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)

Cachexia is a syndrome characterized by profound tissue wasting that frequently complicates malignancies. In a cancer cachexia model we have shown that protein depletion in the skeletal muscle, which is a prominent feature of the syndrome, is mostly due to enhanced proteolysis. There is consensus on the views that the ubiquitin/proteasome pathway plays an important role in such metabolic response and that cytotoxic cytokines such as TNFalpha are involved in its triggering (Costelli and Baccino, 2000), yet the mechanisms by which the relevant extracellular signals are transduced into protein hypercatabolism are largely unknown. Moreover, little information is presently available as to the possible involvement in muscle protein waste of the Ca(2+)-dependent proteolysis, which may provide a rapidly activated system in response to the extracellular signals. In the present work we have evaluated the status of the Ca(2+)-dependent proteolytic system in the gastrocnemius muscle of AH-130 tumour-bearing rats by assaying the activity of calpain as well as the levels of calpastatin, the natural calpain inhibitor, and of the 130 kDa Ca(2+)-ATPase, both of which are known calpain substrates. After tumour transplantation, total calpastatin activity progressively declined, while total calpain activity remained unchanged, resulting in a progressively increasing unbalance in the calpain/calpastatin ratio. A decrease was also observed for the 130 kDa plasma membrane form of Ca(2+)-ATPase, while there was no change in the level of the 90 kDa sarcoplasmic Ca(2+)-ATPase, which is resistant to the action of calpain. Decreased levels of both calpastatin and 130 kDa Ca(2+)-ATPase have been also detected in the heart of the tumour-bearers. These observations strongly suggest that Ca(2+)-dependent proteolysis was activated in the skeletal muscle and heart of tumour-bearing animals and raise the possibility that such activation may play a role in sparking off the muscle protein hypercatabolic response that characterizes cancer cachexia.
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PMID:Activation of Ca(2+)-dependent proteolysis in skeletal muscle and heart in cancer cachexia. 1128 75

We describe a 21 month old male infant who presented with failure to thrive associated with severe hypokalaemia and metabolic acidosis, together with hypomagnesaemia. Evaluation revealed marked renal and probable faecal potassium wasting, distal renal tubular acidosis, mild urinary magnesium wasting, and a normal gastric pH (gastric H(+)-K(+)-ATPase). Hypokalaemic forms of metabolic acidosis, such as diabetic ketoacidosis and proximal renal tubular acidosis were ruled out from the clinical picture. The hypokalaemia of distal renal tubular acidosis usually improves with alkali therapy, but this was not observed: despite correction of acidosis with 5 mmol/kg potassium citrate per day, an additional 5 mmol/kg potassium chloride was required to bring serum potassium to 3.5 mmol/l. At 3 years of age potassium was provided in the absence of potential alkali and acidosis ensued; serum bicarbonate fell to 10 mmol/l. Although a specific genetic analysis is not yet possible, the abnormalities are consistent with a novel form of distal renal tubular acidosis. The pathophysiology probably does not stem from defects in the vacuolar H(+)-ATPase but more likely from deficient activity of the colonic isoform of H(+)-K(+)-ATPase that is resident in the medullary collecting duct and mediates potassium absorption and proton secretion.
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PMID:Distal renal tubular acidosis with severe hypokalaemia, probably caused by colonic H(+)-K(+)-ATPase deficiency. 1136 70

A number of acute wasting conditions are associated with an upregulation of the ubiquitin-proteasome system in skeletal muscle. Eicosapentaenoic acid (EPA) is effective in attenuating the increased protein catabolism in muscle in cancer cachexia, possibly due to inhibition of 15-hydroxyeicosatetraenoic acid (15-HETE) formation. To determine if a similar pathway is involved in other catabolic conditions, the effect of EPA on muscle protein degradation and activation of the ubiquitin-proteasome pathway has been determined during acute fasting in mice. When compared with a vehicle control group (olive oil) there was a significant decrease in proteolysis of the soleus muscles of mice treated with EPA after starvation for 24 h, together with an attenuation of the proteasome "chymotryptic-like" enzyme activity and the induction of the expression of the 20S proteasome alpha-subunits, the 19S regulator and p42, an ATPase subunit of the 19S regulator in gastrocnemius muscle, and the ubiquitin-conjugating enzyme E2(14k). The effect was not shown with the related (n-3) fatty acid docosahexaenoic acid (DHA) or with linoleic acid. However, 2,3,5-trimethyl-6-(3-pyridylmethyl)1,4-benzoquinone (CV-6504), an inhibitor of 5-, 12- and 15-lipoxygenases also attenuated muscle protein catabolism, proteasome "chymotryptic-like" enzyme activity and expression of proteasome 20S alpha-subunits in soleus muscles from acute fasted mice. These results suggest that protein catabolism in starvation and cancer cachexia is mediated through a common pathway, which is inhibited by EPA and is likely to involve a lipoxygenase metabolite as a signal transducer.
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PMID:Downregulation of ubiquitin-dependent proteolysis by eicosapentaenoic acid in acute starvation. 1145 34

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 two variants of the gamma subunit of the rat renal sodium pump, gamma(a) and gamma(b), have similar effects on the Na,K-ATPase. Both increase the affinity for ATP due to a shift in the enzyme's E(1) <--> E(2) conformational equilibrium toward E(1). In addition, both increase K(+) antagonism of cytoplasmic Na(+) activation. To gain insight into the structural basis for these distinct effects, extramembranous N-terminal and C-terminal mutants of gamma were expressed in rat alpha1-transfected HeLa cells. At the N terminus, the variant-distinct region was deleted (gammaNDelta7) or replaced by alanine residues (gammaN7A). At the C terminus, four (gamma(a)CDelta4) or ten (gamma(a)CDelta10) residues were deleted. None of these mutations abrogates the K(+)/Na(+) antagonism as evidenced in a similar increase in K'(Na) seen at high (100 mm) K(+) concentration. In contrast, the C-terminal as well as N-terminal deletions (gammaNDelta7, gamma(a)CDelta4, and gamma(a)CDelta10) abolished the decrease in K'(ATP) seen with wild-type gamma(a) or gamma(b). It is concluded that different regions of the gamma chain mediate the distinct functional effects of gamma, and the effects can be long-range. In the transmembrane region, the impact of G41R replacement was analyzed since this mutation is associated with autosomal dominant renal Mg(2+)-wasting in man (Meij, I. C., Koenderink, J. B., van Bokhoven, H., Assink, K. F. H., Groenestege, W. T., de Pont, J. J. H. H. M., Bindels, R. J. M., Monnens, L. A. H., Van den Heuvel, L. P. W. J., and Knoers, N. V. A. M. (2000) Nat. Genet. 26, 265-266). The results show that Gly-41 --> Arg prevents trafficking of gamma but not alphabeta pumps to the cell surface and abrogates functional effects of gamma on alphabeta pumps. These findings underscore a potentially important role of gamma in affecting solute transport, in this instance Mg(2+) reabsorption, consequent to its primary effect on the sodium pump.
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PMID:Distinct regulatory effects of the Na,K-ATPase gamma subunit. 1192 68

The present clinical taxonomy of distal renal tubular acidoses includes "gradient," "secretory," and "voltage" defects. These categories refer to presumed collecting duct defects in which the epithelium may be abnormally permeable and unable to sustain an ion gradient, in which luminal proton ATPases are defective, or in which electrogenic Na+ reabsorption is impaired and luminal electronegativity is reduced. Classification of affected individuals is based on urinary pH and ion concentrations during spontaneous acidosis and during SO(4)(2-) infusion, as well as urinary PCO2 during HCO(3)(-) loading. A model of rat CD has been developed that has been used to examine determinants of urinary acidification (Weinstein AM. Am J Physiol Renal Physiol 283: F1252-F1266, 2002) and the interplay of HCO(3)(-) and PO(4)(3-) loads to generate a disequlibrium pH and equilibrium PCO2. In this paper, pure forms of gradient, voltage, and secretory defects are simulated, with attention to variability in the locus of the defect in the cortical (CCD), outer medullary (OMCD), or inner medullary collecting duct (IMCD). The objective of these calculations is to discover whether the intuitive description of these defects is sustained quantitatively. The most important positive finding is that the locus of the transport defect along the CD plays a critical role in the apparent severity of the lesion, with more proximal defects being less severe and more easily correctable. In particular, model calculations suggest that for gradient or secretory defects to be clinically detectable they need to involve the OMCD and/or IMCD. Additionally, the calculations reveal a possible mechanism for CD K+ wasting, which does not involve failure of H+ - K+-ATPase but derives from a paracellular anion leak and thereby a more electronegative lumen. The most important negative finding is the lack of support for the category of renal tubular acidosis associated with a voltage defect. Although CD lesions that present with both K+ and H+ secretory defects suggest mediation by transepithelial electrical potential difference (PD), both PD changes and proton pump PD sensitivity appear too small to account for the observed abnormalities.
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PMID:A mathematical model of rat collecting duct. III. Paradigms for distal acidification defects. 1238 80

The Na,K-ATPase gamma subunit is present primarily in kidney as two splice variants, gammaa and gammab, which differ only at their extracellular N-termini. Two distinct effects of gamma are seen in biochemical Na,K-ATPase assays of mammalian (HeLa) cells transfected with gammaa or gammab, namely, (i) a decrease in K'(ATP) probably secondary to a shift in steady-state E(1) <--> E(2) poise in favor of E(1) and (ii) an increase in cytoplasmic K(+)/Na(+) antagonism seen as an increase in K'(Na) at high K(+) concentration. Mutagenesis experiments involving alterations in extramembranous regions of gamma indicate that different regions mediate the aforementioned distinct effects and that the effects appear to be long range. Studies of ouabain-sensitive fluxes with intact cells confirm the gamma effects seen with membranes and also suggest an additional effect (increase) in apparent affinity for extracellular K(+). Alteration in gamma function was also evidenced in the behavior of a G41 -->R mutation within the transmembrane domain of gamma. G41R is associated with autosomal dominant renal magnesium wasting. Our studies show that this mutation in the gammab variant retards trafficking of gamma, but not alphabeta pumps, to the cell surface and abolishes functional effects of gamma, consistent with the conclusion that the Mg(2+) transport defect is secondary to loss of gamma modulation of Na,K-ATPase function.
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PMID:Structure/function studies of the gamma subunit of the Na,K-ATPase. 1276 60

Hereditary primary hypomagnesemia comprises a clinically and genetically heterogeneous group of disorders in which hypomagnesemia is due to either renal or intestinal Mg(2+) wasting. These disorders share the general symptoms of hypomagnesemia, tetany and epileptiformic convulsions, and often include secondary or associated disturbances in calcium excretion. In a large Dutch family with autosomal dominant renal hypomagnesemia, associated with hypocalciuria, we mapped the disease locus to a 5.6-cM region on chromosome 11q23. After candidate screening, we identified a heterozygous mutation in the FXYD2 gene, encoding the Na(+),K(+)-ATPase gamma-subunit, cosegregating with the patients of this family, which was not found in 132 control chromosomes. The mutation leads to a G41R substitution, introducing a charged amino acid residue in the predicted transmembrane region of the gamma-subunit protein. Expression studies in insect Sf9 and COS-1 cells showed that the mutant gamma-subunit protein was incorrectly routed and accumulated in perinuclear structures. In addition to disturbed routing of the G41R mutant, Western blot analysis of Xenopus oocytes expressing wild-type or mutant gamma-subunit showed mutant gamma-subunit lacking a posttranslational modification. Finally, we investigated two individuals lacking one copy of the FXYD2 gene and found their serum Mg(2+) levels to be within the normal range. We conclude that the arrest of mutant gamma-subunit in distinct intracellular structures is associated with aberrant posttranslational processing and that the G41R mutation causes dominant renal hypomagnesemia associated with hypocalciuria through a dominant negative mechanism.
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PMID:Dominant isolated renal magnesium loss is caused by misrouting of the Na+,K+-ATPase gamma-subunit. 1276 62

Circulating levels of glucocorticoids are increased in many traumatic and muscle-wasting conditions that include insulin-dependent diabetes, acidosis, infection, and starvation. On the basis of indirect findings, it appeared that these catabolic hormones are required to stimulate Ub (ubiquitin)-proteasome-dependent proteolysis in skeletal muscles in such conditions. The present studies were performed to provide conclusive evidence for an activation of Ub-proteasome-dependent proteolysis after glucocorticoid treatment. In atrophying fast-twitch muscles from rats treated with dexamethasone for 6 days, compared with pair-fed controls, we found (i) increased MG132-inhibitable proteasome-dependent proteolysis, (ii) an enhanced rate of substrate ubiquitination, (iii) increased chymotrypsin-like proteasomal activity of the proteasome, and (iv) a co-ordinate increase in the mRNA expression of several ATPase (S4, S6, S7 and S8) and non-ATPase (S1, S5a and S14) subunits of the 19 S regulatory complex, which regulates the peptidase and the proteolytic activities of the 26 S proteasome. These studies provide conclusive evidence that glucocorticoids activate Ub-proteasome-dependent proteolysis and the first in vivo evidence for a hormonal regulation of the expression of subunits of the 19 S complex. The results suggest that adaptations in gene expression of regulatory subunits of the 19 S complex by glucocorticoids are crucial in the regulation of the 26 S muscle proteasome.
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PMID:Glucocorticoids regulate mRNA levels for subunits of the 19 S regulatory complex of the 26 S proteasome in fast-twitch skeletal muscles. 1463 57

Regarding the mechanisms of ifosfamide (IFO)-induced nephrotoxicity and hemorrhagic cystitis, several hypotheses have been put forward, among which oxidative stress and depletion of glutathione (GSH) are suggested. This investigation elucidates the role of free radicals in IFO-induced toxicity and the protection by melatonin. Wistar albino rats were injected intraperitoneally with saline (0.9% NaCl; control-C group), melatonin (Mel group; 10 mg/kg daily for 5 days) or ifosfamide (50 mg/kg daily for 5 days; IFO group) or IFO + Mel. On the 5th day (120 hr) after the first IFO dose, animals were killed by decapitation and trunk blood was collected. Kidney and bladder tissues were obtained for biochemical and histological analysis. Urine was collected 24 hr before the rats were killed. The results demonstrated that IFO induced a Fanconi syndrome (FS) characterized by wasting of sodium, phosphate, and glucose, along with increased serum creatinine and urea. Melatonin markedly ameliorated the severity of renal dysfunction induced by IFO with a significant decrease in urinary sodium, phosphate, and glucose and increased creatinine excretion. Moreover, melatonin significantly improved the IFO-induced GSH depletion, malondialdehyde accumulation and neutrophil infiltration in both renal and bladder tissues. In the kidney, Na+,K+ -ATPase activity which was significantly reduced by IFO, was increased with melatonin treatment. Increased collagen contents of the kidney and bladder tissues by IFO treatment were reversed back to the control levels with melatonin. Our results suggest that IFO causes oxidative damage in renal and bladder tissues and melatonin, via its antioxidant effects, protects these tissues. These data suggest that melatonin may be of therapeutic use in preventing acquired FS due to IFO toxicity.
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PMID:Melatonin attenuates ifosfamide-induced Fanconi syndrome in rats. 1523 Aug 64


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