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)

1. Reactive oxygen species (ROS) can be generated in biological tissues, including the retina, in particular under or after ischemia. They can provoke cell necrosis by reacting with cell components or they can trigger programmed cell death by activating specific targets. 2. Experiments based on electroretinography and electron spin resonance spin trapping analysis show that ROS are produced in the rabbit retina during ischemic episodes themselves as well as reperfusion. ROS are also generated as a consequence of ischemia by overstimulation of glutamate ionotropic receptors and calcium-dependent activation of enzymes such as phospholipase A2 and nitric oxide synthase. 3. The targets of ROS that can be responsible for functional damage of the retina are numerous: Na+-K+-ATPase inhibition leads to ionic imbalance and electroretinogram alteration; inhibition of glutamate transporter contributes to excitotoxicity. In addition, ROS can be deleterious by inducing protein synthesis (e.g., apoptotic proteins, vascular endothelial growth factor/vascular permeability factor). 4. In this short review, we consider the various mechanisms of ROS generation in retinal ischemia and the different effects of ROS so as to suggest possible effects of neuroprotective agents.
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PMID:Free radicals in retinal ischemia. 951 74

The role of cell type-specific Na+,K+-ATPase isozymes in function-related glucose metabolism was studied using differentiated rat brain cell aggregate cultures. In mixed neuron-glia cultures, glucose utilization, determined by measuring the rate of radiolabeled 2-deoxyglucose accumulation, was markedly stimulated by the voltage-dependent sodium channel agonist veratridine (0.75 micromol/L), as well as by glutamate (100 micromol/L) and the ionotropic glutamate receptor agonist N-methyl-D-aspartate (NMDA) (10 micromol/L). Significant stimulation also was elicited by elevated extracellular potassium (12 mmol/L KCl), which was even more pronounced at 30 mmol/L KCl. In neuron-enriched cultures, a similar stimulation of glucose utilization was obtained with veratridine, specific ionotropic glutamate receptor agonists, and 30 mmol/L but not 12 mmol/L KCl. The effects of veratridine, glutamate, and NMDA were blocked by specific antagonists (tetrodotoxin, CNQX, or MK801, respectively). Low concentrations of ouabain (10(-6) mol/L) prevented stimulation by the depolarizing agents but reduced only partially the response to 12 mmol/L KCl. Together with previous data showing cell type-specific expression of Na+,K+-ATPase subunit isoforms in these cultures, the current results support the view that distinct isoforms of Na+,K+-ATPase regulate glucose utilization in neurons in response to membrane depolarization, and in glial cells in response to elevated extracellular potassium.
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PMID:Separate neuronal and glial Na+,K+-ATPase isoforms regulate glucose utilization in response to membrane depolarization and elevated extracellular potassium. 1047 57

Spermine has been shown to influence NMDA receptor function through an interaction at the coagonist site for glycine in the central nervous system (CNS) and the retina. In order to support a role for spermine as neurotransmitter or neuromodulator in the chick retina, specific stimulated-release of spermine should be demonstrated. Isolated chick retinas, preloaded with [3H]spermine, were stimulated with 1 mM NMDA and other glutamate agonists at ionotropic receptors, in a continuous superfusion system. [3H]spermine was released from the retina by depolarization with 50 mM KCl, in a Ca2+-independent manner. Inhibition of Na+/K+-ATPase by ouabain or digitoxigenin also induced spermine release following 36 min in the presence of the drugs; such effect seems unrelated to changes in Na+ electrochemical gradients, since nigericin and veratrine did not induce release in Na+ containing medium. The lack of effect of glutamate, NMDA and kainate at 1 mM concentration, suggests that release of spermine in the retina is mediated by the reversal of uptake and not necessarily linked to EAA-receptor activation.
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PMID:Calcium-independent release of [3H]spermine from chick retina. 1078 99

The mode of Na+ entry and the dynamics of intracellular Na+ concentration ([Na+]i) changes consecutive to the application of the neurotransmitter glutamate were investigated in mouse cortical astrocytes in primary culture by video fluorescence microscopy. An elevation of [Na+]i was evoked by glutamate, whose amplitude and initial rate were concentration dependent. The glutamate-evoked Na+ increase was primarily due to Na+-glutamate cotransport, as inhibition of non-NMDA ionotropic receptors by 6-cyano-7-nitroquinoxiline-2,3-dione (CNQX) only weakly diminished the response and D-aspartate, a substrate of the glutamate transporter, produced [Na+]i elevations similar to those evoked by glutamate. Non-NMDA receptor activation could nevertheless be demonstrated by preventing receptor desensitization using cyclothiazide. Thus, in normal conditions non-NMDA receptors do not contribute significantly to the glutamate-evoked Na+ response. The rate of Na+ influx decreased during glutamate application, with kinetics that correlate well with the increase in [Na+]i and which depend on the extracellular concentration of glutamate. A tight coupling between Na+ entry and Na+/K+ ATPase activity was revealed by the massive [Na+]i increase evoked by glutamate when pump activity was inhibited by ouabain. During prolonged glutamate application, [Na+]i remains elevated at a new steady-state where Na+ influx through the transporter matches Na+ extrusion through the Na+/K+ ATPase. A mathematical model of the dynamics of [Na+]i homeostasis is presented which precisely defines the critical role of Na+ influx kinetics in the establishment of the elevated steady state and its consequences on the cellular bioenergetics. Indeed, extracellular glutamate concentrations of 10 microM already markedly increase the energetic demands of the astrocytes.
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PMID:A quantitative analysis of L-glutamate-regulated Na+ dynamics in mouse cortical astrocytes: implications for cellular bioenergetics. 1106 79

It is widely accepted that energy deprivation causes a neuronal death that is mainly determined by an increase in the extracellular level of glutamate. Consequently an excessive membrane depolarization and a rise in the intracellular concentration of sodium and calcium are produced. In spite of this scenario, the function of excitatory and inhibitory amino acids during an episode of energy failure has not been studied yet at a cellular level. In a model of cerebral hypoglycemia in the rat substantia nigra pars compacta, we measured neuronal responses to excitatory amino acid agonists. Under single-electrode voltage-clamp mode at -60 mV, the application of the ionotropic glutamate receptor agonists N-methyl-D-aspartate, alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid, kainate, and the metabotropic group I agonist (S)-3,5-dihydroxyphenilglycine (DHPG) produced reversible inward currents in the dopaminergic cells. In addition, an outward current was caused by the superfusion of the metabotropic GABA(B) agonist baclofen. Glucose deprivation enhanced the inward responses caused by each ionotropic glutamate agonist. In contrast, hypoglycemia depressed the DHPG-induced inward current and the baclofen-induced outward current. These effects of hypoglycemia were reversible. To test whether a failure of the Na(+)/K(+) ATPase pump could account for the modification of the agonist-induced currents during hypoglycemia, we treated the midbrain slices with strophanthidin (1-3 microM). Strophanthidin enhanced the inward currents caused by glutamate agonists. However, it did not modify the GABA(B)-induced outward current. Our data suggest that glucose deprivation enhances the inward current caused by the stimulation of ionotropic glutamate receptors while it dampens the responses caused by the activation of metabotropic receptors. Thus a substantial component of the augmented neuronal response to glutamate, during energy deprivation, is very likely due to the failure of Na(+) and Ca(2+) extrusion and might ultimately favor excitotoxic processes in the dopaminergic cells.
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PMID:Hypoglycemia enhances ionotropic but reduces metabotropic glutamate responses in substantia nigra dopaminergic neurons. 1124 85

Recent studies indicate that effects of ATP on unmyelinated afferent nerve fibres contribute to the transduction of nociceptive and non-nociceptive stimuli. In the present study, effects of ATP were studied on axons and Schwann cells of C fibres in isolated rat vagus nerves. A combination of a computerised threshold tracking technique with photometric and confocal measurements of the free intracellular Ca2+ concentration revealed differences in the effect of ATP and related compounds. Pyridoxal-phosphate-6-azophenyl-2',5'-disulphonic acid (iso-PPADS, an antagonist of ionotropic P2X receptors) completely blocked the excitatory effect of alpha,beta-meATP on unmyelinated axons, whereas the effects of ATP and 2-Cl-ATP were only slightly changed. Moreover, the threshold lowering effects of ATP and 2-Cl-ATP, but not of alpha,beta-meATP, were accompanied by intracellular Ca2+ transients. In confocal imaging experiments, the lectin IB4 was used to identify unmyelinated nerve fibres and their ensheathing Schwann cells. The Schwann cells were identified as the cellular elements underlying ATP-induced Ca2+ transients. In addition, an increase in axonal excitability of C fibres was seen during a rise in [Ca2+]i induced by inhibition of the endoplasmic Ca2 ATPase with cyclopiazonic acid. These data show that an increase of the extracellular ATP concentration in an intact peripheral nerve trunk activates both axons and Schwann cells. It appears that P2 nucleotide receptors on Schwann cells may contribute to the excitatory effect of ATP observed on unmyelinated, including nociceptive, axons.
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PMID:ATP affects both axons and Schwann cells of unmyelinated C fibres. 1137 7

Potentiation of ionotropic glutamate receptor activity by metabotropic glutamate receptors (mGluRs) is thought to modulate activity at glutamatergic synapses in the hippocampus. However, the precise pathway by which this modulation occurs is not well understood. The present study tests the hypothesis that mGluR1-mediated potentiation of N-methyl-D-aspartate receptors (NMDARs) occurs via a phospholipase C (PLC)-initiated cascade. NMDAR functional activity was examined by whole-cell recording from Xenopus oocytes expressing recombinant NMDARs and mGluR1alpha. The mGluR1 agonist (1S,3R)-1-amino-cyclopentane-1,3-dicarboxylic acid (ACPD) significantly potentiated NMDA-elicited currents. mGluR1alpha-mediated potentiation of NMDA responses was eliminated by the PLC inhibitor U-73122. Buffering of intracellular Ca2+ by BAPTA-AM or depletion of intracellular Ca2+ by the Ca2+/ATPase inhibitor thapsigargin greatly reduced ACPD potentiation. ACPD potentiation was reduced by the specific protein kinase C (PKC) inhibitor Ro-32-0432 and eliminated by the broad spectrum kinase inhibitor staurosporine. ACPD produced no further potentiation after potentiation of NMDARs by the PKC-activating phorbol ester 12-O-tetradecanoyl phorbol-13-acetate (TPA). Thus, Group I mGluRs potentiate NMDA responses via activation of PLC; at least part of the potentiation is due to rise in intracellular Ca2+ and stimulation of PKC. Cytochalasin D, which disrupts the actin cytoskeleton, blocked ACPD-elicited chloride currents and ACPD-induced potentiation of NMDAR currents, consistent with a role for cytoskeletal protein(s) in the signaling pathway. As Group I mGluRs are localized to the perisynaptic region in juxtaposition to NMDARs at glutamatergic synapses, mGluR-mediated potentiation of NMDAR activity may play a role in synaptic transmission and plasticity including LTP.
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PMID:mGluR1-mediated potentiation of NMDA receptors involves a rise in intracellular calcium and activation of protein kinase C. 1137 56

The effect of trichloroethanol (TCEt), the active metabolite of chloral hydrate, on the intracellular concentration of calcium ([Ca(2+)](i)) was investigated in rat submandibular glands (RSMG) acini loaded with fura-2. TCEt (1 - 10 mM) increased the [Ca(2+)](i) independently of the presence of calcium in the extracellular medium. Dichloroethanol (DCEt) and monochloroethanol (MCEt) reproduced the stimulatory effect of TCEt but at much higher concentrations (about 6 fold higher for DCEt and 20 fold higher for MCEt). TCEt mobilized an intracellular pool of calcium, which was depleted by a pretreatment with thapsigargin, an inhibitor of the sarcoplasmic and endoplasmic reticulum calcium-dependent ATPases, but not with FCCP, an uncoupler of mitochondria. TCEt 10 mM inhibited by 50% the thapsigargin-sensitive microsomal Ca(2+)-ATPase. DCEt 10 mM and MCEt 10 mM inhibited the ATPase by 20 and 10%, respectively. TCEt inhibited the increase of the [Ca(2+)](i) and the production of inositol phosphates in response to carbachol, epinephrine and substance P. TCEt inhibited the uptake of calcium mediated by the store-operated calcium channel (SOCC). ATP and Bz-ATP increased the [Ca(2+)](i) in RSMG acini and this effect was blocked by extracellular magnesium, by Coomassie blue and by oxydized ATP (oATP). TCEt potentiated the increase of the [Ca(2+)](i) and of the uptake of extracellular calcium in response to ATP and Bz-ATP. TCEt had no effect on the uptake of barium and of ethidium bromide in response to purinergic agonists. These results suggest that TCEt, at sedative concentrations, exerts various effects on the calcium regulation: (1) it mobilizes a thapsigargin-sensitive intracellular pool of calcium in RSMG acini; (2) it inhibits the uptake of calcium via the SOCC; (3) it inhibits the activation by G protein-coupled receptors of a polyphosphoinositide-specific phospholipase C. It does not interfere with the activation of the ionotropic P2X receptors. The use of chloral hydrate should be avoided in studies exploring the in vivo responses to sialagogues.
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PMID:Multiple effects of trichloroethanol on calcium handling in rat submandibular acinar cells. 1205 35

The mechanism of action of an endogenous Na(+), K(+)-ATPase inhibitor, termed endobain E, on phosphoinositide hydrolysis was studied in neonatal rat brain cortex and compared with that of ouabain. Lack of additivity for endobain E and glutamate paired stimulation on inositol phosphates accumulation suggested that they share at least a common step on inositol phosphate metabolism, as previously advanced for ouabain. In addition, Cd(2+) sensitivity of endobain E and ouabain effects strengthened the involvement of glutamate receptors. The participation of ionotropic glutamate receptors on endobain E- and ouabain-induced phosphoinositide hydrolysis seems untenable, since antagonists dizocilpine and CNQX proved unable to inhibit these effects. However, the endobain E effect was blocked by 2 x 10 (-4) M L-AP3 (an antagonist for group I mGluRs) when at least a 15-min preincubation protocol was employed. Maximal inhibition of endobain E effect (42%) occurred when L-AP3 preincubation was extended to 60 min, as already shown with glutamate, but only a trend to decrease was recorded with ouabain. At variance, the ouabain effect was reduced to 50% employing 5 x 10 (-4) M MCPG (a competitive antagonist for group I mGluRs), whereas no blockade was observed with endobain E or glutamate. In addition, MPEP (a selective mGluR5 antagonist) partially reduced ouabain, endobain E and glutamate responses and the selective mGluR1 antagonist LY367385 showed no activity at all. To sum up, the present findings support the involvement of mGluR5 in both endobain E and ouabain phosphoinositide hydrolysis stimulation in neonatal rat brain, in spite of dissimilar response to tested antagonists.
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PMID:Metabotropic glutamate receptor involvement in phosphoinositide hydrolysis stimulation by an endogenous Na(+), K(+)-ATPase inhibitor and ouabain in neonatal rat brain. 1235 44

Na/K-ATPase prepared from cerebellum granule cells of 10-12-day-old mice is inhibited by glutamate and its agonists, NMDA (ligand for ionotropic receptors) and ACPD (ligand for metabotropic receptors). The inhibition is specific and prevented by subsequent antagonists (MK-801 for ionotropic NMDA-receptors and MCPG for metabotropic receptors). The inhibiting effect of NMDA is significantly reversed by cysteine and that of ACPD by chelerythrine or indolyl maleimide. It is concluded that ionotropic receptors inhibit Na/K-ATPase because of intracellular production of reactive oxygen species, and metabotropic receptors mediate their effect via protein kinase C.
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PMID:Activation of glutamate receptors inhibits Na/K-ATPase of cerebellum granule cells. 1238 13


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