Only 24,25(OH)2D3 administration rectified the supernormal PTH-stimulated uremic bone AC, and only 1,25(OH)2D3 medication normalized the diminished CT-elicited AC. The obliterated uremic bone PTH-sensitive PL-C was fully normalized by all drug regimens. Femoral shaft inner zone diameter was enhanced by uremia, however, all drug treatments normalized it. Ditto effect was registered with either drug treatment on the subnormal outer and inner zone widths. Histomorphometrical analyses showed that 1,25(OH)2D3 administration reduced both eroded and osteoid surfaces. Most prominently, adjuvant 24,25(OH)2D3 or CT administration potentiated the beneficial effect of 1,25(OH)2D3 on fibrosis and osteomalacia. We assert that vitamin D3 treatment markedly reverses the development of renal osteodystrophy, and CT potentiates the effect of vitamin D3.
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PMID:Vitamin D3 analogs and salmon calcitonin partially reverse the development of renal osteodystrophy in rats. 856 2

Changes in the extracellular calcium concentration [Ca2+]o modulate several aspects of renal function through unknown mechanism(s). cDNA encoding a Ca2+o-sensing receptor from bovine parathyroid and rat kidney that appears to mediate several of the known effects of Ca2+o on parathyroid and renal function were recently isolated. The expressed receptor activates phospholipase C, showing a pharmacologic profile very similar to that of the native receptor. Its deduced amino acid sequence identifies it as a member of the superfamily of G protein-coupled receptors. The physiologic relevance of the receptor has been established by the demonstration that mutations in it cause three inherited diseases of calcium metabolism. Two hypercalcemic disorders, familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism, result from inactivating mutations when present in the heterozygous and homozygous states, respectively. An activating mutation, in contrast, causes an autosomal dominant form of hypocalcemia. In the kidney, the receptor is expressed most abundantly in the thick ascending limb, where it likely modulates sodium chloride, calcium, and magnesium reabsorption and, perhaps, urinary concentrating ability. Studies are currently underway to determine whether it also mediates the effects of Ca2+o on other parameters of kidney function, such as RBF, glomerular filtration, renin secretion, and vitamin D metabolism. Thus, this Ca2+o-sensing receptor permits extracellular calcium ions to act not only as an intracellular second messenger but also in a "hormone-like" role as an extracellular first messenger.
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PMID:A cloned Ca(2+)-sensing receptor: a mediator of direct effects of extracellular Ca2+ on renal function? 874 77


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