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)

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

Binding of TNP-ATP [2',3'- O-(2,4,6-trinitrophenyl)adenosine 5'-triphosphate, a fluorescent analogue of ATP] to the K605 protein was studied. This is an isolated N-domain in the cytoplasmic loop of the Na/K-ATPase alpha-subunit, lying between membrane-spanning segments 4 and 5 (sequence L(354)-I(604)). A titration equation is derived that explicitly makes it possible to relate the fluorescence of TNP-ATP and K605 solutions to total probe concentration in the sample. Using this, it is possible to obtain the value of the dissociation constant from the titration experiment without resorting to the Scatchard plot, which is far from optimal from the statistical point of view. Using the new formula with non-linear regression analysis, a value of the dissociation constant K(D) for TNP-ATP binding to the K605 protein of 3.03 +/- 0.28 microM at 22 degrees C was obtained. A series of fits to simulated data with added noise demonstrated clearly the advantage of non-linear regression using the new formula over the commonly employed linear regression using the Scatchard plot. The procedure presented is generally applicable to binding assays using changes in the fluorescence of ligands on binding.
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PMID:Limitations in linearized analyses of binding equilibria: binding of TNP-ATP to the H4-H5 loop of Na/K-ATPase. 1285 94

Familial hemiplegic migraine (FHM) is a rare, severe, autosomal dominant subtype of migraine with aura. Up to 75% of FHM families have a mutation in the P/Q-type calcium channel Ca(v)2.1 subunit CACNA1A gene on chromosome 19p13. Some CACNA1A mutations also may cause epilepsy. Here, we describe novel missense mutations in the ATP1A2 Na(+),K(+)-ATPase pump gene on chromosome 1q23 in two families with FHM. The M731T mutation was found in a family with pure FHM. The R689Q mutation was identified in a family in which FHM and benign familial infantile convulsions partially cosegregate. In this family, all available affected family members with FHM, benign familial infantile convulsions, or both, carry the ATP1A2 mutation. Like FHM linked to 19p13, FHM linked to 1q23 also involves dysfunction of ion transportation and epilepsy is part of its phenotypic spectrum.
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PMID:Novel mutations in the Na+, K+-ATPase pump gene ATP1A2 associated with familial hemiplegic migraine and benign familial infantile convulsions. 1295 68

Ascorbate is an antioxidant vitamin that is found in high concentrations in the brain which seems to have neuroprotective properties in some experimental models of excitotoxic neurological disorders, including convulsive behavior and reactive species-related damage. In this study we tested whether ascorbate (30, 100 or 300 mg/kg, i.p.) protects against the convulsions, protein carbonylation and inhibition of Na(+),K(+)-ATPase activity induced by pentylenetetrazol (PTZ; 1.8 micromol/striatum), a classical convulsant agent that has been fairly used for the study of epilepsy and screening of new compounds with antiepileptic activity. The intrastriatal injection of PTZ caused convulsive behavior in a dose-dependent manner and an increase in the total protein carbonyl content of the injected striatum. However, duration of PTZ-induced convulsive episodes did not correlate with protein carbonyl content of the injected striatum. Ascorbate, at high doses (300 mg/kg), protected against PTZ-induced convulsions, protein carbonylation and inhibition of Na(+),K(+)-ATPase activity in the rat striatum, further suggesting a anticonvulsant and neuroprotective role for this vitamin. Conversely, intermediate doses of ascorbate (100 mg/kg) potentiated the duration of the convulsive episodes, but had no additive effects on protein carbonylation or Na(+),K(+)-ATPase activity inhibition induced by PTZ. Low doses of ascorbate (30 mg/kg) prevented PTZ-induced increase of total striatal carbonyl protein content, but did not alter PTZ-induced convulsions and Na(+),K(+)-ATPase activity inhibition. Collectively, these data indicate that the anticonvulsant activity of ascorbate is not related to its antioxidant action and support a dual role for this compound as a neuroprotective agent, since while it protects against PTZ-induced cellular oxidative damage, it has a biphasic effect on PTZ-induced convulsions.
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PMID:Ascorbate modulates pentylenetetrazol-induced convulsions biphasically. 1546 80

Mitochondrial function is a key determinant of both excitability and viability of neurons. Present studies were carried out to decipher cerebral mitochondrial oxidative energy metabolism and membrane function in the chronic condition of generalized seizures induced by picrotoxin (PTX) in rats. PTX-induced convulsions resulted in decreased respiration rates (14-41%) with glutamate, pyruvate + malate, and succinate as substrate. The ADP phosphorylation rates were drastically reduced by 44-65%. An opposite trend was observed with ascorbate + N,N,N',N'-tetramethyl-p-phenylenediamine [corrected] (TMPD) as substrate. In general, uncoupling of the mitochondrial electron transport was observed after PTX treatment. Malate dehydrogenase (MDH) and succinate dehydrogenase (SDH) activities were decreased by 20-80%; also, there was significant reduction in cytochrome b content after PTX treatment, while the F(o)F(1) ATPase (complex V) activity increased in basal and 2,4-dinitrophenol (DNP)-stimulated condition, indicating increased membrane fragility. The substrate kinetics analysis had shown that K(m) and V(max) of the higher affinity kinetic component of ATPase increased significantly by 1.2- to 1.4-fold in epileptic condition. Temperature kinetic analysis revealed 1.2-fold increase in energies of activation with decreased transition temperature. The total phospholipid (TPL) and cholesterol (CHL) contents decreased significantly with lowering of diphosphatidylglycerol (DPG), phosphatidylethanolamine (PE), phosphatidylinositol (PI), and phosphatidylserine (PS), while lysophospholipid (lyso), sphingomyelin (SPM), and phosphatidylcholine components were found to be elevated. Brain mitochondrial membrane was somewhat more fluidized in epileptic animals. Possible consequences of mitochondrial respiratory chain (MRC) dysfunction are discussed. In conclusion, impairment of MRC function along with structural alterations suggests novel pathophysiological mechanisms important for chronic epileptic condition.
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PMID:Structural and functional alterations in mitochondrial membrane in picrotoxin-induced epileptic rat brain. 1569 21

This study describes specific intramolecular covalent cross-linking of the gamma to alpha and gamma to beta subunits of pig kidney Na,K-ATPase and rat gamma to alpha co-expressed in HeLa cells. For this purpose pig gammaa and gammab sequences were determined by cloning and mass spectrometry. Three bifunctional reagents were used: N-hydroxysuccinimidyl-4-azidosalicylic acid (NHS-ASA), disuccinimidyl tartrate (DST), and 1-ethyl-3-[3dimethylaminopropyl]carbodiimide (EDC). NHS-ASA induced alpha-gamma, DST induced alpha-gamma and beta-gamma, and EDC induced primarily beta-gamma cross-links. Specific proteolytic and Fe(2+)-catalyzed cleavages located NHS-ASA- and DST-induced alpha-gamma cross-links on the cytoplasmic surface of the alpha subunit, downstream of His(283) and upstream of Val(440). Additional considerations indicated that the DST-induced and NHS-ASA-induced cross-links involve either Lys(347) or Lys(352) in the S4 stalk segment. Mutational analysis of the rat gamma subunit expressed in HeLa cells showed that the DST-induced cross-link involves Lys(55) and Lys(56) in the cytoplasmic segment. DST and EDC induced two beta-gamma cross-links, a major one at the extracellular surface within the segment Gly(143)-Ser(302) of the beta subunit and another within Ala(1)-Arg(142). Based on the cross-linking and other data on alpha-gamma proximities, we modeled interactions of the transmembrane alpha-helix and an unstructured cytoplasmic segment SKRLRCGGKKHR of gamma with a homology model of the pig alpha1 subunit. According to the model, the transmembrane segment fits in a groove between M2, M6, and M9, and the cytoplasmic segment interacts with loops L6/7 and L8/9 and stalk S5.
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PMID:Covalent cross-links between the gamma subunit (FXYD2) and alpha and beta subunits of Na,K-ATPase: modeling the alpha-gamma interaction. 1574 68

A computational model for the mitochondrial respiratory chain that appropriately balances mass, charge, and free energy transduction is introduced and analyzed based on a previously published set of data measured on isolated cardiac mitochondria. The basic components included in the model are the reactions at complexes I, III, and IV of the electron transport system, ATP synthesis at F1F0 ATPase, substrate transporters including adenine nucleotide translocase and the phosphate-hydrogen co-transporter, and cation fluxes across the inner membrane including fluxes through the K+/H+ antiporter and passive H+ and K+ permeation. Estimation of 16 adjustable parameter values is based on fitting model simulations to nine independent data curves. The identified model is further validated by comparison to additional datasets measured from mitochondria isolated from rat heart and liver and observed at low oxygen concentration. To obtain reasonable fits to the available data, it is necessary to incorporate inorganic-phosphate-dependent activation of the dehydrogenase activity and the electron transport system. Specifically, it is shown that a model incorporating phosphate-dependent activation of complex III is able to reasonably reproduce the observed data. The resulting validated and verified model provides a foundation for building larger and more complex systems models and investigating complex physiological and pathophysiological interactions in cardiac energetics.
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PMID:A biophysical model of the mitochondrial respiratory system and oxidative phosphorylation. 1616 94

Monosialoganglioside (GM1) is a glycosphingolipid that protects against some neurological conditions, such as seizures and ischemia. Glutaric acidemia type I (GA-I) is an inherited disease characterized by striatal degeneration, seizures, and accumulation of glutaric acid (GA). In this study, we show that GA inhibits Na+,K+-ATPase activity and increases oxidative damage markers (total protein carbonylation and thiobarbituric acid-reactive substances-TBARS) production in striatal homogenates from rats in vitro and ex vivo. It is also shown that GM1 (50 mg/kg, i.p., twice) protects against GA-induced (4 micromol/striatum) seizures, protein carbonylation, TBARS increase, and inhibition of Na+,K+-ATPase activity ex vivo. Convulsive episodes induced by GA strongly correlated with Na+,K+-ATPase activity inhibition in the injected striatum but not with oxidative stress marker measures. Muscimol (46 pmol/striatum), but not MK-801 (3 nmol/striatum) and DNQX (8 nmol/striatum) prevented GA-induced convulsions, increase of TBARS and protein carbonylation and inhibition of Na+,K+-ATPase activity. The protection of GM1 and muscimol against GA-induced seizures strongly correlated with Na+,K+-ATPase activity maintenance ex vivo. In addition, GM1 (50-200 microM) protected against Na+,K+-ATPase inhibition induced by GA (6 mM) but not against oxidative damage in vitro. GM1 also decreased pentylenetetrazole (PTZ)-induced (1.8 micromol/striatum) seizures, Na+,K+-ATPase inhibition, and increase of TBARS and protein carbonyl in the striatum. These data suggest that Na+,K+-ATPase and GABA(A) receptor-mediated mechanisms may play important roles in GA-induced seizures and in their prevention by GM1.
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PMID:GM1 ganglioside prevents seizures, Na+,K+-ATPase activity inhibition and oxidative stress induced by glutaric acid and pentylenetetrazole. 1651 83

We report here on an investigation of net nitrate and proton fluxes in root cells of maize (Zea mays L.) seedlings grown without (noninduced) and with (induced) 0.1 millimolar nitrate. A microelectrode system described previously (IA Newman, LV Kochian, MA Grusak, WJ Lucas [1987] Plant Physiol 84: 1177-1184) was utilized to quantify net ionic fluxes from the measurement of electrochemical potential gradients for NO(3) (-) and H(+) within the unstirred layer at the root surface. The nitrate-inducibility, pH dependence, and concentration dependence of net NO(3) (-) uptake correlated quite closely with the electrical response of maize roots to nitrate under the same experimental conditions (as described in PR McClure, LV Kochian, RM Spanswick, JE Shaff [1990] Plant Physiol 93: 281-289). Additionally, it was found that potential inhibitors of the plasmalemma H(+)-ATPase (vandate, diethylstilbestrol), which were shown to abolish the electrical response to NO(3) (-) (in PR McClure, LV Kochian, RM Spanswick, JE Shaff [1990] Plant Physiol 93: 281-289), dramatically inhibited NO(3) (-) absorption. These results strongly indicate that the NO(3) (-) electrical response is due to the operation of a NO(3) (-) transport system in the plasmalemma of maize root cells. Furthermore, the results from the H(+)-ATPase inhibitor studies indicate that the NO(3) (-) transport system is linked to the H(+)-ATPase, presumably as a NO(3) (-)/H(+) symport. This is further supported by the pH response of the NO(3) (-) transport system (inhibition at alkaline pH values) and the change in net H(+) flux from a moderate efflux in the absence of NO(3) (-), to zero net H(+) flux after exposing the maize root to exogenous nitrate. Although these results can be explained by other interpretations, the simplest model that fits both the electrical responses and the NO(3) (-)/H(+) flux data is a NO(3) (-)/H(+) symport with a NO(3) (-):H(+) flux stoichiometry >1, whose operation results in the stimulation of the H(+)-ATPase due to the influx of protons through the cotransport system.
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PMID:Evidence for Cotransport of Nitrate and Protons in Maize Roots : II. Measurement of NO(3) and H Fluxes with Ion-Selective Microelectrodes. 1666 49

Rho is a ring-shaped hexameric motor protein that translocates along nascent mRNA transcript and terminates transcription of select genes in bacteria. Using a numerical optimization algorithm that simultaneously fits all of the presteady-state ATPase kinetic data, we determine how Rho utilizes the chemical energy of ATP hydrolysis to translocate RNA. A random hydrolysis mechanism is ruled out by the observed inhibition of ATPase in a mixed hexamer containing wt and an inactive Rho mutant. We propose a mechanism in which (1) all six subunits are catalytically competent and hydrolyze ATP sequentially, (2) translocation of RNA is driven by the weak to tight binding transition of nucleotide in the catalytic site, (3) hydrolysis is coordinated between adjacent subunits by the transmission of stress via the catalytic arginine finger, (4) hydrolysis weakens the affinity of a subunit for RNA, and (5) the slow release of inorganic phosphate is controlled by changes in circumferential stress around the ring.
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PMID:Mechanochemistry of transcription termination factor Rho. 1679 40


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