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)

Studies of local glucose utilization in neural tissues in vivo with the autoradiographic [14C]deoxyglucose method have demonstrated that energy metabolism increases almost linearly with the degree of functional activation, i.e. spike frequency, in the terminal projection zones of activated pathways. The increased metabolism is found in neuropil and is minimal or undetectable in neuronal cell bodies. Electrical stimulation, increased extracellular [K+] ([K+]o), or opening of Na+ channels with veratridine stimulates metabolism in neutral tissues, and this increase is blocked by ouabain, a specific inhibitor of Na+,K(+)-ATPase. Activation of this enzyme to restore ionic gradients across cellular membranes appears to mediate the function-related increase in energy metabolism. The metabolic activation is, therefore, not directly related to the functional activity itself but to processes operating to recover from that activity. The limited spatial resolution of the [14C]DG method precludes identification of cellular elements in neuropil participating in the metabolic activation, e.g. axonal terminals, dendrites, or astrocytic processes enveloping the synapses. We have, therefore, attempted to stimulate in vitro conditions to be expected from functional activation and increased spike activity in vivo, e.g. increased extracellular [K+], intracellular [Na+], or extracellular neurotransmitter levels, and examined their effects on glucose metabolism in neurons and astroglia in culture. Increased [K+]o stimulated [14C]DG phosphorylation in neuronal and mixed neuronal-astroglial cultures, but not in astroglial cultures assayed in bicarbonate buffer; it did occasionally stimulate metabolism in astroglia when assayed in HEPES or phosphate buffers, but these effects were variable and inconsistent. Veratridine (75 microM) stimulated [14C]DG phosphorylation in neurons and astroglia; these stimulations were blocked by 1 mM ouabain or 10 microM tetrodotoxin (TTX), which blocks voltage-dependent Na+ channels. The Na+ ionophore monensin (10 microM) doubled the rate of metabolism, a stimulation that was only partially blocked by ouabain and unaffected by TTX. L-Glutamate (500 microM) stimulated [14C]DG phosphorylation in astroglia, but this stimulation was probably secondary to Na+ uptake into the cells via a sodium/glutamate co-transporter because it was not blocked by inhibitors of NMDA or non-NMDA receptors but was absent in Na(+)-free medium. These results indicate that astroglia contribute to the increased energy metabolism in neuropil during functional activation by mechanisms that promote Na+ entry into the cells.
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PMID:Contribution of astroglia to functionally activated energy metabolism. 894 Jun 5

We have investigated the effects of glutamate and glutamate receptor ligands on the intracellular free Ca2+ concentration ([Ca2+]i) and the membrane potential (Em) of single, identified neuropile glial cells in the central nervous system of the leech Hirudo medicinalis. Exposed glial cells of isolated ganglia were filled iontophoretically with the Ca2+ indicator dye Fura-2. Application of glutamate (200-500 mumoll-1) caused biphasic membrane potential shifts and increases in [Ca2+]i, which were only partly reduced by either removing extracellular Ca2+ or blocking ionotropic glutamate receptors with 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 50-100 mumol l-1. Metabotropic glutamate receptor (mGluR) ligands had the following rank of potency in inducing a rise in [Ca2+]i: quisqualate (QQ, 200 mumol l-1) > glutamate (200 mumol l-1) > L(+)2-amino-3-phosphonopropionic acid (L-AP3, 200 mumol l-1 > trans-1-aminocyclopentane-1,3-dicarboxylic acid (t-ACPD, 400 mumol l-1). The mGluR-selective antagonist (RS)-alpha-methyl-4-carboxyphenylglycine [(RS)-MCPG, 1 mmol l-1] significantly reduced glutamate-evoked increases in [Ca2+]i by 20%. Incubation of the ganglia with the endoplasmic ATPase inhibitor cyclopiazonic acid (CPA, 10 mumol l-1) caused a significant (53%) reduction of glutamate-induced [Ca2+]i transients, while incubation with lithium ions (2 mmol l-1) resulted in a 46% reduction. The effects of depleting the Ca2+ stores with CPA and of CNQX were additive. We conclude that glutamate-induced [Ca2+]i transients were mediated by activation of both Ca(2+)-permeable ionotropic non-NMDA receptors and of metabotropic glutamate receptors leading to Ca2+ release from intracellular Ca2+ stores.
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PMID:Intracellular Ca2+ release mediated by metabotropic glutamate receptor activation in the leech giant glial cell. 936 87

The present study examined the relationship between an important energy-generating enzyme (cytochrome oxidase; CO), a key energy-consuming enzyme (Na+ K+ ATPase) and neurochemicals associated with excitatory glutamatergic synapses (NMDAR1 and neuronal nitric oxide synthase, nNOS) in the adult macaque retina. Polyclonal antibodies against neuronal nitric oxide synthase and N-methyl-D-aspartate receptor subunit I were generated for immunohistochemical examination and labeled sites not previously reported were found. We have also isolated cDNAs for cytochrome oxidase subunits III (mitochondrial-encoded) and IV (nuclear-encoded), as well as for a fragment of neuronal nitric oxide synthase, from a human cDNA library. The distributions of mRNAs of these genes were analyzed by in situ hybridization. We found that three or more of the markers examined coexisted in a number of sites: (a) In the inner segments of photoreceptors, high energy demand for maintaining the dark current was placed by Na+ K+ ATPase. This was partially met by ATP-generating enzymes such as CO. Neuronal NOS was also present there for the synthesis of NO and the cascading event leading to the generation of cGMP and the gating of channels for visual transduction. (b) Both the outer and inner plexiform layers had detectable amounts of all four markers, although the levels varied among them. This was most likely due to the presence of depolarizing glutamatergic synapses arising from photoreceptors and bipolar cells and such synaptic events were energy-demanding. The involvement of NMDA receptors and nNOS in these synaptic layers is strongly implicated in the present study. (c) All four markers were present in the majority of retinal ganglion cells, with some inherent heterogeneity related to intensity and size. Retinal ganglion cells are known to receive excitatory synapses from glutamatergic bipolar cells and are themselves highly active. The presence of both NMDAR1 and nNOS in these cells were verified in the present study and the energy demands related to these synaptic activities were necessarily high. Thus, active ion transporting functions related to synaptic or non-synaptically induced repolarization from the basis for an interrelationship between the neurochemicals/enzymes studied. Finally, (d) all four markers and the gene expression of CO and nNOS in the macaque retina were regulated by neuronal activity.
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PMID:Neurochemical organization of the macaque retina: effect of TTX on levels and gene expression of cytochrome oxidase and nitric oxide synthase and on the immunoreactivity of Na+ K+ ATPase and NMDA receptor subunit I. 966 11

Ammonia is a main factor in the pathogenesis of hepatic encephalopathy. We found that acute ammonia toxicity is mediated by activation of NMDA receptors. Chronic moderate hyperammonemia prevents acute ammonia toxicity in rats. Chronic exposure of cultured neurons to 1 mM ammonia leads to impaired response of the NMDA receptor to activation by its agonists (due to decreased protein kinase C-mediated phosphorylation) and prevents glutamate (Glu) neurotoxicity. Compounds that prevent ammonia toxicity in mice (e.g. carnitine) also prevent Glu toxicity in cultured neurons. These compounds did not prevent activation of NMDA receptor or the rise of Ca2+. They interfered with subsequent steps in the toxic process. The protective effect of carnitine is mediated by activation of metabotropic Glu receptors. Agonists of mGluRs, especially of mGluR5, prevent Glu toxicity. Agonists of muscarinic receptors also prevent Glu toxicity and there seems to be an interplay between muscarinic and metabotropic Glu receptors in the protective effect. We have tried to identify intracellular events involved in the process of neuronal death. It is known that the rise of Ca2+ is an essential step. Glu leads to depletion of ATP; some compounds (e.g. carnitine) prevent Glu-induced neuronal death without preventing ATP depletion: additional events are required for neuronal death. Glu induces activation of Na+/K+-ATPase, which could be involved in the toxic process. Inhibitors of protein kinase C, calcineurin or nitric oxide synthase prevent Glu toxicity. Our results indicate that Glu toxicity can be prevented at different steps or by activating receptors coupled to the transduction pathways interfering with the toxic process. Agents acting on these steps could prevent excitotoxicity in vivo in animals.
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PMID:Neurotoxicity of ammonia and glutamate: molecular mechanisms and prevention. 974 28

1. Possible mechanisms responsible for the increases in intracellular calcium ([Ca2+]i) and sodium ([Na+]i) levels seen during metabolic inhibition were investigated by continuous [Ca2+]i and [Na+]i measurement in cultured rat cerebellar granule cells. An initial small mitochondrial Ca2+ release was seen, followed by a large influx of extracellular Ca2+. A large influx of extracellular Na+ was also seen. 2. The large [Ca2+]i increase was not due to opening of voltage-dependent or voltage-independent calcium channels, activation of NMDA/non-NMDA channels, activation of the Na+i-Ca2+o exchanger, or inability of plasmalemmal Ca2+-ATPase to extrude, or mitochondria to take up, calcium. 3. The large [Na+]i increase was not due to activation of the TTX-sensitive Na+ channel, the Na+i-Ca2+o exchanger, the Na+-H+ exchanger, or the Na+-K+-2Cl- cotransporter, or an inability of Na+-K+-ATPase to extrude the intracellular sodium. 4. Phospholipase A2 (PLA2) activation may be involved in the large influx, since both were completely inhibited by PLA2 inhibitors. Moreover, melittin (a PLA2 activator) or lysophosphatidylcholine or arachidonic acid (both PLA2 activation products) caused similar responses. Inhibition of PLA2 activity may help prevent the influx of these ions that may result in serious brain injury and oedema during hypoxia/ischaemia.
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PMID:Early metabolic inhibition-induced intracellular sodium and calcium increase in rat cerebellar granule cells. 992 84

Glucose utilization (ICMRglc) increases linearly with spike frequency in neuropil but not perikarya of functionally activated neural tissues. Electrical stimulation, increased extracellular [K+] ([K+]o), or opening of Na+ channels with veratridine stimulates ICMRglc in neural tissues; these increases are blocked by ouabain, an inhibitor of Na+,K+-ATPase. Stimulating Na+,K+-ATPase activity to restore ionic gradients degraded by enhanced spike activity appears to trigger these increases in ICMRglc. Cultured neurons behave similarly. Astrocytic processes that envelop synapses in neuropil probably contribute to the increased ICMRglc. ICMRglc in cultured astroglia is unaffected by elevated [K+]o but is stimulated by increased intracellular [Na+] ([Na+]i), and this stimulation is blocked by ouabain or tetrodotoxin. L-Glutamate also stimulates ICMRglc in astroglia. This effect is unaffected by inhibitors of NMDA or non-NMDA receptors, blocked by ouabain, and absent in Na+-free medium; it appears to be mediated by increased [Na+]i due to combined uptake of Na+ with glutamate via Na+/glutamate co-transporters.
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PMID:Energetics of functional activation in neural tissues. 997 82

1. The metabotropic glutamate receptor (mGluR) agonist trans-(+/-)-1-amino-1,3-cyclopentanedicarboxylic acid (trans-ACPD) (10-100 microM) depolarized isolated frog spinal cord motoneurones, a process sensitive to kynurenate (1.0 mM) and tetrodotoxin (TTX) (0.783 microM). 2. In the presence of NMDA open channel blockers [Mg2+; (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate (MK801); 3,5-dimethyl-1-adamantanamine hydrochloride (memantine)] and TTX, trans-ACPD significantly potentiated NMDA-induced motoneurone depolarizations, but not alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionate (AMPA)- or kainate-induced depolarizations. 3. NMDA potentiation was blocked by (RS)-alpha-methyl-4-carboxyphenylglycine (MCPG) (240 microM), but not by alpha-methyl-(2S,3S,4S)-alpha-(carboxycyclopropyl)-glycine (MCCG) (290 microM) or by alpha-methyl-(S)-2-amino-4-phosphonobutyrate (L-MAP4) (250 microM), and was mimicked by 3,5-dihydroxyphenylglycine (DHPG) (30 microM), but not by L(+)-2-amino-4-phosphonobutyrate (L-AP4) (100 microM). Therefore, trans-ACPD's facilitatory effects appear to involve group I mGluRs. 4. Potentiation was prevented by the G-protein decoupling agent pertussis toxin (3-6 ng ml(-1), 36 h preincubation). The protein kinase C inhibitors staurosporine (2.0 microM) and N-(2-aminoethyl)-5-isoquinolinesulphonamide HCI (H9) (77 microM) did not significantly reduce enhanced NMDA responses. Protein kinase C activation with phorbol-12-myristate 13-acetate (5.0 microM) had no effect. 5. Intracellular Ca2+ depletion with thapsigargin (0.1 microM) (which inhibits Ca2+/ATPase), 1,2-bis(O-aminophenoxy)ethane-N,N,N',N'-tetracetic acid acetyl methyl ester (BAPTA-AM) (50 microM) (which buffers elevations of [Ca2+]i), and bathing spinal cords in nominally Ca2+-free medium all reduced trans-ACPD's effects. 6. The calmodulin antagonists N-(6-aminohexyl)-5-chloro-1-naphthalenesulphonamide (W7) (100 microM) and chlorpromazine (100 microM) diminished the potentiation. 7. In summary, group I mGluRs selectively facilitate NMDA-depolarization of frog motoneurones via a G-protein, a rise in [Ca2+]i from the presumed generation of phosphoinositides, binding of Ca2+ to calmodulin, and lessening of the Mg2+-produced channel block of the NMDA receptor.
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PMID:Mechanisms involved in the metabotropic glutamate receptor-enhancement of NMDA-mediated motoneurone responses in frog spinal cord. 1005 Nov 53

NMDA produced whole-cell membrane currents in cultured human astrocytes. The currents were not inhibited by the selective NMDA receptor antagonist, APV, while they were partially inhibited by the broad G-protein inhibitor, GDPbetaS. NMDA-induced currents were enhanced by either the microsomal Ca2+/ATPase inhibitors, thapsigargin and cyclopiazonic acid, or the ATP-uncoupler, dinitrophenol (DNP). In the Ca2+ assay, NMDA increased intracellular calcium concentration. The increase was inhibited by 26% in Ca2+-free extracellular solution, and it was not inhibited by APV. The results of the present study suggest that NMDA responses in human astrocytes are regulated by store Ca2+ depletion-associated signal.
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PMID:Store Ca2+ depletion enhances NMDA responses in cultured human astrocytes. 1036 75

Granule cells in a dissociated neuro-glial cell culture of cerebellum when exposed to ouabain (10(-3) M) for 25 min apparently swell, increase their [Ca2+]i with obvious depolarization of the mitochondrial membrane. In 3 h after ouabain was omitted from the solution, 62 +/- 3% of granule cells had pycnotic nuclei. The supplement of a solution with competitive specific antagonist of NMDA receptors, L-2-amino-7-phosphonoheptanoate (10(-4) M, APH) together with ouabain prevented cells from swelling, mitochondrial deenergization, neuronal death and increase of [Ca2+]i. These data suggest that cellular Na+/K+-ATPase inactivation in neuro-glial cell cultures of cerebellum leads to glutamate (Glu) accumulation, hyperstimulation of glutamate receptors, higher Ca2+ and Na+ influxes into the cells through the channels activated by Glu. This process leads to cell swelling, mitochondrial deenergization and death of granule cells. Possibly, the decrease of Na+/K+-ATPase activity in brain cells can lead to the onset of at least some chronic neurological disorders.
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PMID:Short-term block of Na+/K+-ATPase in neuro-glial cell cultures of cerebellum induces glutamate dependent damage of granule cells. 1045 26

An increase of intracellular calcium ion concentration and of the 45Ca2+ entry, a decrease in Na+,K(+)-ATPase activity, and activation of Na+/Ca2+ exchange were shown to be initiated by glutamate in the rat brain cortex synaptosomes. These effects could be prevented with antagonists and blocking agents of the NMDA receptors. Pre-incubation of the synaptosomes with alpha-tocopherol, superoxide dismutase, and ganglioside GM1 was shown to normalise [45Ca2+], the rate of 45Ca2+ entry, and the activity of Na+,K(+)-ATPase in the synaptosomes. The data obtained suggest that calcium ions entering the brain cortex neurones via the NMDA receptors in presence of excessive glutamate, trigger activation of free radical reactions damaging the neurones in ischemia, cerebral lesions, and other pathological conditions.
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PMID:[The antioxidant prevention of disorders in calcium ion metabolism under the action of glutamate on the synaptosomes of the rat cerebral cortex]. 1051 81


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