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. Dendrites of rat neocortical layer V pyramidal neurons were loaded with the Ca2+ indicator dye Calcium Green-1 (CG-1) or fluo-3, and the mechanisms which govern action potential (AP)-evoked transient changes in dendritic cytosolic Ca2+ concentration ([Ca2+]i) were examined. APs were initiated either by synaptic stimulation or by depolarizing the soma or dendrite by current injection, and changes in fluorescence of the indicator dye were measured in the proximal 170 microns of the apical dendrite. 2. Simultaneous two-pipette recordings of APs from the soma and apical dendrite, and dendritic fluorescence imaging indicated that a single AP propagating from the soma into the apical dendrite evokes a rapid transient increase in fluorescence indicating a transient increase in [Ca2+]i. At 35-37 degrees C the decay time constant of the fluorescence transient following an AP was around 80 ms. 3. Voltage-activated Ca2+ channels (VACCs) of several subtypes mediated the AP-evoked fluorescence transient in the proximal (100-170 microns) apical dendrite. The AP-evoked fluorescence transient resulted from Ca2+ entry through L-type (nifedipine sensitive; 25%), N-type (omega-conotoxin GVIA sensitive; 28%) and P-type (omega-agatoxin IVA sensitive; 10%) Ca2+ channels and through Ca2+ channels (R-type) not sensitive to L-, N- and P-type Ca2+ channel blockers (cadmium ion sensitive; 37%). 4. The decay time course of the dendritic fluorescence transient was prolonged by the blockers of endoplasmic reticulum (ER) Ca(2+)-ATPase, cyclopiazonic acid and thapsigargin, suggesting that uptake of Ca2+ into the ER in dendrites governs clearance of dendritic Ca2+. 5. The decay time course of the fluorescence transient was slightly prolonged by benzamil, a blocker of plasma membrane Na(+)-Ca2+ exchange and by calmidazolium, a blocker of the calmodulin-dependent plasma membrane Ca(2+)-ATPase, suggesting that these pathways are less important for dendrite Ca2+ clearance following a single AP. Neither the mitochondrial uncoupler carbonyl cyanide p-(trifluoromethoxy)phenylhydrazone (FCCP) nor the blocker of Ca2+ uptake into mitochondria, Ruthenium Red, had any measurable effect on the decay time course of the fluorescence transient. 6. Dendritic fluorescence transients measured during trains of dendritic APs began to summate at impulse frequencies of 5 APs s-1. At higher frequencies APs caused a concerted and maintained elevation of dendritic fluorescence during the train.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Dendritic calcium transients evoked by single back-propagating action potentials in rat neocortical pyramidal neurons. 765 65

Small cell lung carcinoma is an aggressive neuroendocrine tumor that secretes several hormones, some of which act as autocrine growth factors. In order to obtain more information on the process of hormone secretion from this tumor, we have studied the role of intracellular free Ca2+ concentrations and voltage-operated calcium channels in the control of [3H]serotonin release from in vitro growing cell lines. We found that the Ca2+ ionophore ionomycin and the Ca(2+)-ATPase antagonist thapsigargin induced a dose-dependent increase of intracellular Ca2+ and a parallel enhancement of [3H]serotonin release. KCl-induced depolarization also stimulated a dose- and Ca(2+)-dependent [3H]serotonin release that in the GLC8 cell line was effectively inhibited by Ca2+ channel antagonists (Cd2+, nitrendipine, verapamil, omega-conotoxin GVIA, and omega-agatoxin IVA) and potentiated by the Ca2+ channel agonist BayK8644. Autoantibodies against Ca2+ channels present in the sera of Lambert-Eaton myasthenic patients antagonized KCl- but not ionomycin-induced [3H]serotonin release. Polymerase chain reaction analysis indicated that GLC8 cells express L-, N-, and P-type neuronal Ca2+ channel alpha 1 subunits, together with two types of Ca2+ channel beta subunits. The presence of three functionally distinct high threshold Ca2+ channels was also revealed by patch clamp experiments; high threshold Ca2+ channels were identified as dihydropyridine-sensitive (L-type), omega-conotoxin GVIA-sensitive (N-type), and omega-agatoxin IVA-sensitive (P-type). Our data demonstrate that [3H]serotonin is released by small cell lung carcinoma cells in a Ca(2+)-dependent manner and that depolarization-induced [3H]serotonin release is mediated by Ca2+ influx through distinct, neuron-like, Ca2+ channel subtypes.
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PMID:Calcium channel subtypes controlling serotonin release from human small cell lung carcinoma cell lines. 825 45

Ouabain, an Na+K+ATPase inhibitor, increases the release of acetylcholine (ACh) from various preparations in a Ca2+ -independent way. However, in other preparations the release of ACh evoked by ouabain is dependent on the presence of extracellular calcium. In the present study, we have labeled the ACh of myenteric plexus longitudinal muscles of guinea pig ileum and compared the effect of calcium channel blockers on ouabain-evoked release of [3H]ACh. Release of [3H]ACh evoked by ouabain is dose dependent and decreased markedly in the absence of calcium or in the presence of cadmium, a nonspecific calcium channel blocker. N-type calcium channel blockage by the omega-conotoxins GVIA (selective N-type calcium channel blocker) and MVIC (a nonselective calcium channel blocker) inhibited by 45 and 55%, respectively, the release of [3H]ACh. L-type calcium channel suppression by low concentrations of verapamil, nifedipine, and diltiazem had no effect on the release of [3H]ACh. The release of transmitter was also not affected significantly by nickel, a T-type calcium channel blocker. In addition, omega-agatoxin-IVA, at concentrations that block P- and Q-type calcium channels, did not affect significantly the release of [3H]ACh. Thus, extracellular Ca2+ is essential for the release of ACh induced by ouabain from guinea pig ileum myenteric plexus. In this preparation, the N-type calcium channel plays a dominant role in transmitter release evoked by inhibition of Na+K+-ATPase, but other routes of calcium entry in addition to these channels can also support the release of neurotransmitter induced by ouabain.
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PMID:Inhibition of Na+,K+-ATPase by ouabain opens calcium channels coupled to acetylcholine release in guinea pig myenteric plexus. 862 96

1. Ca2+ signaling elicited by ionotropic alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate (iGluR) and metabotropic (mGluR) glutamate receptor agonists was studied in the somatic and dendritic regions of cultured cerebellar Purkinje neurons using microscopic video imaging and the Ca2+ sensitive dye fura-2. 2. iGluR and mGluR agonists and K+ depolarization applied by brief micropressure pulses evoked Ca2+ signals in both the somatic and dendritic regions of all Purkinje neurons studied. The Ca2+ signals were generated simultaneously in both cellular regions. The Ca+ signals to these stimulants were similar in general form, consisting of an initial peak and slow recovery phase, but differed in details of amplitude, time course, and complexity. 3. Removal of extracellular Ca2+ abolished the Ca2+ signal to the iGluR agonist AMPA, indicating that Ca2+ influx was essential to the generation of Ca2+ signals by iGluR agonists. The Ca2+ channel blocker lanthanum almost completely eliminated the Ca2+ signals to AMPA, indicating that Ca2+ influx through voltage-sensitive Ca2+ channels was the main pathway for Ca2+ influx. Omega-agatoxin IVA, a P-type Ca2+ channel blocker, significantly reduced the Ca2+ signals to AMPA suggesting that Ca2+ influx was predominately through P-type Ca2+ channels. 4. Pharmacological manipulation of intracellular Ca2+ stores significantly reduced the Ca2+ signals to AMPA, indicating that release of Ca2+ from intracellular Ca2+ stores also plays a prominent role in the generation of the Ca2+ signals to iGluR agonists. These manipulations included blocking Ca2+ release from intracellular stores with dantrolene, an antagonist at the ryanodine receptor that controls Ca2+ release from one pool of intracellular Ca2+ stores, and depletion of intracellular Ca2+ stores with caffeine or ryanodine. 5. Ca2+ influx through voltage-sensitive Ca2+ channels did not appear to be involved in the Ca2+ signals to mGluR activation, because neither lanthanum nor omega-agatoxin IVA altered Ca2+ signals to mGluR agonists. Manipulation of intracellular stores with Ca(2+)-ATPase inhibitors and dantrolene significantly reduced the Ca2+ signal to mGluR agonists, indicating that Ca2+ signals were derived from both the inositol trisphosphate (IP3) and the ryanodine receptor-controlled intracellular Ca2+ stores. 6. Ca2+ signals to the iGluR agonist AMPA correlated temporally with the prolonged, multiphasic membrane responses elicited by similar agonist application in parallel electrophysiological studies. Pharmacological manipulation of Ca2+ influx and release of Ca2+ from intracellular stores significantly influenced components of the membrane response to AMPA, indicating a potential modulator or mediator role for Ca2+ in the membrane response to iGluR activation.
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PMID:Ca2+ signaling pathways linked to glutamate receptor activation in the somatic and dendritic regions of cultured cerebellar purkinje neurons. 893 Feb 76

Numerous neurotoxins that alter Na(+)-channel function have been shown to be useful tools for characterizing Na+ channels. Polypeptide blockers of voltage-dependent K+ channels (dendrotoxins, etc.) and Ca(2+)-activated K+ channels (apamine, etc.) have been studied extensively by numerous investigators. Peptide toxins, calciseptine and omega-conotoxins have been attracting much attention as inhibitors of L-type and N-type Ca2+ channels, respectively, while omega-conotoxins-MVIIC and omega-agatoxin IVA have been used as new types of Ca(2+)-channel blockers. Ryanodine and bromoeudistomin D analogues have been extensively used to elucidate Ca(2+)-release-channel functions and to purify its target protein. Polypeptide toxins (myotoxin alpha, etc.) and macrolides (FK 506, etc.) are useful Ca2+ releasers with a novel mechanism, while natural products such as thapsigargin and gingerol have been used as modulators of Ca(2+)-pumping ATPase. Some modulators of the function of myosin (purealin, etc.) and actin (goniodomin A, etc.) have been demonstrated to be important chemical probes for understanding the physiological roles of the contractile proteins in structural changes and their interaction in muscle contraction. A large number of protein kinase inhibitors (staurosporine, etc.) and phosphatase inhibitors (okadaic acid, etc.) are widely used as first-choice reagents for studying protein phosphorylation. These natural products have become essential tools for studying the regulatory mechanism of cellular ion movements, muscle contraction and protein phosphorylation.
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PMID:Application of physiologically active substances isolated from natural resources to pharmacological studies. 916 64

Single-electrode voltage-clamp recordings were obtained from CA3 pyramidal cells in rat hippocampal organotypic slice cultures, and the slow Ca2+-dependent K+ current or afterhyperpolarization current (IAHP) was elicited with brief depolarizing voltage jumps. The slow IAHP was suppressed by the selective L-type Ca2+ channel antagonists isradipine (2 microM) or nifedipine (10 microM). In contrast, neither omega-conotoxin MVIIA (1 microM) nor omega-agatoxin IVA (200 nM), N-type and P/Q-type Ca2+ channel antagonists, respectively, attenuated this slow outward current. The slow IAHP was significantly reduced by thapsigargin (10 microM), a Ca2+ ATPase inhibitor that depletes intracellular Ca2+ stores, and by ryanodine (10-100 microM), which blocks Ca2+-induced Ca2+ release from intracellular compartments. At this concentration thapsigargin did not modify high-threshold Ca2+ current, which was, however, blocked by isradipine. Thus, in hippocampal CA3 pyramidal cells, Ca2+ influx through L-type Ca2+ channels is necessary to trigger the slow IAHP. Furthermore, intracellular Ca2+-activated Ca2+ stores represent a critical component in the transduction pathway leading to the generation of the slow IAHP.
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PMID:L-Type Ca2+ channels mediate the slow Ca2+-dependent afterhyperpolarization current in rat CA3 pyramidal cells in vitro. 981 42

The effects of 2,5-di(tert-butyl)-1,4-benzohydroquinone (tBHQ), a synthetic phenolic antioxidant and a blocker of the sarco-endoplasmic ATPase, were evaluated on low and high voltage-activated Ca(2+) currents (ICas) with rodent dorsal root ganglion, hippocampal, and motor neurons. In all cell types tested, tBHQ (IC(50) = 35 microM) blocked ICa at concentrations used to inhibit sarco-endoplasmic ATPase. This effect was specific to tBHQ because the other sarco-endoplasmic reticulum calcium ATPase pump inhibitors (thapsigargin and cyclopiazonic acid) had no effect. Selective blockade of the N-type current with omega-conotoxin GVIA and of P- (motoneuron) or Q-type currents (hippocampal neuron) with omega-agatoxin IVA indicated that tBHQ inhibited N, P, and Q types of ICa. tBHQ had no effect on nitrendipine-sensitive (L-type) and residual drug-resistant (R-type) ICa, nor on the low voltage-activated T-type ICa. Contrary to neuronal cells, the L-type ICa was inhibited by tBHQ in a differentiated mouse neuroblastoma and rat glioma hybrid cell line. Injection of cDNAs encoding the alpha1A, alpha1B, alpha1C, and alpha1E subunits into oocytes showed that tBHQ blocked ICas at the level of the pore-forming protein. This effect of tBHQ on ICa should be considered when interpreting results obtained with tBHQ used on neuronal preparations. It also may be useful for developing new strategies for the generation of more potent intracellular calcium transient inhibitors.
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PMID:Sarco-endoplasmic ATPase blocker 2,5-Di(tert-butyl)-1, 4-benzohydroquinone inhibits N-, P-, and Q- but not T-, L-, or R-type calcium currents in central and peripheral neurons. 1086 Sep 23

The effects of neomycin on voltage-activated Ca(2+) channels (VACCs) were studied by Ca(2+)-dependent K(+)- and veratridine-evoked [3H]dopamine release from rat striatal slices. Neomycin (0.01-1 mM) concentration dependently reduced K(+)-evoked [3H]dopamine release (IC(50) approximately 25 microM), producing approximately 98% inhibition at 1 mM. Contribution of N-, P- and Q-type Ca(2+) channels to this neomycin-sensitive [3H]dopamine release was tested by the combined application of 100 microM neomycin and selective Ca(2+) channel blockers. The effects of neomycin combined with 1 microM of omega-conotoxin GVIA (N-type Ca(2+) channels) or with 100 nM of omega-conotoxin MVIIC (Q-type Ca(2+) channels) were additive, excluding involvement of N- and Q-type Ca(2+) channels. However, the combined effects of neomycin with 30 nM of omega-agatoxin-IVA (P-type Ca(2+) channels) were not additive, suggesting involvement of P-type Ca(2+) channels in neomycin-induced inhibition of [3H]dopamine release. On the other hand, veratridine-evoked [3H]dopamine release was shown to be mediated by Q-type Ca(2+) channels only. In addition, neither the inhibitor of sarcoplasmic reticulum Ca(2+)-ATPase thapsigargin (500 nM) nor the blocker of sarcoplasmic reticulum ryanodine Ca(2+) channels ryanodine (30 microM) modulate veratridine-evoked [3H]dopamine release, suggesting no contribution of intracellular Ca(2+) stores. Neomycin (up to 100 microM) did not affect veratridine-evoked [3H]dopamine release, suggesting that intracellular Ca(2+) stores are not a prerequisite for the action of neomycin. Lack of inhibitory effect of neomycin is taken as additional indirect evidence for the involvement of P-type Ca(2+) channels. In conclusion, therapeutically relevant concentrations of neomycin preferentially block P-type Ca(2+) channels which regulate dopamine release in rat striatum. This block could be responsible for aminoglycoside-induced toxicity.
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PMID:Therapeutically relevant concentrations of neomycin selectively inhibit P-type Ca2+ channels in rat striatum. 1258 5

1. Patients affected by isovaleric acidemia (IVAcidemia) suffer from acute episodes of encephalopathy. However, the mechanisms underlying the neuropathology of this disease are poorly known. The objective of the present study was to investigate the in vitro effects of the metabolites that predominantly accumulate in IVAcidemia, namely isovaleric acid (IVA), 3-hydroxyisovaleric acid (3-OHIVA) and isovalerylglycine (IVG), on important parameters of energy metabolism, such as (14)CO(2) production from acetate and the activities of the respiratory chain complexes I-IV, creatine kinase and Na(+), K(+)-ATPase in synaptic plasma membranes from cerebral cortex homogenates of 30-day-old rats. 2. We observed that 3-OHIVA acid and IVG did not affect all the parameters analyzed. Similarly, (14)CO(2) production from acetate (Krebs cycle activity), the activities of creatine kinase, and of the respiratory chain complexes was not modified by IVA. In contrast, IVA exposition to cortical homogenates provoked a marked inhibition of Na(+), K(+)-ATPase activity. However, this activity was not changed when IVA was directly exposed to purified synaptic plasma membranes, suggesting an indirect effect of this organic acid on the enzyme. Furthermore, pretreatment of cortical homogenates with alpha-tocopherol and creatine totally prevented IVA-induced inhibition on Na(+), K(+)-ATPase activity from synaptic plasma membranes, whereas glutathione (GSH) and the NO synthase inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME) did not alter this inhibition. 3. These data indicate that peroxide radicals were probably involved in this inhibitory effect. Since Na(+), K(+)-ATPase is a critical enzyme for normal brain development and functioning and necessary to maintain neuronal excitability, it is presumed that the inhibitory effect of IVA on this activity may be involved in the pathophysiology of the neurological dysfunction of isovaleric acidemic patients.
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PMID:Isovaleric acid reduces Na+, K+-ATPase activity in synaptic membranes from cerebral cortex of young rats. 1739 58

Isovaleric acidemia (IVAcidemia) is an inborn error of metabolism due to deficiency of isovaleryl-CoA dehydrogenase activity, leading to predominant accumulation of isovaleric acid (IVA). Patients affected by IVAcidemia suffer from acute episodes of encephalopathy, whose underlying mechanisms are poorly known. In the present study we investigated whether an intracerebroventricular injection of IVA could compromise energy metabolism in cerebral cortex of young rats. IVA administration significantly inhibited (14)CO(2) production from acetate (22%) and citrate synthase activity (20%) in cerebral cortex homogenates prepared 24 h after injection. However, no alterations of these parameters were observed 2 h after injection. In contrast, no significant differences were found in the activities of succinate dehydrogenase, isocitrate dehydrogenase, electron transfer chain complexes or creatine kinase in rats sacrificed 2 or 24 h after IVA administration. Moreover, IVA injection significantly inhibited Na(+),K(+)-ATPase activity (25%) in cerebral cortex of rats 2 or 24 h after IVA administration, while pre-treatment of rats with creatine completely prevented the inhibitory effects of IVA on Na(+),K(+)-ATPase. In conclusion, in vivo administration of IVA inhibits the citric acid cycle probably through the enzyme citrate synthase, as well as Na(+),K(+)-ATPase, a crucial enzyme responsible for maintaining the basal potential membrane necessary for a normal neurotransmission. It is presumed that inhibition of these activities may be involved in the pathophysiology of the neurological dysfunction of isovaleric academic patients. The present findings are of particular interest because treatment with creatine supplementation may represent a potential novel adjuvant therapeutic strategy in IVAcidemia.
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PMID:Creatine administration prevents Na+,K+-ATPase inhibition induced by intracerebroventricular administration of isovaleric acid in cerebral cortex of young rats. 1921 Sep 57


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