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)

Within 2 min of stroke onset, neurons and glia in brain regions most deprived of blood (the ischemic core) undergo a sudden and profound loss of membrane potential caused by failure of the Na+/K+ ATPase pump. This anoxic depolarization (AD) represents a collapse in membrane ion selectivity that causes acute neuronal injury because neurons simply cannot survive the energy demands of repolarization while deprived of oxygen and glucose. In vivo and in live brain slices, the AD resists blockade by antagonists of neurotransmitter receptors (including glutamate) or by ion channel blockers. Our neuroprotective strategy is to identify AD blockers that minimally affect neuronal function. If the conductance underlying AD is not normally active, its selective blockade should not alter neuronal excitability. Imaging changes in light transmittance in live neocortical and hippocampal slices reveal AD onset, propagation, and subsequent dendritic damage. Here we identify several sigma-1 receptor ligands that block the AD in slices that are pretreated with 10-30 microM of ligand. Blockade prevents subsequent cell swelling, dendritic damage, and loss of evoked field potentials recorded in layers II/III of neocortex and in the CA1 region of hippocampus. Even when AD onset is merely delayed, electrophysiological recovery is markedly improved. With ligand treatment, evoked axonal conduction and synaptic transmission remain intact. The large nonselective conductance that drives AD is still unidentified but represents a prime upstream target for suppressing acute neuronal damage arising during the first critical minutes of stroke. Sigma receptor ligands provide insight to better define the properties of the channel responsible for anoxic depolarization. Video clips of anoxic depolarization and spreading depression can be viewed at http://anatomy.queensu.ca/faculty/andrew.cfm.
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PMID:Blocking the anoxic depolarization protects without functional compromise following simulated stroke in cortical brain slices. 1545 3

Polygodial is a naturally occurring sesquiterpene dialdehyde that exhibits several pharmacologically interesting activities. Among them, its antifungal properties have been more thoroughly studied. The mitochondrial ATPase has been suggested as one of the possible targets for polygodial action. However, its mechanism of action is not well defined yet. The effect of polygodial on the mitochondrial energy metabolism is described in this paper. Polygodial inhibited ATP synthesis coupled to succinate oxidation in beef-heart submitochondrial particles at concentrations (IC(50)=2.4+/-0.1 microM) which marginally affected electron transport and ATPase activity (IC(50)=97+/-4 microM). A transitory stimulation of the electron transport in intact rat liver mitochondria in state 4 was also obtained at low polygodial concentrations (EC(50)=20+/-4 microM). These results suggest that polygodial uncouples ATP synthesis from electron transport at low concentrations. Similar concentrations of polygodial partially abolished the ANS fluorescence enhancement (IC(50)=2.2+/-0.4 microM) induced by succinate oxidation in submitochondrial particles but did not collapse the DeltapH. We postulate that polygodial uncouples mitochondrial ATP synthesis by affecting the electrical properties of the membrane surface and consequently collapsing the membrane potential (Deltapsi) and/or the localized transmembrane pH difference (DeltapH(S)) without affecting the DeltapH between the two bulk aqueous phases (DeltapH(B)). The relevance of these findings for the understanding of the biochemical basis of the antifungal activity of polygodial and the evaluation of its potentiality as a therapeutic agent are discussed.
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PMID:Inhibition of the mitochondrial ATP synthesis by polygodial, a naturally occurring dialdehyde unsaturated sesquiterpene. 1589 93

The hypersensitive response (HR) is defined as rapid cell collapse at the infection site and often accompanies plant resistance. The physiological processes leading to HR are not well understood. Here, we report an electrophysiological characterization of bacterial HR caused by a single avirulence gene in the absence of other bacterial signals. We used dexamethasone (dex)-inducible transgenic Arabidopsis (Arabidopsis thaliana) plants containing the avrRpt2 gene from Pseudomonas syringae pv tomato. Membrane depolarization in these plants began 1 to 1.5 h after dex application, hours before electrolyte leakage. Progressive depolarization was a sensitive early indicator of HR that occurred only in Arabidopsis leaf cells expressing both avrRpt2 and a functional RPS2 gene. Hyperpolarization of fully depolarized membranes by fusicoccin, a fungal toxin that activates the H(+)-ATPase, indicates that depolarization did not result from a nonfunctional pump or leaky membranes. Depolarization and electrolyte leakage were inhibited in RPS2 plants by the calcium channel blocker LaCl(3), highly correlating these events and suggesting that Ca(2+) entry into cells is required for both. Also correlated were inhibition of depolarization, electrolyte leakage, and HR following salicylic acid pretreatment. In salicylic acid-pretreated RPS2 seedlings, avrRpt2 transcript was produced after dex treatment. However, AvrRpt2 protein accumulation was greatly reduced, suggesting a possible mechanism for inhibition of HR in plants with induced resistance. This experimental system is a very sensitive assay that lends itself to the dissection of physiological processes leading to HR in plants, and provides a baseline for future research within a genetic framework.
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PMID:Electrophysiological characterization of the Arabidopsis avrRpt2-specific hypersensitive response in the absence of other bacterial signals. 1590 9

Lactobacillus rhamnosus GG is an industrially significant probiotic strain with proven health benefits. In this study, the effect of glucose on L. rhamnosus GG survival was analyzed in simulated gastric juice at pH 2.0. It was found that the presence of 19.4 mM glucose resulted in up to 6-log10-enhanced survival following 90 min of exposure. Further work with dilute HCl confirmed that glucose was the sole component responsible. Comparative analysis with other Lactobacillus strains revealed that enhanced survival was apparent in all strains, but at different pH values. The presence of glucose at concentrations from 1 to 19.4 mM enhanced L. rhamnosus GG survival from 6.4 to 8 log10 CFU ml(-1) in simulated gastric juice. The mechanisms behind the protective effect of glucose were investigated. Addition of N',N'-dicyclohexylcarbodiimide to simulated gastric juice caused survival to collapse, which was indicative of a prominent role in inhibition of F0F1-ATPase. Further work with neomycin-resistant mutants that exhibited 38% to 48% of the F0F1-ATPase activity of the parent confirmed this, as the survival in the presence of glucose of these mutants decreased 3 x 10(6)-fold compared with the survival of the wild type (which had a viability of 8.02 log10 CFU ml(-1)). L. rhamnosus GG survival in acidic conditions occurred only in the presence of sugars that it could metabolize efficiently. To confirm the involvement of glycolysis in the glucose effect, iodoacetic acid was used to inhibit glyceraldehyde-3-phosphate dehydrogenase (GAPDH) activity. The reduction in GAPDH activity caused survival to decrease by 8.30 log10 CFU ml(-1) in the presence of glucose. The data indicate that glucose provides ATP to F0F1-ATPase via glycolysis, enabling proton exclusion and thereby enhancing survival during gastric transit.
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PMID:Survival of probiotic lactobacilli in acidic environments is enhanced in the presence of metabolizable sugars. 1593 2

Neuronal development requires highly coordinated regulation of the cytoskeleton within the developing axon. This dynamic regulation manifests itself in axonal branching, turning and pathfinding, presynaptic differentiation, and growth cone collapse and extension. Semaphorin 3A (Sema3A), a secreted guidance cue that primarily functions to repel axons from inappropriate targets, induces cytoskeletal rearrangements that result in growth cone collapse. These effects require intra-axonal messenger RNA translation. Here we show that transcripts for RhoA, a small guanosine triphosphatase (GTPase) that regulates the actin cytoskeleton, are localized to developing axons and growth cones, and this localization is mediated by an axonal targeting element located in the RhoA 3' untranslated region (UTR). Sema3A induces intra-axonal translation of RhoA mRNA, and this local translation of RhoA is necessary and sufficient for Sema3A-mediated growth cone collapse. These studies indicate that local RhoA translation regulates the neuronal cytoskeleton and identify a new mechanism for the regulation of RhoA signalling.
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PMID:Local translation of RhoA regulates growth cone collapse. 1610 49

The potential toxicity of the herbicide Roundup and its fundamental substance (glyphosate) was tested in bioenergetic functions of isolated rat liver mitochondria. Roundup stimulates succinate-supported respiration twice, with simultaneous collapse of transmembrane electrical potential, while glyphosate used in the same concentrations does not induce any significant effect. Additionally, Roundup depresses state 3 respiration by about 40%, at 15 mM, whereas uncoupled respiration in the presence of FCCP is depressed by about 50%. Depression of uncoupled respiratory activity is mediated through partial inhibition of mitochondrial complexes II and III, but not of complex IV. The phosphorylative system was affected by both a direct and an indirect effect on the F0F1 ATPase activity. The addition of uncoupled concentrations of Roundup to Ca2+-loaded mitochondria treated with Ruthenium Red resulted in non-specific membrane permeabilization, as evidenced by mitochondrial swelling in isosmotic sucrose medium. Therefore, the uncoupling of oxidative phosphorylation is also related to the non-specific membrane permeabilization induced by Roundup. Glyphosate alone does not show any relevant effect on the mitochondrial bioenergetics, in opposition to Roundup formulation products. The differences in the toxicity observed could be either attributed to some products of Roundup or to a synergic effect of glyphosate and formulation products. Bearing in mind that mitochondria is provided with a variety of bioenergetic functions mandatory for the regulation of intracellular aerobic energy production and electrolyte homeostasis, these results question the safety of Roundup on animal health.
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PMID:Comparative effects of the Roundup and glyphosate on mitochondrial oxidative phosphorylation. 1626 81

The fluorescent compound Hoechst 33342 is a substrate for many multidrug resistance (MDR) transporters and is widely used to characterize their transport activity. We have constructed mutants of the adenosine triphosphate (ATP) binding cassette (ABC)-type MDR transporter LmrA of Lactococcus lactis that are defective in ATP hydrolysis. These mutants and wild-type LmrA exhibited an atypical behavior in the Hoechst 33342 transport assay. In membrane vesicles, Hoechst 33342 transport was shown to be independent of the ATPase activity of LmrA, and it was not inhibited by orthovanadate but sensitive to uncouplers that collapse the proton gradient and to N,N'-dicyclohexylcarbodiimide, an inhibitor of the F0F1-ATPase. In contrast, transport of Hoechst 33342 by the homologous, heterodimeric MDR transporter LmrCD showed a normal ATP dependence and was insensitive to uncouplers of the proton gradient. With intact cells, expression of LmrA resulted in an increased rate of Hoechst 33342 influx while LmrCD caused a decrease in the rate of Hoechst 33342 influx. Cellular toxicity assays using a triple knockout strain, i.e., L. lactis delta lmrA delta lmrCD, demonstrate that expression of LmrCD protects cells against the growth inhibitory effects of Hoechst 33342, while in the presence of LmrA, cells are more susceptible to Hoechst 33342. Our data demonstrate that the LmrA-mediated Hoechst 33342 transport in membrane vesicles is influenced by the transmembrane pH gradient due to a pH-dependent partitioning of Hoechst 33342 into the membrane.
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PMID:Proton motive force-dependent Hoechst 33342 transport by the ABC transporter LmrA of Lactococcus lactis. 1636 6

We set out to identify molecular mechanisms underlying the onset of necrotic Ca(2+) overload, triggered in two epithelial cell lines by oxidative stress or metabolic depletion. As reported earlier, the overload was inhibited by extracellular Ca(2+) chelation and the cation channel blocker gadolinium. However, the surface permeability to Ca(2+) was reduced by 60%, thus discarding a role for Ca(2+) channel/carrier activation. Instead, we registered a collapse of the plasma membrane Ca(2+) ATPase (PMCA). Remarkably, inhibition of the Na(+)/K(+) ATPase rescued the PMCA and reverted the Ca(2+) rise. Thermodynamic considerations suggest that the Ca(2+) overload develops when the Na(+)/K(+) ATPase, by virtue of the Na(+) overload, clamps the ATP phosphorylation potential below the minimum required by the PMCA. In addition to providing the mechanism for the onset of Ca(2+) overload, the crosstalk between cation pumps offers a novel explanation for the role of Na(+) in cell death.
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PMID:ATP steal between cation pumps: a mechanism linking Na+ influx to the onset of necrotic Ca2+ overload. 1641 Jul 94

The correlations between ATP concentration in corn (Zea mays) root tissue and the rate of phosphate absorption by the tissue have been examined. Experimental variation was secured with 2,4-dinitrophenol, oligomycin, mersalyl, l-ethionine, 2-deoxyglucose, N(2) gassing and inhibition of protein synthesis. It is concluded that ATP could be the energy source for potassium phosphate absorption, but only if the transport mechanism possesses certain properties: oligomycin-sensitivity; creation of a proton gradient susceptible to collapse by uncouplers; phosphate transport via a mersalyl-sensitive Pi(-)-OH(-) transporter; good activity at energy charge as low as 0.4; short enzymatic half-life for the ATPase or phosphate transporter; a linked mechanism for K(+)-H(+) exchange transport, possibly electrogenic.
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PMID:Phosphate absorption rates and adenosine 5'-triphosphate concentrations in corn root tissue. 1665 69

Evidence is presented that K(+) uptake in corn root segments is coupled to an electrogenic H(+)/K(+) -exchanging plasmalemma ATPase while phosphate uptake is coupled to an OH(-)/Pi antiporter. The plasmalemma ATPase inhibitor, diethylstilbestrol, or the stimulator, fusicoccin, altered K(+) uptake directly and phosphate uptake indirectly. On the other hand, mersalyl, an OH(-)/Pi antiporter inhibitor, inhibited phosphate uptake instantly but only slightly affected K(+) uptake. Collapse of the proton gradient across the membrane by (p-trifluoromethoxy) carbonyl cyanide phenylhydrazone resulted in immediate inhibition of K(+) uptake but only later inhibited phosphate uptake. Changing the pH of the absorption solution had opposite effects on K(+) and phosphate uptake. In addition, a 4-hour washing of corn root tissue induced a 5-fold increase in the rate of K(+) uptake with little or no lag, but only a 2- to 3-fold increase in phosphate uptake with a 30- to 45-minute lag. Collectively these differences strongly support the coupling of an electrogenic H(+)/K(+) -exchanging ATPase to an OH(-)/Pi antiporter in corn root tissue.
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PMID:Potassium and Phosphate Uptake in Corn Roots: Further Evidence for an Electrogenic H/K Exchanger and an OH/Pi Antiporter. 1666 Aug 43


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