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)

Na+, K+-ATPase 2 subunit gene (Atp1a2) knock-out homozygous mice (Atp1a2-/-) died immediately after birth resulting from lack of breathing. The respiratory-related neuron activity in Atp1a2-/- was investigated using a brainstem-spinal cord en bloc preparation. The respiratory motoneuron activity recorded from the fourth cervical ventral root (C4) was defective in Atp1a2-/- fetuses of embryonic day 18.5. The C4 response to electrical stimulation of the ventrolateral medulla (VLM) recovered more slowly in Atp1a2-/- than in wild type during superfusion with Krebs' solution, consistent with the high extracellular GABA in brain of Atp1a2-/-. Lack of inhibitory neural activities in VLM of Atp1a2-/- was observed by optical recordings. High intracellular Cl- concentrations in neurons of the VLM of Atp1a2-/- were detected in gramicidin-perforated patch-clamp recordings. The alpha2 subunit and a neuron-specific K-Cl cotransporter KCC2 were coimmunoprecipitated in a purified synaptic membrane fraction of wild-type fetuses. Based on these results, we propose a model for functional coupling between the Na+, K+-ATPase alpha2 subunit and KCC2, which excludes Cl- from the cytosol in respiratory center neurons.
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PMID:Malfunction of respiratory-related neuronal activity in Na+, K+-ATPase alpha2 subunit-deficient mice is attributable to abnormal Cl- homeostasis in brainstem neurons. 1556 86

We studied the effect of furosemide on GABAA-induced 36Cl transport and GABAA-induced Cl- -ATPase activity in synaptic membranes of fish brain. At physiological pH of 7.4, GABA (0.1-100 microM) stimulated 36Cl transport in synaptoneurosomes and Cl- -ATPase activity in synaptic membranes. Furosemide (0.1-0.5 mM) removed the activating effect of the mediator on chlorine transport and enzyme activity (I50 equaled 0.16 and 0.12 mM, respectively). In the absence of the mediator, picrotoxin (50 microM) activated the basal 36Cl influx in synaptoneurosomes and the basal Mg2+ -ATPase activity of synaptic membranes. Furosemide (1 mM) removed the activating effect of picrotoxin on both biochemical processes. The obtained data demonstrated similar sensitivities of GABAA-induced transport of 36Cl in synaptoneurosomes and of GABAA-induced Cl- -ATPase activity in synaptic membranes to furosemide and indicated the involvement of the ATPase in GABAA-induced processes. The soluble ATPase, recovered by sodium deoxycholate solubilization of the membranes, remained sensitive to GABAA-ergic ligands, which suggested proximity of their binding sites with ATP hydrolysis sites of protein molecule and their structural contingency.
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PMID:[Effect of furosemide on GABAA-induced 36Cl transport on ATPase activity in synaptic membranes of carp (Cyprinus carpio L.)]. 1576 29

The effects of anxiolytic honokiol derivative, dihydrohonokiol-B (DHH-B), on amyloid beta protein (Abeta(25-35), 10 nM)-induced changes in Cl(-)-ATPase activity, intracellular Cl- concentration ([Cl-]i) and glutamate neurotoxicity were examined in cultured rat hippocampal neurons. DHH-B (10 ng/ml) recovered Abeta-induced decrease in neuronal Cl(-)-ATPase activity without any changes in the activities of Na+/K+-ATPase and anion-insensitive Mg2+-ATPase. A GABA(C) receptor antagonist (1,2,5,6,-tetrahydropyridin-4-yl) methyl-phosphinic acid (TPMPA, 15 microM), inhibited the protective effects of DHH-B on Cl(-)-ATPase activity. DHH-B reduced Abeta-induced elevation of [Cl-]i as assayed using a Cl(-)-sensitive fluorescent dye, and prevented Abeta-induced aggravation of glutamate neurotoxicity. These data suggest that DHH-B exerts the neuroprotective action against Abeta through GABA(C) receptor stimulation.
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PMID:Anxiolytic agent, dihydrohonokiol-B, recovers amyloid beta protein-induced neurotoxicity in cultured rat hippocampal neurons. 1589 48

Two types of neurons are involved in the regulation of rapid eye movement (REM) sleep, the REM-ON and the REM-OFF neurons. As the name suggests, the REM-OFF neurons cease firing during REM sleep and they are norepinephrinergic. It has been shown that cessation of these neurons is a pre-requisite for the generation of REM sleep and GABA shuts them off. Further, if these neurons do not shut off, there is increased levels of norepinephrine in the brain and loss of REM sleep. The REM sleep deprivation induced increase in norepinephrine is responsible for mediating at least REM sleep loss induced increase in Na(+)-K(+) ATPase activity, which is likely to be the primary factor for causing REM sleep deprivation induced effects.
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PMID:Neural mechanism of rapid eye movement sleep generation: Cessation of locus coeruleus neurons is a necessity. 1609 86

Cecropia pachystachya Mart. is popularly called "ambay" and extensively used in herbal medicine of South America for cough and asthma. In Argentina it grows in neotropical rainforest (Ntr C.p.) and in a temperate region (Tp C.p.). In a previous work we showed their hypotensive properties with different potency and toxicity, and now we studied the Tp C.p. effects in isolated heart from rats and central effects of both plants on the open-field test for mice. Tp C.p. produced a positive inotropic effect on isolated rat hearts, which was not affected by 1 microM propranolol, suggesting that it is not due to a beta-adrenergic effect. In contrast, it was prevented by pretreatment with high [K](o) media, which stimulates the Na,K-ATPase pump, suggesting an inhibition of the pump by "ambay", as digital do. In the open-field test, both Ntr C.p. and Tp C.p. similarly decreased the spontaneous locomotion and exploratory behavior of mice at doses between 180 and 600 mg/kg. Ntr C.p. potentiated the effect of 3 mg/kg diazepam to one similar to 10 mg/kg diazepam, but was not antagonized by 0.5 mg/kg flumazenil. Amphetamine at 5 mg/kg prevented the sedative effect of Ntr C.p. Chromatographic analysis showed that both plants have a qualitatively similar fingerprint but quantitatively differed in at least three components. Although the purpose was not to identify them, both plants have at least 10 compounds. Two of them were in higher amount in Tp C.p. than in Ntr C.p., and then, they could be responsible for the cardiovascular toxicity of Tp C.p. In conclusion, the results suggest that ambay has cardiotonic and sedative properties. The sedative effect could be useful in cough treatment. The extract resulted additive to benzodiazepines but it did not bind to the same site on GABA-A receptor, and it was interfered by the dopamine release produced with amphetamine.
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PMID:Cardiotonic and sedative effects of Cecropia pachystachya Mart. (ambay) on isolated rat hearts and conscious mice. 1641 16

Phosphorylation of the sensitive to GABA(A)-ergic ligands Cl-, HCO3--stimulated Mg2+-ATPase of the plasma membranes from fish brain by [gamma-32P]ATP was investigated in the presence of Mg2+. It was established, that formation of the phosphoprotein at 0-1 degrees C is dependent on time incubation and concentration of Mg2+ in the incubation medium. Hydroxylamine (50 mM) and pH (10) completely inhibited formation of phosphorylated intermediate. Ions of Cl- (10 mM)+HCO3- (2 mM) and also GABA (1-100 microM) dephosphorylated the enzyme. The dephosphorylating effect of GABA on the membrane samples did not appear in the presence of bicuculline. o-Vanadate (10 microM) eliminates the dephosphorylating effect of anions and GABA on the phosphoprotein. It was established by SDS-PAAG electrophoresis and autoradiographia that investigated phosphorylation and GABA(A)-induced dephosphorylation is performed by the protein with molecular weight aproximately 56 kDa. Such molecular weight has a subunit which forms oligomer composition of the sensitive to GABA(A)-ergic ligands Cl-, HCO3--ATPase from fish brain. The obtained data demonstrated that Cl, HCO3- ATPase from fish brain can be directly phosphorylated by [gamma-32P]ATP in the presence of Mg2+ and forms the phosphorylation intermediate.
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PMID:[Phosphorylation of Cl-, HCO3--stimulated Mg2+-ATPase of plasma membranes of carp (Cyprinus carpio L.) brain sensitive to GABA(A)-ergic ligands]. 1714 68

One important complication of diabetes is damage to the peripheral nervous system. However, in spite of the number of studies on human and experimental diabetic neuropathy, the current therapeutic arsenal is meagre. Consequently, the search for substances to protect the nervous system from the degenerative effects of diabetes has high priority in biomedical research. Neuroactive steroids might be interesting since they have been recently identified as promising neuroprotective agents in several models of neurodegeneration. We have assessed whether chronic treatment with progesterone (P), dihydroprogesterone (DHP) or tetrahydroprogesterone (THP) had neuroprotective effects against streptozotocin (STZ)-induced diabetic neuropathy at the neurophysiological, functional, biochemical and neuropathological levels. Using gas chromatography coupled to mass-spectrometry, we found that three months of diabetes markedly lowered P plasma levels in male rats, and chronic treatment with P restored them, with protective effects on peripheral nerves. In the model of STZ-induced of diabetic neuropathy, chronic treatment for 1 month with P, or with its derivatives, DHP and THP, counteracted the impairment of nerve conduction velocity (NCV) and thermal threshold, restored skin innervation density, and improved Na(+),K(+)-ATPase activity and mRNA levels of myelin proteins, such as glycoprotein zero and peripheral myelin protein 22, suggesting that these neuroactive steroids, might be useful protective agents in diabetic neuropathy. Interestingly, different receptors seem to be involved in these effects. Thus, while the expression of myelin proteins and Na(+),K(+)-ATPase activity are only stimulated by P and DHP (i.e. two neuroactive steroids interacting with P receptor, PR), NCV, thermal nociceptive threshold and intra-epidermal nerve fiber (IENF) density are also affected by THP, which interacts with GABA-A receptor. Because, a therapeutic approach with specific synthetic receptor ligands could avoid the typical side effects of steroids, future experiments will be devoted to evaluating the role of PR and GABA-A receptor in these protective effects.
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PMID:Progesterone and its derivatives are neuroprotective agents in experimental diabetic neuropathy: a multimodal analysis. 1718 35

Glutamate triggers an acute stimulation of the glucose transporter GLUT1 in cultured astrocytes, a phenomenon thought to facilitate energy delivery to active areas in the brain. Here we have explored the cell signaling mechanisms involved in this response. Half-stimulation of GLUT1 occurred at low micromolar glutamate, thus within the physiological range estimated in brain interstitium. The effect was mimicked by D-aspartate and inhibited by L-threo-beta-benzyloxyaspartate or Na(+) replacement with NMDG(+), showing the participation of the Na(+)-glutamate co-transporter. AMPA and the mGLURI agonist DHPG had no effect. The stimulation of GLUT1 was fully inhibited by ouabain, but independent activation of the Na(+)/K(+) ATPase pump with gramicidin did not affect glucose transport. Simultaneous with the Na(+) rise, glutamate and D-aspartate triggered a Ca(2+)signal, whose inhibition with BAPTA prevented the stimulation of GLUT1. However, an isolated Ca(2+) signal, triggered with endothelin 1, ATP or DHPG, did not affect glucose transport. The stimulation of GLUT1 could finally be mimicked by simultaneous induction of Na(+) and Ca(2+) signals. The requirement for both cations in the stimulation of the astrocytic glucose transporter, may help to explain how glucose metabolism in the brain is strongly activated by glutamate, but not by GABA or by inter-astrocytic signaling.
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PMID:Na(+)-Ca(2+) cosignaling in the stimulation of the glucose transporter GLUT1 in cultured astrocytes. 1792 81

In the adult brain, chloride (Cl-) influx through GABA(A) receptors is an important mechanism of synaptic inhibition. However, under a variety of circumstances, including acquired epilepsy, neuropathic pain, after trains of action potentials or trauma, and during normal early brain development, GABA(A) receptor activation excites neurons by gating Cl- efflux because the intracellular Cl- concentration (Cl(i)) is elevated. These findings require an inducible, active mechanism of chloride accumulation. We used gramicidin-perforated patch recordings to characterize Cl- transport via NKCC1, the principal neuronal Cl- accumulator, in neonatal CA1 pyramidal neurons. NKCC1 activity was required to maintain elevated Cl(i) such that GABA(A) receptor activation was depolarizing. Kinetic analysis of NKCC1 revealed reversible transmembrane Cl- transport characterized by a large maximum velocity (vmax) and high affinity (Km), so that NKCC1 transport was limited only by the net electrochemical driving force for Na+, K+, and Cl-. At the steady-state Cl(i), NKCC1 was at thermodynamic equilibrium, and there was no evidence of net Cl- transport. Trains of action potentials that have been previously shown to induce persistent changes in neuronal E(Cl) (reversal potential for Cl-) did not alter vmax or Km of NKCC1. Rather, action potentials shifted the thermodynamic set point, the steady-state Cl(i) at which there was no net NKCC1-mediated Cl- transport. The persistent increase in Cl(i) required intact alpha2/alpha3 Na+-K+-ATPase activity, indicating that trains of action potentials reset the thermodynamic equilibrium for NKCC1 transport by lowering Na(i). Activity-induced changes in Na+-K+-ATPase activity comprise a novel mechanism for persistent alterations in synaptic signaling mediated by GABA.
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PMID:Thermodynamic regulation of NKCC1-mediated Cl- cotransport underlies plasticity of GABA(A) signaling in neonatal neurons. 1825 50

GABA-mediated interactions between horizontal cells (HCs) and bipolar cells (BCs) transform signals within the image-processing circuitry of distal retina. To further understand this process, we have studied the GABA-driven membrane responses from isolated retinal neurons. Papain-dissociated retinal cells from adult zebrafish were exposed to GABAergic ligands while transmembrane potentials were monitored with a fluorescent voltage-sensitive dye (oxonol, DiBaC4(5)). In HCs hyperpolarizing, ionotropic GABA responses were almost never seen, nor were responses to baclofen or glycine. A GABA-induced depolarization followed by after hyperpolarization (dep/AHP) occurred in 38% of HCs. The median fluorescence increase (dep component) was 0.17 log units, about 22 mV. HC dep/AHP was not blocked by bicuculline or picrotoxin. Muscimol rarely evoked dep/AHP responses. In BCs picrotoxin sensitive, hyperpolarizing, ionotropic GABA and muscimol responses occurred in most cells. A picrotoxin insensitive dep/AHP response was seen in about 5% of BCs. The median fluorescence increase (dep component) was 0.18 log units, about 23 mV. Some BCs expressed both muscimol-induced hyperpolarizations and GABA-induced dep/AHP responses. For all cells, the pooled Hill fit to median dep amplitudes, in response to treatments with a GABA concentration series, gave an apparent k of 0.61 muM and an n of 1.1. The dep/AHP responses of all cells required both extracellular Na+ and Cl(-), as dep/AHP was blocked reversibly by Li+ substituted for Na+ and irreversibly by isethionate substituted for Cl(-). All cells with dep/AHP responses in zebrafish have the membrane physiology of neurons expressing GABA transporters. These cells likely accumulate GABA, a characteristic of GABAergic neurons. We suggest Na+ drives GABA into these cells, depolarizing the plasma membrane and triggering Na+, K+-dependent ATPase. The ATPase activity generates AHP. In addition to a GABA clearance function, these large-amplitude transporter responses may provide an outer plexiform layer GABA sensor mechanism.
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PMID:Transporter-mediated GABA responses in horizontal and bipolar cells of zebrafish retina. 1844 38


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