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 SH-reactive HgCl2 inhibits the Na,K-ATPase activity potently in a manner antagonized only partially by EDTA or cysteine; solely dimercaprol, a dithiol antidote for mercury, blocks the HgCl2 effects entirely as confirmed also by 203Hg-binding experiments. The results reveal the presence of a chelating component in pure Na,K-ATPase with an affinity for mercury superior to EDTA. The mercury-sensitivity of the Na,K-ATPase is not related to the ouabain-sensitivity. This criterion will be useful for the distinction between ouabain-like and mercury-like inhibitors from body fluids and tissues.
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PMID:Chelation of mercury by ouabain-sensitive and ouabain-resistant renal Na,K-ATPase. 215 24

Mercuric chloride (HgCl2), a neurotoxic compound, inhibited the adenosine triphosphatase (ATPase) system in a concentration-dependent manner. Hydrolysis of ATP was linear with time with or without HgCl2 in the reaction mixtures. Higher inhibition of (Na(+)-K+)ATPase activity by HgCl2 was observed in alkaline (8.0 to 9.0) pH and at lower temperatures (17 to 32 degrees). Activation energy values were increased slightly in the presence of HgCl2. Activation of (Na(+)-K+)ATPase by ATP in the presence of HgCl2 showed a decrease in Vmax from 15.29 to 5.0 mumol of inorganic phosphate (Pi)/mg protein/hr with no change in Km. Similarly, activation of K(+)-stimulated p-nitrophenyl phosphatase (K(+)-PNPPase) in the presence of HgCl2 showed a decrease in Vmax from 3.26 to 1.35 mumols of p-nitrophenol (PNP)/mg protein/hr with no change in Km. K(+)-activation kinetic studies indicated that HgCl2 decreased Vmax from 14.01 to 4.30 mumols Pi/mg protein/hr in the case of (Na(+)-K+)ATPase and from 3.45 to 2.40 mumols PNP/mg protein/hr in the case of K(+)-PNPPase with no changes in Km. Na(+)-activation of (Na(+)-K+)ATPase in the presence of HgCl2 showed a decrease in Vmax from 11.06 to 3.23 mumols Pi/mg protein/hr and an increase in Km from 1.06 to 2.08 mM. Preincubation of microsomes with sulfhydryl (SH) agents dithiothreitol, cysteine and glutathione protected HgCl2-inhibition of (Na(+)-K+)ATPase. The data suggest that HgCl2 inhibited (Na(+)-K+)ATPase by interfering with the dephosphorylation of the enzyme-phosphoryl complex.
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PMID:Effect of mercuric chloride on the kinetics of cationic and substrate activation of the rat brain microsomal ATPase system. 216 72

Effects of HgCl2 (100 microM) para-chloromercuribenzene sulfonate (PCMBS) (1 mM), and oxophenylarsine (OPA) (250 microM) were determined on (a) the rate of Na pump activity in intact winter flounder intestine; (b) activity of Na-K-ATPase in tissue homogenates; and (c) Na-dependent and Na-independent uptake of tyrosine in brush border membrane vesicles. Initial rate of uptake (influx) of 86Rb from the serosal solution of tissues mounted in Ussing chambers, a measure of Na-K-ATPase activity in the intact cell, was inhibited by all three agents with differing time courses. Rapidly permeating HgCl2 inhibited influx to the same degree as ouabain at 30 min, whereas the effects of PCMBS and OPA required 90 min. Cell potassium was also measured as an indirect indicator of ATPase activity and cell membrane permeability. All three agents decreased cell K, although effects on cell K lagged behind those for inhibition of the ATPase. At the concentrations used in the Ussing chamber (or at one-tenth concentration), all agents completely inhibited Na-K-ATPase activity in enzyme assays performed with tissue homogenates. In contrast, only HgCl2 decreased Na-dependent uptake of tyrosine by brush border membrane vesicles. These results suggest that mercurial and arsenical effects on tyrosine absorption are due to inhibition of the Na-K-ATPase thus decreasing the driving force for the cellular uptake by the Na-tyrosine cotransport system. Direct effects on Na-tyrosine cotransport may play a role in the inhibition observed with HgCl2, but not for PCMBS or OPA.
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PMID:Mechanisms of mercurial and arsenical inhibition of tyrosine absorption in intestine of the winter flounder Pseudopleuronectus americanus. 216 23

The apical membrane of mammalian proximal tubule undergoes rapid membrane cycling by exocytosis and endocytosis. Osmotic water and ATP-driven proton transport were measured in endocytic vesicles from rabbit and rat proximal tubule apical membrane labeled in vivo with the fluid phase marker fluorescein-dextran. Osmotic water permeability (Pf) was determined from the time course of fluorescein-dextran fluorescence after exposure of endosomes to an inward osmotic gradient in a stopped-flow apparatus. Pf was 0.009 (rabbit) and 0.029 cm/s (rat) (23 degrees C) and independent of osmotic gradient size. Pf in rabbit endosomes was inhibited reversibly by HgCl2 (KI = 0.2 mM) and had an activation energy of 6.4 +/- 0.5 kcal/mol (15-35 degrees C). Endosomal proton ATPase activity was measured from the time course of internal pH, measured by fluorescein-dextran fluorescence, after the addition of external ATP. Endosomes contained an ATP-driven proton pump that was sensitive to N-ethylmaleimide and insensitive to vanadate and oligomycin. In response to saturating [ATP] the pump acidified the endosomal compartment at a rate of 0.17 (rat) and 0.029 pH unit/s (rabbit); at an external pH of 7.4, the steady-state pH was 6.4 (rat) and 6.5 (rabbit). To examine whether water channels and the proton ATPase were present in the same endosome, the time course of fluorescein-dextran fluorescence was measured in response to an osmotic gradient in the presence and absence of ATP. ATP did not alter endosome Pf, but decreased the amplitude of the fluorescence signal by 43 +/- 3% (rabbit) and 47 +/- 4% (rat).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Functional colocalization of water channels and proton pumps in endosomes from kidney proximal tubule. 247 63

Electrophysiological studies employing amphibian neuromuscular preparations have shown that mercuric chloride (HgCl2) in vitro increases both spontaneous and evoked neurotransmitter release. The present study examines the effect of HgCl2 on the release of [3H]dopamine from synaptosomes prepared from mammalian brain tissue. Mercuric chloride (3-10 microM) produces a concentration-dependent increase in spontaneous [3H]dopamine release from "purified" rat striatal synaptosomes, in both the presence and absence of extra-synaptosomal calcium. The effects of HgCl2 on transmitter release from amphibian neuromuscular junction preparations resemble those produced by the Na+, K+-ATPase inhibitor ouabain. Experiments were performed to determine whether the HgCl2 effects on mammalian synaptosomal dopamine release are a consequence of Na+, K+-ATPase inhibition. Na+, K+-ATPase activity in lysed synaptosomal membranes is inhibited by HgCl2 (IC50 = 160 nM). However, mercuric chloride in the presence of 1 mM ouabain still increased [3H]dopamine release. The specific inhibitor of Na+-dependent, high-affinity dopamine transport, RMI81,182 inhibited ouabain-induced [3H]dopamine release whereas it had no effect on HgCl2-induced [3H]dopamine release. These data suggest that augmentation of spontaneous [3H]dopamine release by HgCl2 probably is not mediated by an inhibition of Na+, K+-ATPase and HgCl2 does not act directly on the dopamine transporter.
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PMID:Effects of mercuric chloride on [3H]dopamine release from rat brain striatal synaptosomes. 254 41

1. Reidentifiable Aplysia neurones were current and voltage clamped in vitro using standard microelectrode techniques. 2. Bath or focal application of Cu2+ at concentrations of 1-100 microM produced a rapid and reversible depolarization of the somal, but not the axonal, membrane potential. The depolarization was accompanied by an increased membrane conductance and activation of an inward current (ICu) which could not be activated by intracellular ionophoretic injection of Cu2+. 3. ICu is carried, in part, by Na+ because the reversal potential of ICu was shifted in a Nernstian fashion by decreasing the extracellular Na+ concentration. The reversal potential of ICu was not affected by removal of extracellular Ca2+ or K+. 4. ICu does not result from (1) activation of known chemically or voltage-gated Na+ conductances, (2) inhibition of the Na+-K+-ATPase or (3) a generalized increase in membrane permeability resulting from lipid peroxidation. 5. A similar inward current was activated by AgNO3 (100 microM) and HgCl2 (100 microM).
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PMID:Copper activates a unique inward current in molluscan neurones. 283 93

Previous experiments indicated that the partial reversal of mercuric chloride-induced renal dysfunction in rats by subsequent dithiothreitol (DTT) administration was not related to increased mercury excretion, decreased renal mercury concentration, a change in renal cortical subcellular mercury distribution, or the formation of a Hg-DTT complex. The present studies investigated whether DTT, a sulfhydryl reducing agent, protected renal cortical sulfhydryl status in general, or the activity of various renal enzymes (Mg- and Na,K-ATPases, alkaline phosphatase, and glutathione peroxidase) in particular. Additionally, the occurrence of conjugated dienes was used to assess the degree of lipid peroxidation. HgCl2 produced significant decreases in renal cortical protein-bound sulfhydryl concentration, alkaline phosphatase activity, and ATPase activity within 2.5 h of administration, with no effect observed on glutathione peroxidase activity or the levels of conjugated dienes in rat renal cortex. Administration of DTT 60 min after mercury neither provided protection from inhibition nor promoted restoration of the affected enzymes or sulfhydryl status. It is concluded that the partial protection of renal function offered by DTT in the early stages of mercury toxicity does not result from maintaining the integrity of renal cortical sulfhydryl status or the activity of the enzymes investigated. Furthermore, the early stages of mercury toxicity did not appear to be related to lipid peroxidation.
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PMID:Enzyme activity and sulfhydryl status in rat renal cortex following mercuric chloride and dithiothreitol administration. 284 77

The effects of HgCl2, CH3HgCl, p-chloromercuribenzene sulfonate (PCMBS), and CdCl2 on plasma membrane and cell metabolic functions of skate (Raja erinacea) hepatocytes in suspension culture were assessed by measuring (a) the rates of Na+-dependent and -independent L-[14C]alanine uptake, (b) Na+-dependent 86Rb+ uptake, a measure of Na-K-ATPase activity, (c) 86Rb+ efflux, a measure of K+ permeability, (d) the difference between the 3H2O and [14C]inulin distribution spaces, a measure of intracellular water volume, (e) cellular ATP concentrations, and (f) glutathione (GSH) and glutathione disulfide (GSSG) levels. The initial rates of L-alanine and 86Rb+ uptake were inhibited by each of these metals in the following order: HgCl2 greater than CH3HgCl greater than PCMBS greater than CdCl2. Inorganic mercury significantly inhibited the initial rates of Na+-dependent L-alanine and 86Rb uptakes at a concentration of 10 microM, whereas 100 microM produced nearly complete inhibition. These effects were dose-dependent, immediate (observed after less than 5 min of incubation with the metal), and persistent. Mercuric chloride also impaired volume regulatory mechanisms in skate hepatocytes: cells treated with 50 microM HgCl2 swelled slowly over a 60-min interval to volumes nearly double those of control cells. In addition, HgCl2 prevented the normal volume regulatory decrease observed after swelling the hepatocytes in hypotonic media. Mercuric chloride (5-50 microM) produced a rapid initial loss of a large fraction of intracellular 86Rb, followed by a slower rate of release of the remaining isotope. These effects were prevented if GSH was added with, but not following HgCl2. In contrast, dithiothreitol, a more permeable thiol, both prevented and even partially reversed the effects of mercury. Mercuric chloride (10 microM) had no effect on cellular ATP, GSH, or GSSG levels for up to 4 hr incubation. These findings indicate that 86Rb+ (K+) efflux is a sensitive indicator of mercury toxicity, and are consistent with the hypothesis that the plasma membrane is a primary target for mercury's effects. A change in membrane permeability to K+ would dissipate transmembrane electrochemical gradients, and may contribute to the apparent inhibition of transport processes energized by these gradients, such as Na+-alanine cotransport, and volume regulatory mechanisms.
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PMID:Altered plasma membrane ion permeability in mercury-induced cell injury: studies in hepatocytes of elasmobranch Raja erinacea. 284 8

Inhibition of glutamate transport is a potential indirect cause of excitotoxic damage by glutamate in the CNS. The mercuric ion, the form in which metallic mercury vapor is believed to exert its neurotoxic action, is a known inhibitor of amino acid transport. This study examines the specificity with which HgCl2 inhibits glutamate transport in mouse cerebral astrocytes by means of comparative measurements of 2-deoxyglucose uptake. Uptake of 2-deoxyglucose is an index of glucose utilization that reflects the function of Na+,K+-ATPase and hexokinase, and is sensitive to Na+ entry. The kinetic parameters, ionic dependence, and substrate specificity of glutamate transport in these astrocyte cultures were consistent with the commonly occurring system designated X-AG. Acute exposure to 0.5 microM HgCl2 inhibited by 50% the initial rate of glutamate transport but did not affect 2-deoxyglucose uptake. Glutamate transport was not detectably inhibited by Al2+, Pb2+, Co2+, Sr2+, Cd2+, or Zn2+ (10 microM as chlorides). The inhibitory action of 0.5 microM HgCl2 on glutamate transport was rapidly reversible. The action of 1-2 microM HgCl2 was progressive when exposures were extended to 1-3 h, and was more slowly reversible. These results suggest that Hg2+ can impair glial glutamate transport reversibly at exposure levels that do not compromise some other vital cell functions.
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PMID:Specificity and reversibility of the inhibition by HgCl2 of glutamate transport in astrocyte cultures. 289 9

Mercuric compounds have been shown to alter several membrane-bound enzymes and associated receptor activities. The present studies were initiated to investigate the in vitro effects of mercuric chloride (HgCl2) and methylmercury chloride (CH3HgCl) on the uptake of [3H]dopamine (3HDA), [3H]norepinephrine (3HNE), and Na+, K+-ATPase in rat brain synaptosomes. Brain synaptosomes were prepared by the ficoll-sucrose gradient method from normal, adult male Sprague-Dawley rats, weighing approx. 200 g. The effect of mercury on Na+, K+-ATPase was determined by using a coupled enzymatic method. Uptake of DA and NE by brain synaptosomes was determined by filtration in the presence and absence of 0-30 microM HgCl2 and 0-100 microM CH3HgCl. A parallel inhibition in the synaptosomal uptake of 3HDA and 3HNE, and the activity of the synaptosomal membrane Na+, K+-ATPase, was observed in both mercuric chloride and methylmercury treatments. The mercury compounds also significantly inhibited the mitochondrial ATPase (Mg2+-oligomycin-sensitive ATPase). The inhibitory influences of the toxins were concentration-dependent. The results suggest that the mercury compound mediated decrease in DA and NE uptake in brain synaptosomes may be related to the inhibition of Na+, K+-ATPase by the same toxins.
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PMID:Influence of mercury on uptake of [3H]dopamine and [3H]norepinephrine by rat brain synaptosomes. 299 49


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