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:3.4.16.2 (PCP)
3,761 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

3'-O-(4-benzoyl)benzoyl ATP (BzATP) was used as a photoaffinity analog of ATP to label potential ATP receptors in ciliated cells. Like ATP, without photoactivation, BzATP stimulated the ciliary beat frequency in tissue culture up to threefold. Irradiation of intact cells in the presence of [alpha-32P]BzATP followed by SDS-PAGE and autoradiography revealed two labeled proteins with molecular masses of 46 and 96 kDa (p46 and p96). Photolabeling of both proteins was susceptible to digestion with trypsin, implying that the labeled proteins are at least partially exposed on the extracellular surface of the plasma membrane. The dependence of 32P incorporation in both proteins on [alpha-32P]BzATP concentration was similar. Labeling of p46 but not p96 required Ca2+ or Mg2+. Various nucleotides stimulated the ciliary frequency, and inhibited the photolabeling of p46 and p96. The rank order of apparent affinity for p46 is: ATP approximately equal to ADP > GTP gamma S > ADP beta S, UTP, 2MeSATP, AMP-PNP > AMP-PCP > AMP > adenosine; for p96 it is: ADP approximately equal to ADP beta S > or = ATP >> AMP-PCP, AMP-PNP > GTP gamma S > or = AMP > 2MeSATP, UTP, adenosine. The rank of stimulation of ciliary beat frequency is: ADP beta S, UTP > or = 2MeSATP, GTP gamma S, AMP-PNP, ATP > or = ADP > AMP-PCP > adenosine > AMP. These results suggest the involvement of p46 in the stimulatory effect of extracellular ATP on the ciliary beat, as a P2 purinoceptor. On the other hand, p96 may represent a P2 purinoceptor or an ectonucleotidase.
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PMID:Extracellular ATP binding proteins as potential receptors in mucociliary epithelium: characterization using [32P]3'-O-(4-benzoyl)benzoyl ATP, a photoaffinity label. 853 Dec 2

To elucidate the psychotropic actions of calcium (Ca) antagonists, we investigated the effect of the voltage-dependent Ca channel antagonists, nifedipine and flunarizine, on phencyclidine (PCP)-induced changes in the monoamine metabolism in the regional brain areas of rats. The results indicate that the administration of nifedipine alone attenuated dopamine (DA) metabolism in the nucleus caudatus putamen while enhancing serotonin (5-HT) metabolism. By contrast, flunarizine increased DA metabolism. PCP significantly increased DA metabolite levels in the prefrontal cortex, the nucleus caudatus putamen, and the amygdala. The PCP-induced increases in DA metabolism in these regions were significantly antagonized by nifedipine, but not by flunarizine. These results indicate that nifedipine attenuates the PCP-induced hyperactivity of the dopaminergic neurons, suggesting antipsychotic properties for this drug.
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PMID:Effects of calcium antagonists nifedipine and flunarizine on phencyclidine-induced changes in the regional dopaminergic metabolism of the rat brain. 853 72

1. The regulation of the cardiac Ca2+ release channel-ryanodine receptor (RyR) by exogenous acid phosphatase (AcPh) and purified Ca(2+)-calmodulin-dependent protein kinase II (CaMKII) was studied in swine and rabbit sarcoplasmic reticulum (SR) vesicles using [3H]ryanodine binding and planar bilayer reconstitution experiments. 2. Addition of AcPh (1-20 U ml-1) to a standard incubation medium increased [3H]ryanodine binding in a Ca(2+)-dependent manner. Stimulation was only readily apparent in media containing micromolar Ca2+ concentrations. 3. Scatchard analysis of [3H]ryanodine binding curves revealed that AcPh enhanced binding by increasing the affinity of the receptor for [3H]ryanodine without recruiting additional receptor sites (Kd, 9.8 +/- 0.85 and 3.9 +/- 0.65 nM; Bmax (the maximal receptor density), 1.45 +/- 0.14 and 1.47 +/- 0.12 pmol mg-1 for control and AcPh, respectively). The failure of AcPh to increase Bmax suggested that the number of receptors that were 'dormant' due to phosphorylation in the SR preparation was very small. 4. At the single channel level, AcPh increased the open probability (Po) of RyR channels by increasing the opening rate and inducing the appearance of a longer open state while having no effect on single channel conductance. Thus AcPh acted directly on RyR channels or a closely associated regulatory protein. 5. CaMKII decreased both [3H]ryanodine binding and Po of RyRs when added to medium supplemented with micromolar levels of Ca2+ and calmodulin (CaM). Addition of a synthetic peptide inhibitor of CaMKII, or replacement of ATP with the non-hydrolysable ATP analogue adenylyl[beta, gamma-methylene]-diphosphate (AMP-PCP), prevented CaMKII inhibition of RyRs, suggesting that CaMKII acted specifically through a phosphorylation mechanism. 6. The inhibition of RyR channel activity by CaMKII was reversed by the addition of AcPh. Thus we showed that an in vitro phosphorylation-dephosphorylation mechanism effectively regulates RyRs. 7. The results suggest that intracellular signalling pathways that lead to activation of CaMKII may reduce efflux of Ca2+ from the SR by inhibition of RyR channel activity. The Ca2+ dependence of CaMKII inhibition suggests that the role of the phosphorylation mechanism is to modulate the RyR response to Ca2+.
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PMID:Modulation of cardiac ryanodine receptors of swine and rabbit by a phosphorylation-dephosphorylation mechanism. 854 25

Neuropeptide Y(NPY) inhibits Ca2+-activated K+ channels reversibly in vascular smooth muscle cells from the rat tail artery. NPY (200 microM) had no effect in the absence of intracellular adenosine 5'-triphosphate (ATP) and when the metabolic poison cyanide-M-chlorophenyl hydrozone (10 microM) was included in the intracellular pipette solution. NPY was also not effective when ATP was substituted by the non-hydrolysable ATP analogue adenosine 5'-[beta gamma-methylene]-triphosphate (AMP-PCP). NPY inhibited Ca2+-activated K+ channel activity when ATP was replaced by adenosine 5'-O-(3-thiotriphosphate) (ATP [gamma-S]) and the inhibition was not readily reversed upon washing. Protein kinase inhibitor (1 microM), a specific inhibitor of adenosine 3', 5'-cyclic monophosphate-dependent protein kinase, had no significant effect on the inhibitory action of NPY. The effect of NPY on single-channel activity was inhibited by the tyrosine kinase inhibitor genistein (10 microM) but not by daidzein, an inactive analogue of genistein. These observations suggest that the inhibition by NPY of Ca2+-activated K+ channels is mediated by ATP-dependent phosphorylation. The inhibitory effect of NPY was antagonized by the tyrosine kinase inhibitor genistein.
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PMID:ATP-Dependent inhibition of Ca2+-activated K+ channels in vascular smooth muscle cells by neuropeptide Y. 858 7

Consistent with the neuroprotective effects of the non-opioid antitussive dextromethorphan (DM) described in several models of CNS injury, micromolar concentrations of three novel analogs of DM markedly attenuated the injury produced by glutamate in cultured rat cortical neurons. Furthermore, the neuroprotective actions of the DM analogs correlated with their effects to block glutamate-induced excitotoxic calcium signals and were unrelated to metabolism to the phencyclidine (PCP)-like drug dextrorphan (DX). These observations establish a new class of compounds related to DM which, by virtue of their efficacy to protect neurons against a severe glutamate insult, may possess therapeutic potential as treatment modalities for a number of neurodegenerative diseases.
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PMID:Dextromethorphan analogs are neuroprotective in vitro and block glutamate-induced excitotoxic calcium signals in neurons. 859 46

Ca2+-activated K+ channels in the basolateral plasma membrane of bullfrog oxynticopeptic cells are intimately involved in the regulation of acid secretion. Patch-clamp techniques were applied to study the regulating mechanism of these channels. In the excised inside-out configuration, intracellular Mg2+ decreased channel activity in a dose-dependent manner. In the absence of Mg2+, administration of adenosine 5'-trisphosphate (ATP) to the cytoplasmic side also inhibited channel activity. On the other hand, in the presence of Mg2+, addition of ATP markedly increased channel activity. At a fixed concentration of free Mg2+, the Mg-ATP complex caused channel activation and shifted the dose response relationship between channel activity and the intracellular Ca2+ concentration to the left. A nonhydrolysable ATP analogue, adenosine 5'-[beta,gamma-imido]triphosphate (AMP-PNP) adenylyl [beta,gamma-methylene]diphosphate (AMP-PCP), could not substitute for ATP in channel activation, but a hydrolysable ATP analogue, adenosine 5'-O-(3-thiotriphosphate) (ATP[gammaS]) could do so. Furthermore, application of alkaline phosphatase to the cytoplasmic side inhibited channel activity. These results demonstrate that Ca2+-activated K+ channels are regulated by Mg2+ and ATP, and suggest that a phosphorylation reaction may be involved in the regulation mechanism of these channels.
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PMID:Modulation of Ca2+-activated K+ channels by Mg2+ and ATP in frog oxyntic cells. 859 91

The regulation of capacitative Ca2+ influx in Xenopus oocytes was investigated using both the two electrode voltage-clamp (where Ca2+ is monitored through the Ca2+-dependent Cl- current) and patch-clamp techniques. Following stimulation of expressed 5-hydroxytryptamine (5-HT) receptors, capacitative Ca2+ influx deactivated in around 15 min. Following injection of [adenosine 5'-O-(3-Thiotriphosphate)] (ATP [gamma-S]), an ATP analogue that is readily used by protein kinases, capacitative Ca2+ influx activated by 5-HT application either did not deactivate or was prolonged around twofold. However, injection of adenylyl 5'-(beta,gamma-methylene)-diphosphonate (AMP-PCP), another ATP analogue that is not utilised by kinases, did not affect the time-course of Ca2+ influx. When capacitative Ca2+ influx was activated by readmission of Ca2+ to oocytes incubated in thapsigargin/0 Ca2+ solution for several hours, Ca2+ influx occurred and a weakly saturating relationship between external Ca2+ and Ca2+ influx was found. Ca2+ influx in thapsigargin-treated cells was unaffected by ATP [gamma-S]. ATP [gamma-s] and several kinases had no effect on the Ca2+-dependent Cl- current when the latter was activated by elevation of Ca2+ independent of capacitative Ca2+ influx. Protein kinase C slowly and partially inhibited the Cl- current. Outside-out patches taken from thapsigargin-treated cells failed to demonstrated any Ca2+ current or Ca2+-dependent Cl- current on reapplying high Ca2+ to the patch, despite the oocyte showing a large capacitative Ca2+ influx. The results suggest that a kinase, activated on receptor stimulation, prolongs the activation time-course of capacitative Ca2+ influx.
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PMID:Effects of protein phosphorylation on the regulation of capacitative calcium influx in Xenopus oocytes. 866 63

Ion entry into neurons occurs either through receptor-operated channels (ROC) or voltage-operated channels (VOC). The function of ROC depends crucially on the action of agonists, antagonists or compounds modulating particular types of receptors (GABA A, NMDA, Ach N receptors). The function of VOC is closely connected with the activity of protein kinases and the processes of phosphorylation of membrane proteins (K+, Na+, Ca2+ channels). Gamma aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the vertebrate brain. The GABA A receptor is a oligomeric complex of multiple binding sites and chloride channel. This complex contains recognition sites for GABA, anxiolytics such as benzodiazepine, anxiogenic--beta-carboline, and convulsant such as picrotoxin. Chloride ion channel plays a crucial role in anxiogenic, anxiolytic and convulsant activities. Glutamic acid is the main endogenous neurotransmitter for N-methyl-D-aspartate (NMDA)-type excitatory amino acid receptor. NMDA receptors connected with Ca2+ channel, have multiple modulatory sites which are affected by a wide range of compounds. There are NMDA and competitive NMDA antagonists site, the glycine site, the phencyclidine (PCP) site and the binding site of Mg2+ ions in this receptor complex. Calcium entry through NMDA receptors may be important in the etiology of many psychiatric disorders. VOC mediate rapid, voltage-gated changes in ion permeability during action potentials in neurons. Electrophysiological studies indicate the existence of three types of VOC (K+, Na+, Ca2+ channels). In number of neurons various subtypes of Ca2+ channels (P, T, N and L-type) occur together. Among them, the L-type calcium channel has been first described and most thoroughly studied. The L-type calcium channel is localized on nerve terminals in the pre and postsynaptic parts, as well as on cell bodies and may be involved in the mechanism of action of psychotropic drugs. Chronic treatment with various psychotropic drugs changes the density of voltage-dependent Ca2+ channels in the central nervous system. Thus calcium entry through both VOC and ROC may be important in the etiology of many psychiatric disorders.
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PMID:Receptor and voltage-operated ion channels in the central nervous system. 871 58

Since unique calcium dynamics have been reported for toxic (40-80 M) and non-toxic (5-10 microM) concentrations of glutamate, we evaluated the effect of neuroprotective sigma ligands on glutamate and potassium chloride (KCl)-stimulated changes in [Ca2+]i using 12-15 day old primary rat neuronal cortical cultures. In approximately 80% of the neurons tested, 80 microM glutamate caused a sustained calcium flux previously shown to be associated with neurotoxicity. The majority of sigma ligands that were evaluated altered glutamate-induced calcium flux. For example, the primary effect of maximally neuroprotective concentrations of the sigma ligands dextromethorphan, (+)-pentazocine, (+)-cyclazocine, (+)-SKF 10047, carbetapentane and haloperidol was a shift from a sustained, to either a biphasic or a monophasic transient calcium response indicative of neuroprotection. (+)-3-PPP, previously shown not to be neuroprotective in this model system, failed to alter glutamate-induced calcium flux. In contrast to glutamate, KCl (50 mM) produced changes in [Ca2+]i which were not neurotoxic to the neurons as measured by LDH release. The primary response observed in 59% of the neurons treated with 50 mM KCl alone was an initial spike in [Ca2+]i which abruptly declined then plateaued above basal levels throughout the 12 min of analysis (modified sustained response). The highly selective sigma ligands produced a shift from the modified sustained response to a monophasic transient calcium response. Again, (+)-3-PPP had no effect on KCl-induced calcium dynamics. Of the PCP-related sigma ligands only (+)-SKF-10047 consistently attenuated the KCl-induced calcium flux. Collectively, these results indicate that modulation of [Ca2+]i through receptor and voltage-gated calcium channels contributes significantly to sigma mediated neuroprotection.
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PMID:Role of calcium in sigma-mediated neuroprotection in rat primary cortical neurons. 875 Sep 59

[3H]Ryanodine binding to, as well as functions of, ryanodine receptor intracellular Ca2+ release channel complexes are modulated by several adenosine-based compounds. In this study, we determined the effects of endogenous compounds termed diadenosine polyphosphates (ApnAs; n = 2-6 phosphate groups) on [3Hlryanodine binding to membranes prepared from rat brain and skeletal and cardiac muscle. Under low ionic strength buffer conditions, [3H]ryanodine binding to brain membranes was significantly increased by 171% with 333 microM P1,P5-di(adenosine-5') pentaphosphate (Ap5A) and by 209% with the same concentration of the metabolism-resistant ATP analogue betagamma-methyleneadenosine 5'-triphosphate (AMP-PCP) compared with control values for [3H]ryanodine binding of 9.6 +/- 1.8 fmol/mg of protein. Dose-related increases in [3H]ryanodine binding were observed for all five ApnAs tested [P1,P2-di(adenosine-5') pyrophosphate (Ap2A), P1,P3-di(adenosine-5') triphosphate (Ap3A), P1,P4-di(adenosine-5') tetraphosphate (Ap4A), Ap5A, and P1,P6-di(adenosine-5') hexaphosphate (Ap6A)] as well as AMP-PCP; oxidized salts of ApnAs stimulated [3H]ryanodine binding to a greater degree than did nonoxidized APnAs. The apparent rank order for the capacity of these agents to increase [3H]-ryanodine binding was oxidized Ap4A = oxidized Ap5A > oxidized Ap3A > Ap6A > AMP-PCP > Ap5A > AP2A. Addition of the approximate EC50 dose of oxidized Ap4A (37 microM) increased the affinity (KD) of ryanodine receptors from 34 +/- 7 to 12 +/- 2 nM, the apparent binding site density (Bmax) was not significantly different from control values of 107 +/- 33 fmol/mg of protein. Increases in [3H]-ryanodine binding by either oxidized Ap4A or nonoxidized Ap5A were not further enhanced by coincubation with AMP-PCP, which suggests a similar site of action for the ApnAs and AMP-PCP. [3H]Ryanodine binding to skeletal and cardiac muscle membranes was enhanced by addition of oxidized AP4A Ap5A, and AMP-PCP. Oxidized AP4A increased the specific binding by ninefold in skeletal muscle and by threefold in cardiac muscle. These results suggest that ApnAs, at physiologically relevant concentrations, may serve as endogenous modulators of ryanodine receptor-gated Ca2+ release channels.
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PMID:Regulation of ryanodine receptor calcium release channels by diadenosine polyphosphates. 876 82


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