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 enzyme catechol-O-methyltransferase (COMT), which plays an important role for dopamine metabolism, is abundantly expressed in the kidney. To test whether the natriuretic effects of dopamine may be related to the rate of dopamine metabolism, rats were treated with nitecapone, a peripheral inhibitor of COMT. Nitecapone, given by gavage, induced a highly significant (5.6-fold) increase in sodium excretion, which was associated with an inhibition of the Na+,K+-ATPase activity in both the proximal convoluted and proximal straight tubules (PCT and PST, respectively). These effects were completely abolished if the rats were also treated with a specific dopamine 1 antagonist, SCH 23390. Furthermore, the natriuretic effect of nitecapone was also observed in rats on a high salt diet. The kidney-specific pro-drug to dopamine, glu-dopa, induced a significant, but less pronounced increase in urinary sodium excretion, associated with a dopamine-dependent inhibition of the Na+,K+-ATPase activity in the PCT but not in the PST. Nitecapone and glu-dopa had an additive natriuretic effect. It is concluded that COMT plays an important role in determining the natriuretic effects of the renal dopamine system.
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PMID:Inhibition of COMT induces dopamine-dependent natriuresis and inhibition of proximal tubular Na+,K+-ATPase. 929 Nov 95

All-trans-retinoic acid (atRA) is a regulator of cellular growth and differentiation. We investigated whether atRA can upregulate Na(+)-dependent cotransporters in opossum kidney (OK) cells and thus increase uptake from tubular fluid of several solutes needed for growth during early stages of ontogenesis. In OK cells, incubation with atRA for 24 h increased the Na+ gradient-dependent cotransports of phosphate, L-proline, L-glutamic acid, and SO(4)2- by a similar degree (approximately 40%) that was prevented by pretreatment with actinomycin D. In contrast, activities of other Na(+)-dependent transporters, Na(+)-K(+)-adenosinetriphosphatase, gamma-glutamyltranspeptidase, and leucine aminopeptidase, were unchanged by atRA. Cell proliferation determined by [3H]thymidine incorporation was not increased by atRA. The stimulatory effects of atRA and phosphate deprivation on Na(+)-Pi cotransport demonstrated additivity, whereas the combination of atRA and 3,5,3'-triiodothyronine did not. atRA stimulated Na(+)-Pi cotransport in LLC-PK1 cells with an analogous time course and to a similar extent as observed in OK cells. We conclude that atRA stimulates several Na(+)-dependent cotransporters via a genomic mechanism and may represent a synchronous adaptation to nutritional requirements of early phases of ontogenesis.
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PMID:Pleiotropic upregulation of Na(+)-dependent cotransporters by retinoic acid in opossum kidney cells. 932 17

The excitatory amino acid glutamate was previously shown to stimulate aerobic glycolysis in astrocytes by a mechanism involving its uptake through an Na+-dependent transporter. Evidence had been provided that Na+,K+-ATPase might be involved in this process. We have now measured the activity of Na+,K+-ATPase in cultured astrocytes, using ouabain-sensitive 86Rb uptake as an index. L-Glutamate increases glial Na+,K+-ATPase activity in a concentration-dependent manner with an EC50 = 67 microM. Both L- and D-aspartate, but not D-glutamate, produce a similar response, an observation that is consistent with an uptake-related effect rather than a receptor-mediated one. Under basal conditions, concentration-dependent inhibition of Na+,K+-ATPase activity in astrocytes by ouabain indicates the presence of a single catalytic site with a low affinity for ouabain (K0.5 = 113 microM), compatible with the presence of an alpha1 isozyme. On stimulation with glutamate, however, most of the increased activity is inhibited by low concentrations of ouabain (K0.5 = 20 nM), thus revealing a high-affinity site akin to the alpha2 isozyme. These results suggest that astrocytes possess a glutamate-sensitive isoform of Na+,K+-ATPase that can be mobilized in response to increased neuronal activity.
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PMID:Glutamate uptake stimulates Na+,K+-ATPase activity in astrocytes via activation of a distinct subunit highly sensitive to ouabain. 934 59

1. An analog of L-glutamic acid, threo-beta-hydroxy-L-glutamic acid (threo-L-BHGA), was applied locally to the giant neuron of an Achatina snail by pneumatic brief pressure ejection and induced an outward current (Iout) on the ventral-left cerebral distinct neurone (v-LCDN). The present study aimed to elucidate the ionic mechanisms of the Iout caused by threo-L-BHGA (ItL-BHGA) of v-LCDN and the effects of ouabain on this current under voltage clamp. 2. The reversal potentials of ItL-BHGA (EtL-BHGA) of v-LCDN in varied K+o were fitted to the Nernst equation as ItL-BHGA = IK (K+ current) and were almost unchanged in Cl-o-free and Na+o-reduced (20% of normal) states. The ItL-BHGA is due to the increase in permeability of the neuromembrane to K+(K(+)-dependent) and is neither Na(+)- nor Cl-(-)-dependent. K(+)-channel blockers, a mixture of tetraethyl-ammonium (TEA) and 4-amino-pyridine (4-AP), blocked ItL-BHGA mainly in a noncompetitive and partly in an uncompetitive manner. 3. Unexpectedly, ItL-BHGA of v-LCDN was almost abolished in the Na+o-free state and significantly reduced in the Cl-o-free state. However, an Na(+)-channel blocker, tetrodotoxin, showed a tendency to enhance ItL-BHGA. On the other hand, ItL-BHGA was enhanced in K+o-free state. 4. Ouabain markedly inhibited ItL-BHGA in both noncompetitive and uncompetitive manners. Benzamil, an inhibitor of the Na(+)-Ca2+ exchange applied simultaneously with ouabain could not prevent ouabain inhibition on ItL-BHGA. The currents induced by other putative neurotransmitters, including a K(+)-dependent Iout caused by dopamine on v-LCDN, were not affected by ouabain. 5. According to our previous study, the threo-L-BHGA receptors are not linked with protein kinases or calmodulin. Then, ItL-BHGA could be produced by the receptor K+ channel complex or the receptor-G-protein-K+ channel combination. The present results indicate that the ATPase activity inhibited by ouabain and the presence of extracellular Na+ and Cl- are needed for threo-L-BHGA to activate the K(+)-dependent structure. Furthermore, the K+o-free state, which inactivates the Na(+)-K+ pump, and tetrodotoxin, which suppresses the Na+ channel at least partly, did not affect the structure to be activated.
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PMID:Ouabain-sensitive K(+)-dependent outward current caused by threo-beta-hydroxy-L-glutamic acid on a snail neuron. 935 13

Using conserved amino acid sequences for the design of oligonucleotide primers, we isolated cDNA clones for two subunits of the V-ATPase from the midgut and Malpighian tubules of Aedes aegypti larvae. The 3.1 kb cDNA of the A subunit of the peripheral catalytic V1 sector codes for a protein of 68.6 kDa. The protein contains conserved motifs, including an ATP/GTP binding site, found in all other A subunits. Southern analysis using the A subunit as a probe suggests the presence of only a single copy of gene in the Aedes aegypti. The 0.85 kb cDNA of the c subunit of the membrane H+ conducting V0 sector codes for a protein of kDa. This protein has four transmembrane domains and contains a conserved glutamic acid that serves as the binding site for dicyclohexylcarbodiimide. Southern analysis using the c subunit as a probe suggests the presence of more than one related gene in the genome of Aedes aegypti. Pileup analysis of various A and c subunits shows that these subunits fall into distinct clusters, including one in which all arthropod proteins are clustered.
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PMID:Isolation of the V-ATPase A and c subunit cDNAs from mosquito midgut and Malpighian tubules. 939 16

Glutamic acid residues in transmembrane segments of the alpha subunit of the Na+,K+-ATPase have been discussed as possible candidates for the binding sites of the transported cations. Here we report on effects of mutations of Glu334, Glu959, and Glu960 to alanine in ouabain-sensitive (OS) as well as ouabain-resistant (OR) ATPases of Torpedo electroplax expressed in Xenopus oocytes. All mutants are incorporated to about the same extend as the wild-type ATPases into the plasma membrane. None of the mutations produces complete inhibition of transport activity as judged from measurements of 86Rb+ uptake, membrane current, and ATPase activity. After conversion of OS to OR by mutation of the bordering residues of the first extracellular loop Gln118 to Arg and Asp129 to Asn, the Km value for inhibition by ouabain increases to 59 microM. Substitution of Glu334 to Ala in the OR pump variant restores ouabain sensitivity with a Km value of 0.12 microM, which is similar to that of the endogenous Xenopus pump. After substitution of Glu960 by Ala in the OR pump, ouabain sensitivity is partially restored. The Km values for pump stimulation by external K+ appear to be reduced in the OR compared to the OS pump. Mutation of Glu959 and Glu960 to Ala has no pronounced effects on the potential-dependent Km values at external pH 7.8; only in the Glu959-mutated OR pump, the apparent Km at 0 mV is raised. We conclude that none of the mutated glutamic acid residues is essential for cation coordination, but that GIu334, and in part also Glu960, seems to be involved in preserving the ouabain-resistant conformation of the enzyme.
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PMID:Significance of the glutamic acid residues Glu334, Glu959, and Glu960 of the alpha subunits of Torpedo Na+, K+ pumps for transport activity and ouabain binding. 945 92

Members of the ABC transporter superfamily contain two nucleotide binding domains. To date, the three dimensional structure of no member of this super-family has been elucidated. To gain structural insight, the known structures of several other nucleotides binding proteins can be used as a framework for modeling these domains. We have modeled both nucleotide binding domains of the protein CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) using the two similar domains of mitochondrial F1-ATPase. The models obtained, provide useful insights into the putative functions of these domains and their possible interaction as well as a rationale for the basis of Cystic Fibrosis causing mutations. First, the two nucleotide binding domains (folds) of CFTR are each predicted to span a 240-250 amino acid sequence rather than the 150-160 amino acid sequence originally proposed. Second, the first nucleotide binding fold, is predicted to catalyze significant rates of ATP hydrolysis as a catalytic base (E504) resides near the y phosphate of ATP. This prediction has been verified experimentally [Ko, Y.H., and Pedersen, P.L. (1995) J. Biol. Chem. 268, 24330-24338], providing support for the model. In contrast, the second nucleotide binding fold is predicted at best to be a weak ATPase as the glutamic acid residue is replaced with a glutamine. Third, F508, which when deleted causes approximately 70% of all cases of cystic fibrosis, is predicted to lie in a cleft near the nucleotide binding pocket. All other disease causing mutations within the two nucleotide binding domains of CFTR either reside near the Walker A and Walker B consensus motifs in the heart of the nucleotide binding pocket, or in the C motif which lies outside but near the nucleotide binding pocket. Finally, the two nucleotide binding domains of CFTR are predicted to interact, and in one of the two predicted orientations, F508 resides near the interface. This is the first report where both nucleotide binding domains of an ABC transporter and their putative domain-domain interactions have been modeled in three dimensions. The methods and the template used in this work can be used to analyze the structures and function of the nucleotide binding domains of all other members of the ABC transporter super-family.
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PMID:Modeling of nucleotide binding domains of ABC transporter proteins based on a F1-ATPase/recA topology: structural model of the nucleotide binding domains of the cystic fibrosis transmembrane conductance regulator (CFTR). 951 35

The mrsC gene of Escherichia coli is required for mRNA turnover and cell growth, and strains containing the temperature-sensitive mrsC505 allele have longer half-lives than wild-type controls for total pulse-labeled and individual mRNAs (L. L. Granger et al., J. Bacteriol. 180:1920-1928, 1998). The cloned mrsC gene contains a long open reading frame beginning at an initiator UUG codon, confirmed by N-terminal amino acid sequencing, encoding a 70,996-Da protein with a consensus ATP-binding domain. mrsC is identical to the independently identified ftsH gene except for three additional amino acids at the N terminus (T. Tomoyasu et al., J. Bacteriol. 175:1344-1351, 1993). The purified protein had a Km of 28 microM for ATP and a Vmax of 21.2 nmol/microg/min. An amino-terminal glutathione S-transferase-MrsC fusion protein retained ATPase activity but was not biologically active. A glutamic acid replacement of the highly conserved lysine within the ATP-binding motif (mrsC201) abolished the complementation of the mrsC505 mutation, confirming that the ATPase activity is required for MrsC function in vivo. In addition, the mrsC505 allele conferred a temperature-sensitive HflB phenotype, while the hflB29 mutation promoted mRNA stability at both 30 and 44 degrees C, suggesting that the inviability associated with the mrsC505 allele is not related to the defect in mRNA decay. The data presented provide the first direct evidence for the involvement of a membrane-bound protein in mRNA decay in E. coli.
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PMID:Escherichia coli mrsC is an allele of hflB, encoding a membrane-associated ATPase and protease that is required for mRNA decay. 953 94

L-Glutamate (L-GLU) induced astrocyte swelling in a time- and concentration-dependent, as well as Na+- and Ca2+-dependent, and Cl(-)-independent manner. Swelling was prevented by MK-801, cystine, and ouabain. Since L-GLU swelling is ionically dependent, we determined the role of various ions in such swelling. Our results indicate that K+ uptake plays a major role in the mechanism of L-GLU-induced astrocyte swelling. Like swelling, K+ uptake is dependent on Ca2+ and Na+, but not on Cl-. Likewise, K+ uptake was inhibited by MK-801, cystine, and ouabain. The K+ channel blockers, Ba2+ and tetraethylammonium, partially prevented L-GLU-induced swelling. In addition to K+ channels, K+ influx may also be mediated through Na+/K+-ATPase, as its activity is increased by L-GLU uptake along with the required Na+. Taken together, the data suggest that K+ influx plays a key role in the mechanism of L-GLU-mediated astrocyte swelling.
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PMID:Ionic mechanisms in glutamate-induced astrocyte swelling: role of K+ influx. 959 Apr 39

In the reaction cycle of P-type ATPases, an acid-stable phosphorylated intermediate is formed which is present in an intracellularly located domain of the membrane-bound enzymes. In some of these ATPases, such as Na+,K+-ATPase and gastric H+, K+-ATPase, extracellular K+ ions stimulate the rate of dephosphorylation of this phosphorylated intermediate and so stimulate the ATPase activity. The mechanism by which extracellular K+ ions stimulate the dephosphorylation process is unresolved. Here we show that three mutants of gastric H+,K+-ATPase lacking a negative charge on residue 820, located in transmembrane segment six of the alpha-subunit, have a high SCH 28080-sensitive, but K+-insensitive ATPase activity. This high activity is caused by an increased 'spontaneous' rate of dephosphorylation of the phosphorylated intermediate. A mutant with an aspartic acid instead of a glutamic acid residue in position 820 showed hardly any ATPase activity in the absence of K+, but K+ ions stimulated ATPase activity and the dephosphorylation process. These findings indicate that the negative charge normally present on residue 820 inhibits the dephosphorylation process. K+ ions do not stimulate dephosphorylation of the phosphorylated intermediate directly, but act by neutralizing the inhibitory effect of a negative charge in the membrane.
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PMID:Constitutive activation of gastric H+,K+-ATPase by a single mutation. 960 85


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