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:3.6.1.3 (ATPase)
65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of OST-766, an inhibitor of vacuolar H+-ATPase activity, on adenylyl cyclase and phospholipase C activity were explored in the osteoblast cell line ROS 17/2.8. In fresh homogenates of ROS 17/2.8 cells, OST-766 inhibited adenylyl cyclase activity (ACA) in response to guanine nucleotide and forskolin but had no effect on basal ACA. OST-766 enhanced the basal generation of IP2, but not that formed in response to Ca2+ or guanine nucleotides. In marked contrast, incubation of intact ROS 17/2.8 cells with OST-766 for at least 48 hours resulted in an increase in basal ACA as well as in response to PTH, guanine nucleotides and forskolin. Under similar conditions, the compound also increased IP1, IP2 and IP3 generation in response to guanine nucleotides and Ca2+. Levels of the guanine nucleotide binding proteins Gs and Gi were also increased in OST-766-treated cells. The results suggest that the actions of this H+-ATPase inhibitor include effects on osteoblasts through PTH-sensitive signal transduction pathways.
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PMID:Influence of antiresorptive agent OST-766 on signal transduction pathways involved in parathyroid hormone action. 991 23

Calbindin-D28k is an intracellular protein with high affinity for calcium. In the kidney, this protein is exclusively localized in the distal tubule and in the proximal part of the collecting ducts. Functionally, calbindin-D28k is supposed to be involved in the regulation of the reabsorption of calcium and possibly magnesium in the distal nephron though the exact regulatory mechanisms are not yet known. Thus, several theories regarding the functional role of calbindin-D28k have been proposed: The carrier theory describes calbindin-D28k as a transport protein which binds calcium and then transports it from the luminal to the basolateralcell membrane. The buffer theory assumes that calbindin-D28k functions by binding calcium ions to prevent intracellular calcium concentrations from reaching toxic levels. The activator theory describes that calbindin-D28k increases the activity of calcium channels or the enzymatic activity of the Ca++-Mg++-ATPase in the luminal membrane and thereby increases the tubular reabsorption of calcium. The renal calbindin-D28k is dependent upon vitamin D. Pharmacological doses of the active vitamin D metabolite 1,25-(OH)2D increases the concentrations of renal calbindin-D28k, whereas the concentration of calbindin-D28k is low in conditions with reduced levels of circulating 1,25-(OH)2D. Likewise, plasma calcium concentrations, uremia and hypertension affect calbindin-D28k expression. However, several studies have rendered probable the effect of additional factors in the regulation of renal calbindin-D28k. The aim of the present dissertation therefore was to examine the regulation of renal calbindin-D28k in a series of physiological and pathophysiological conditions established in vivo in the rat. A possible correlation between hypertension and calbindin-D28k was examined in three models of experimental hypertension: the genetically defined spontaneous hypertensive rat, the salt-sensitive Dahl rat and the renovascular hypertensive rat. These three models clearly demonstrated three separate patterns in the calcium metabolism, but the studies were unable to support a role for calbindin-D28k in the development of hypertension. In all three models the development of hypertension caused an increased plasma 1,25-(OH)2D. This increase was accompanied by either unaltered or reduced levels of renal calbindin-D28k possibly secondary to a cellular resistance against 1,25-(OH)2D. Magnesium binds to calbindin-D28k with a relatively high affinity. The regulation of urinary magnesium excretion takes place in the distal tubule where calbindin-D28k is found in high concentrations. Therefore, a possible relation between magnesium and calbindin-D28k was examined. The studies demonstrated not previously known connections between magnesium intake, urinary magnesium excretion and renal calbindin-D28k which suggests that this protein is involved in the regulation of magnesium homeostasis by the kidney. Calcitonin increases the reabsorption of calcium in the distal tubule. Therefore, the effect ofcalcitonin on renal calbindin-D28k was examined both by eliminating the endogeneous calcitonin production by a selective thyroidectomy followed by an autotransplantation of the parathyroid glands and further by infusion of calcitonin. These studies demonstrated unchanged concentrations of renal calbindin-D28k. It was concluded that the increased calcium reabsorption induced by calcitonin in the distal tubule is not mediated by calbindin-D28k. Urinary calcium excretion is in part regulated by the action of PTH on calcium reabsorption in the distal nephron. Previous reports of increased expression of renal calbindin-D28k in uremic rats led us to suggest that secondary hyperparathyroidism associated with uremia induced the synthesis of renal calbindin-D28k. Therefore, the effect of PTH was examined in a study comprising selective parathyroidectomy and infusions of PTH, PTHrP, 1,25-(OH)2D and calcium. (ABSTRACT TRUNCATED)
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PMID:Regulation of renal calbindin-D28K. 1109 7

Isolated hereditary renal magnesium (Mg) wasting may result from mutations in the renal tubular epithelial cell tight junction protein paracellin-1 gene or the tubular Na(+),K(+)-ATPase gamma-subunit gene FXYD2. The FXYD2 gene mutation was discovered in two Dutch families as an autosomal dominant disorder. It is characterized by isolated renal Mg wasting with resultant symptomatic hypomagnesemia. The defective FXYD2 gene in these families mapped to chromosome 11q23. Here, we describe an American family with a similar phenotype but without linkage to the 11q23 locus; in testing 22 individuals in the pedigree multipoint LOD scores for five different loci from the 11q23 region were equal to -2.97. Compared with unaffected family members and normal controls, affected family members harbored significant reductions in the serum and lymphocyte Mg concentrations and in the serum immunoreactive PTH level with a 4-fold increase in the mean fractional urinary Mg excretion rate during a normomagnesemic clamp. Bone mineral density at the lumbar spine and proximal femur was significantly reduced in affected family members. In conclusion, our data demonstrate locus heterogeneity for the phenotype of isolated renal Mg wasting with hypomagnesemia and suggest that hypomagnesemia, at least in this pedigree, may be associated with low bone mass.
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PMID:Genetic heterogeneity in familial renal magnesium wasting. 1183 93

The final step in the maternal-fetal transfer of calcium in the placenta involves transport against a concentration gradient across the syncytiotrophoblast basal plasma membrane (BM). Based on animal studies, it has been proposed that parathyroid hormone-related peptide (PTHrP) plays a major role in maintaining the maternal-fetal concentration gradient of calcium. In this study, we tested the hypothesis that a highly conserved mid-region fragment (38-94) of PTHrP directly affects the ATP-dependent calcium transport across BM isolated from full-term human placentas. PTHrP (38-94) stimulated ATP-dependent calcium transport at a concentration within the physiological range (5 pg/ml) and the effect (10-38% increase) was concentration dependent over the range 5 pg/ml to 5 ng/ml (n=8; P<0.05). In contrast, PTH, PTHrP (1-34), PTHrP (67-86) and calcitonin increased BM calcium transport only at concentrations much higher than physiological. The increased calcium uptake was inhibited by the protein kinase C (PKC) inhibitor chelerythrine (n=6; P<0.05). In addition, PTHrP (38-94) increased inositol trisphosphate (IP(3)) production and PKC phosphorylation in human placental BM (n=12; P<0.05). Our data indicate that PTHrP (38-94) stimulates Ca(2+)ATPase in the human syncytiotrophoblast BM vesicles by activating the IP(3)-DAG-PKC pathway. We suggest that PTHrP (38-94) is important in maintaining the calcium concentration gradient across the placental barrier in the human.
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PMID:Parathyroid hormone-related peptide (38-94) amide stimulates ATP-dependent calcium transport in the Basal plasma membrane of the human syncytiotrophoblast. 1242 49

The Ca(2+)-sensing receptor (CaR), a G protein-coupled receptor, is expressed in many epithelial tissues including the parathyroid glands, kidney, and GI tract. Although its role in regulating PTH levels and Ca(2+) metabolism are best characterized, it may also regulate salt and water transport in the kidney as demonstrated by recent reports showing association of potent gain-of-function mutations in the CaR with a Bartter-like, salt-wasting phenotype. To determine whether this receptor interacts with novel proteins that control ion transport, we screened a human adult kidney cDNA library with the COOH-terminal 219 amino acid cytoplasmic tail of the CaR as bait using the yeast two-hybrid system. We identified two independent clones coding for approximately 125 aa from the COOH terminus of the inwardly rectifying K(+) channel, Kir4.2. The CaR and Kir4.2 as well as Kir4.1 (another member of Kir4 subfamily) were reciprocally coimmunoprecipitated from HEK-293 cells in which they were expressed, but the receptor did not coimmunoprecipitate with Kir5.1 or Kir1.1. Both Kir4.1 and Kir4.2 were immunoprecipitated from rat kidney extracts with the CaR. In Xenopus laevis oocytes, expression of the CaR with either Kir4.1 or Kir4.2 channels resulted in inactivation of whole cell current as measured by two-electrode voltage clamp, but the nonfunctional CaR mutant CaR(R796W), and that does not coimmunoprecipitate with the channels, had no effect. Kir4.1 and the CaR were colocalized in the basolateral membrane of the distal nephron. The CaR interacts directly with Kir4.1 and Kir4.2 and can decrease their currents, which in turn could reduce recycling of K(+) for the basolateral Na(+)-K(+)-ATPase and thereby contribute to inhibition of Na(+) reabsorption.
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PMID:Interaction of the Ca2+-sensing receptor with the inwardly rectifying potassium channels Kir4.1 and Kir4.2 results in inhibition of channel function. 1712 84

There is considerable evidence that osteoclasts are involved in the pathogenesis of juxta-articular bone destruction in rheumatoid arthritis. Vacuolar ATPases (V-ATPases), which are highly expressed in the ruffled border membrane of osteoclasts, play a central role in the process of bone resorption, and V-ATPase inhibitors are effective in preventing bone destruction in several animal models of lytic bone diseases. Here, we evaluated for the first time the effects of V-ATPase inhibition in rats with adjuvant-induced arthritis (AIA) using FR177995, a novel V-ATPase inhibitor. FR177995 completely inhibited H(+) transport driven by V-ATPase, but exerted no effect on the H(+) transport activities of F- and P-ATPase, indicating that FR177995 is a specific inhibitor of V-ATPase. FR177995 acted directly on osteoclastic bone resorption and equally inhibited in vitro bone resorption stimulated by IL-1, IL-6 or PTH. In addition, FR177995 dose-dependently reduced retinoic acid-induced hypercalcemia in thyroparathyroidectomized-ovariectomized rats. When FR177995 was administered to AIA rats once a day, the loss of femoral bone mineral density was significantly improved. Moreover, indicators of cartilage damage (arthritis score and glycosaminoglycan content in the femoral condyles) and inflammation parameters (paw swelling volume, erythrocyte sedimentation rate and plasma sialic acid level) were found to be unexpectedly ameliorated. These results strongly suggest that V-ATPase may be an interesting drug target in the treatment of rheumatoid arthritis.
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PMID:FR177995, a novel vacuolar ATPase inhibitor, exerts not only an inhibitory effect on bone destruction but also anti-immunoinflammatory effects in adjuvant-induced arthritic rats. 1715 74

Recent advances that have given rise to marked progress in clarifying actions of alpha-Klotho (alpha-Kl) and FGf23 can be summarized as follows ; (i) alpha-Kl binds to Na(+), K(+)-ATPase, and Na(+), K(+)-ATPase is recruited to the plasma membrane by a novelalpha-Kl dependent pathway in correlation with cleavage and secretion ofalpha-Kl in response to extracellular Ca(2+) fluctuation. (ii) The increased Na(+) gradient created by Na(+), K(+)-ATPase activity drives the transepithelial transport of Ca(2+) in the choroid plexus and the kidney, this is defective in alpha-kl(-/-) mice. (iii) The regulated PTH secretion in the parathyroid glands is triggered via recruitment of Na(+), K(+)-ATPase to the cell surface in response to extracellular Ca(2+) concentrations. (iv) alpha-Kl, in combination with FGF23, regulates the production of 1,25 (OH) (2)D in the kidney. In this pathway, alpha-Kl binds to FGF23, andalpha-Kl converts the canonical FGF receptor 1c to a specific receptor for FGF23, enabling the high affinity binding of FGF23 to the cell surface of the distal convoluted tubule where alpha-Kl is expressed. (v) FGF23 signal down-regulates serum phosphate levels, due to decreased NaPi-IIa abundance in the apical membrane of the kidney proximal tubule cells. (vi) alpha-Kl in urine increases TRPV5 channel abundance at the luminal cell surface by hydrolyzing the N-linked extracellular sugar residues of TRPV5, resulting in increased Ca(2+) influx from the lumen. These findings revealed a comprehensive regulatory scheme of mineral homeostasis that is illustrated by the mutually regulated positive/negative feedback actions of alpha-Kl, FGF23, PTH and 1,25 (OH) (2)D. In this regard, alpha-Kl and FGF23 might play pivotal roles in mineral metabolism as regulators that integrate calcium and phosphate homeostasis, although this concept requires further verification in the light of related findings. Here, the unveiling of the molecular functions of alpha-Klotho and FGF23 has recently given new insight into the field of calcium and phosphate homeostasis. Unveiled molecular functions of alpha-Kl and FGF23 provided answers for several important questions regarding the mechanisms of calcium and phosphate homeostasis that remained to be solved, such as : (i) what is the non-hormonal regulatory system that directly responds to the fluctuation of extracellular Ca(2+), (ii) how is Na(+), K(+)-ATPase activity enhanced in response to low calcium stimuli in the parathyroid glands, (iii) what is the exact role of FGF23 in calcium and phosphorus metabolism, (iv) how is Ca(2+) influx through TRPV5 controlled in the DCT nephron, and finally (v) how is calcium homeostasis regulated in cerebrospinal fluid. However, several critical questions still remain to be solved. So far reported,alpha-Kl binds to Na(+), K(+)-ATPase, FGF receptors and FGF23, and alpha-Kl hydrolyzes the sugar moieties of TRPV5. Does alpha-Kl recognize these proteins directly or indirectly?Is there any common mechanism?How can we reconcile such diverse functions of alpha-Kl?What is the Ca(2+) sensor machinery and how can we isolate it?How do hypervitaminosis D and the subsequently altered mineral-ion balance lead to the multiple phenotypes?What is the phosphate sensor machinery and how can we isolate it? How does the Fgf23/alpha-Kl system regulate phosphorus homeostasis?How are serum concentrations of Ca(2 + ) and phosphate mutually regulated?
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PMID:[Discovery of alpha-Klotho and FGF23 unveiled new insight into calcium and phosphate homeostasis]. 1859 43

TRPV5 is a Ca(2+)-selective channel involved in transcellular Ca(2+) absorption expressed in kidney and in the ruffled border of osteoclasts. Studies in hypercalciuric TRPV5 knockout (TRPV5(-/-)) mice, which display significantly increased vitamin D levels, showed that TRPV5 ablation increases number and size of osteoclasts but impairs osteoclast-mediated bone resorption. The latter is not in line with the observed decreased bone thickness in TRPV5(-/-) mice. Bisphosphonates also inhibit osteoclast-mediated bone resorption. The aim of this study was to evaluate the effect of alendronate on the expression of the Ca(2+) transporters in bone, kidney, and duodenum and, importantly, the bone phenotype in TRPV5(-/-) mice. Wildtype (TRPV5(+/+)) and TRPV5(-/-) mice were treated during 10 wk with 2 mg/kg alendronate or vehicle weekly and housed in metabolic cages at the end of treatment. Urine and blood samples were taken for biochemical analysis, and duodenum, kidney, and femur were sampled. Expression of Ca(2+) transporters and osteoclast ruffled border transporters in bone and cultured osteoclasts was determined by QPCR analysis. Femurs were scanned using muCT, and resorption pit assays were performed in bone marrow cultures isolated from TRPV5(+/+) and TRPV5(-/-) mice. Alendronate treatment enhanced bone thickness in TRPV5(+/+) mice but also normalized the disturbed bone morphometry parameters in TRPV5(-/-) mice. Bone TRPV5 expression was specifically enhanced by alendronate, whereas the expression of Ca(2+) transporters in kidney and intestine was not altered. The expression of the osteoclast ruffled border membrane proteins chloride channel 7 (CLC-7) and the vacuolar H(+)-ATPase did not differ between both genotypes, but alendronate significantly enhanced the expression and PTH levels in TRPV5(-/-) mice. The expression of TRPV5, CLC-7, and H(+)-ATPase in osteoclast cultures was not affected by alendronate. The number of resorption pits was reduced in TRPV5(-/-) bone marrow cultures, but the response to vitamin D was similar to that in TRPV5(+/+) cultures. The alendronate-induced upregulation of TRPV5 in bone together with the decreased resorptive capacity of TRPV5(-/-) osteoclasts in vitro suggests that TRPV5 has an important role in osteoclast function. However, our data indicate that significant bone resorption still occurs in TRPV5(-/-) mice, because alendronate treatment normalized bone thickness in these mice. Thus, TRPV5(-/-) mice are able to rescue the resulting defect in osteoclast-mediated bone resorption, possibly mediated by the long-term hypervitaminosis D or other (non)hormonal compensatory mechanisms.
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PMID:Bone resorption inhibitor alendronate normalizes the reduced bone thickness of TRPV5(-/-) mice. 1859 25

The discovery that two recently identified molecules, klotho and fibroblast growth factor 23 (FGF23), played an important role in calcium, phosphate, and vitamin D metabolism has transformed our traditional physiological view in which bone and mineral homeostasis was mainly regulated by parathyroid hormone, vitamin D, and calcitonin, according to mineral body needs. FGF23 is a 251-amino acid secreted protein produced by osteoblasts and osteocytes in bone following the stimulation by phosphate and vitamin D or the inhibition by dentin matrix protein 1. Originally isolated from tumoral cells of patients with tumor-induced osteomalacia and hypophosphatemia, FGF23 inhibits phosphate reabsorption in renal proximal tubular cells and 1alpha-hydroxylase activity, resulting in decreased synthesis of calcitriol. To exert these actions, FGF23 requires the conversion, by klotho, of the canonical FGF receptor 1 (IIIc) in a specific high affinity FGF23 receptor. On the other hand, klotho is a putative antiaging gene identified in 1997 when a particular mouse strain, created by random insertion mutagenesis, was found to be short-lived and displayed premature atherosclerosis, osteopenia, skin atrophy, pulmonary emphysema, hyperphosphatemia, hypercalcemia, and high serum calcitriol levels. The gene of klotho encodes a 1012-amino acid cell-surface protein with a short cytoplasmic tail and an extracellular domain that consists in tandem duplicated copies of a beta-glucuronidase-like sequence, which can be released into the circulation as soluble forms after being cleaved by metalloproteinases such as ADAM10 and ADAM17. By modulating FGF23 action, klotho regulates urinary phosphate excretion and calcitriol synthesis. By virtue of its beta-glucuronidase activity, klotho deglycosylates the calcium channel TRPV5 (transient receptor potential vallinoid-5) and regulates urinary calcium excretion. klotho also binds to Na(+),K(+)-ATPase in parathyroid cells and regulates calcium-stimulated PTH secretion. Finally, klotho extends life span via several mechanisms, including the reduction of calcitriol synthesis, serum calcium, and phosphorus levels; the induction of insulin resistance; and by increasing the resistance to oxidative stress.
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PMID:Klotho gene, phosphocalcic metabolism, and survival in dialysis. 1912 71

Since the discovery of alphaklotho-mutant mice, it has been questioned whether the responsible gene, alphaklotho, makes any effect on 'intrinsic aging' process. So far we found that alphaKlotho regulates transcellular calcium transport by mediating Na,K-ATPase activity and dominates mineral-regulating hormones such as PTH, vitamin D and FGF23. A new concept is now emerged that alphaklotho integrates mineral homeostasis. Findings of human cases with mineral disorders revealed impairment of alphaklotho expression as a pathological cause. Mineral metabolic system contributes to health and thus its disruption should result in acceleration of aging and disease.
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PMID:[Aspects of mammalian aging from alphaklotho study]. 1959 Dec 73


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