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)

Phencyclidine (PCP) was tested on the metathoracic tibialis muscles of Locusta migratoria. In physiological solution, the peak amplitude of the excitatory postsynaptic currents (EPSCs) evoked by nerve stimulation was linearly related to membrane potential between -50 and -150 mV. The decay time constant of the EPSC (tau EPSC) was exponentially dependent on voltage and decreased with hyperpolarization. The membrane potential change required to produce an e-fold change in tau EPSC was 315 mV. PCP (5-40 microM) produced a concentration-dependent depression of both EPSC peak amplitude and tau EPSC. A slight nonlinearity in the current-voltage relationship could be discerned at high concentrations of PCP. The shortening of the decay time constant of EPSC (tau EPSC) occurred without significant change in the voltage sensitivity observed under control conditions. Under all experimental conditions, the decay of the EPSCs remained a single exponential of time. Fluctuation analysis indicated that 5 microM PCP shortens the lifetime of the glutamate-activated channels by 25.7 +/- 3%. PCP (10-80 microM) did not induced desensitization of the glutamate receptors. These results suggest that PCP interacts with the open conformation of ion channels activated by the glutamate receptor.
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PMID:Phencyclidine (PCP) blocks glutamate-activated postsynaptic currents. 286 72

In the present study, the authors found that, in Mg++-free buffer, N-methyl-D-aspartate (NMDA) was able to evoke the Ca++-dependent and tetrodotoxin-sensitive release of striatal acetylcholine (ACh), presumably via interaction with receptors on cholinergic interneurons. In Mg++-free buffer containing pargyline, NMDA also evoked a Ca++-dependent and tetrodotoxin-sensitive release of striatal [3H]dopamine (DA). Phencyclidine (PCP) and physiological concentrations of Mg++ (1.2 mM) also inhibited ACh release evoked by L-glutamate, L-aspartate and DL-homocysteate, but not ACh release evoked by the glutamate analogs quisqualate and kainate, suggesting that PCP is selective for the magnesium-sensitive, NMDA-preferring glutamate-aspartate receptor subtype. Comparison of PCP inhibition of NMDA-stimulated ACh and DA release with that produced by the competitive NMDA antagonist 2-amino-5-phosphonovalerate indicates that PCP is probably not altering release by a direct action on the NMDA recognition site. The ability of 2-amino-5-phosphonovalerate, but not PCP, to prevent desensitization of NMDA-induced ACh release is consistent with this interpretation. Binding studies did, however, reveal a reduction in the apparent affinity of the PCP binding site by high concentrations of NMDA. This may suggest an allosteric link between the PCP-sigma receptor and the NMDA-type glutamate-aspartate receptor. The receptors mediating excitatory amino acid-induced DA release were somewhat less selective than those on cholinergic neurons in their sensitivity to both Mg++ and PCP. Structure-activity-relationship studies suggested that the inhibition off ACh and DA release evoked by NMDA involves biding to the PCP-sigma receptor.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Characterization of the inhibition of excitatory amino acid-induced neurotransmitter release in the rat striatum by phencyclidine-like drugs. 287 74

Glutamine synthetase of plants is the physiological target of tabtoxinine-beta-lactam, a toxin produced by several disease-causing pathovars of Pseudomonas syringae. This toxin, a unique amino acid, is an active site-directed, irreversible inhibitor of glutamine synthetase from pea. ATP is required for inactivation. Neither ADP, AMP, nor adenosine 5'-(beta,gamma-methylene)triphosphate (AMP-PCP) supports inactivation. Adenyl-5'-yl imidophosphate (AMP-PNP) is slowly hydrolyzed by glutamine synthetase to produce adenyl-5'-yl phosphoramidate (AMP-PN) and inorganic phosphate as identified by 31P NMR spectroscopic analysis. AMP-PNP also supports a slow inactivation of glutamine synthetase by tabtoxinine-beta-lactam. These data are consistent with gamma-phosphate transfer being involved in the inactivation. Completely inactivated glutamine synthetase has 0.9 mumol of toxin bound/mumol of subunit. One mumol of ATP is bound per mumol of subunit of glutamine synthetase in the absence of either the toxin or another active site-directed inhibitor, methionine sulfoximine; whereas, a 2nd mumol of either [alpha- or gamma-32P]ATP is bound per mumol of subunit when glutamine synthetase is incubated in the presence of either toxin or methionine sulfoximine until all enzyme activity is lost. These data suggest that the gamma-phosphate hydrolyzed from ATP during inactivation remains with the enzyme-inhibitor complex, as well as the ADP. The open chain form, tabtoxinine, was neither a reversible nor an irreversible inhibitor of glutamine synthetase, suggesting that the beta-lactam ring is necessary for inhibition. The inactivation of glutamine synthetase with tabtoxinine-beta-lactam is pseudo-first-order when done in buffer containing 15% (v/v) ethylene glycol. The rate constant for this reaction is 3 X 10(-2) S-1, and the Ki for the toxin is 1 mM. Removal of the ethylene glycol from the buffer allows the reaction to proceed in a non-first-order manner with the apparent rate constant decreasing with time. As the enzyme is inactivated in these conditions, the binding affinity for the toxin appears to decrease, while the Km observed for glutamate does not change.
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PMID:Inactivation of pea seed glutamine synthetase by the toxin, tabtoxinine-beta-lactam. 287 40

In primary cultures of cerebellar granule cells excitatory amino acid recognition sites are coupled with the stimulation of inositol phospholipid (PI) hydrolysis, cGMP formation and 45Ca2+ uptake. Mg2+, 2-amino-5-phosphonovalerate (APV) and phencyclidine (PCP) potently inhibit signal transduction in response to N-methyl-D-aspartate (NMDA), glutamate (GLU) and aspartate (ASP). Activation by quisqualate (QUIS) is transduced selectively into stimulation of PI hydrolysis and this response is not sensitive to inhibition by Mg2+, APV and PCP. Activation by kainate (KA) is transduced into potent stimulation of cGMP formation and 45Ca2+ uptake. Transduction of KA signal is not affected by Mg2+ and is relatively insensitive to PCP and APV.
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PMID:Excitatory amino acid signal transduction in cerebellar cell cultures. 288 6

Biochemical and electrophysiological studies have provided evidence that a complex comprising the N-methyl-D-aspartate (NMDA)-type excitatory amino acid (EAA) receptor and the phencyclidine (PCP) recognition site exists in mammalian brain. This complex, which has been compared to that established for the inhibitory amino acid, gamma-aminobutyric acid, and the benzodiazepine anxiolytic, diazepam, is sensitive to the effects of the divalent cation Mg2+, which has suggested the presence of a third, ion channel component. Using a radioreceptor assay for the PCP receptor, L-glutamate (L-Glu) produced a concentration-dependent increase in the binding of [3H]thienyl cyclohexylpiperazine ([3H]TCP) in well washed membranes from rat forebrain. The EAA produced a maximal increase in specific binding of 400%, with an EC50 value of 340 nM. The ability of L-Glu to enhance [3H]TCP binding was 10-fold more potent in the presence of 30 microM Mg2+, which inhibits NMDA-evoked responses in intact tissue preparations and produces a 50% increase in [3H]TCP binding on its own. Analysis of saturation curves indicated that the effect of both L-Glu and Mg2+ could be attributed to an increase in receptor affinity as well as increases in the proportion of a high affinity state of the PCP-binding site. Assessment of the effect of a number of EAAs on basal [3H]TCP binding (well washed membranes in the absence of either L-Glu or Mg2+) showed that the EAA recognition site involved in the effects of L-Glu was the NMDA subtype. Further studies examined a series of compounds thought to interact with either the NMDA or PCP components of the receptor complex under four binding conditions: basal, +Mg2+; +L-Glu; and +Mg2+/L-Glu. These results showed that dissociative anesthetics, such as dexoxadrol and PCP, as well as the novel anticonvulsant MK-801, selectively interact with the high affinity state of the PCP receptor. NMDA antagonists, such as CPP, were also found to inhibit binding to the high affinity state of the PCP receptor, although not as potently as the dissociative anesthetics. Interestingly, the NMDA antagonists did not inhibit any of the binding to the low affinity state of the receptor. The sigma ligands (+/-)-SKF 10,047 and haloperidol recognized two components of [3H]TCP binding only in the presence of L-Glu. The results of the present study are consistent with the finding that agonists of the NMDA receptor induce a high affinity state of the PCP receptor.
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PMID:Interaction of L-glutamate and magnesium with phencyclidine recognition sites in rat brain: evidence for multiple affinity states of the phencyclidine/N-methyl-D-aspartate receptor complex. 289 25

Phencyclidine (PCP) receptors were successfully solubilized from rat forebrain membranes with 1% sodium cholate. Approximately 58% of the initial protein and 20-30% of the high-affinity PCP binding sites were solubilized. The high affinity toward PCP-like drugs, the stereo-selectivity of the sites, and the sensitivity to N-methyl-D-aspartate (NMDA) receptor ligands were preserved. Binding of the potent PCP receptor ligand N-[3H][1-(2-thienyl)cyclohexyl] piperidine ([3H]TCP) to the soluble receptors was saturable (KD = 35 nM), and PCP-like drugs inhibited [3H]TCP binding in a rank order of potency close to that observed for the membrane-bound receptors; the most potent inhibitors were TCP (Ki = 31 nM) and the anticonvulsant MK-801 (Ki = 50 nM). The NMDA receptor antagonist 2-amino-5-phosphonovaleric acid inhibited binding of [3H]TCP to the soluble receptors; glutamate or NMDA diminished this inhibition in a dose-dependent manner. Taken together, the results indicate that the soluble PCP receptor preparation contains the glutamate recognition sites and may represent a single receptor complex for PCP and NMDA, as suggested by electrophysiological data. The successful solubilization of the PCP receptors in an active binding form should now facilitate their purification.
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PMID:Solubilization of rat brain phencyclidine receptors in an active binding form that is sensitive to N-methyl-D-aspartate receptor ligands. 289 2

Using a sensitive histofluorescence staining method that allows for a quantitation of neuronal death, we compared the protective effects of gangliosides (a group of naturally occurring glycosphingolipids), phencyclidine (PCP), and MK-801 (dibenzocyclohepteneimine) on glutamate- and kainate-induced neuronal death in primary cultures of cortical and cerebellar neurons prepared from neonatal rats. PCP and MK-801 block neurotoxicity induced by glutamate doses 50 times higher than the LD50 (LD50 in Mg2+-free medium, 10 microM) but only partially block the kainate neurotoxicity (LD50 in presence of Mg2+, 100 microM). In contrast, pretreatment with gangliosides (GT1b greater than GD1b greater than GM1) results in complete and insurmountable protection against the neurotoxicity elicited by glutamate or kainate. In primary cultures of cerebellar granule cells gangliosides, unlike PCP and MK-801, fail to block glutamate-gated cationic currents and the glutamate-evoked increase of (i) inositol phospholipid hydrolysis (ii) c-fos mRNA content, and (iii) nuclear accumulation of c-fos protein. Protection of glutamate neurotoxicity by gangliosides does not require their presence in the incubation medium; however, it is proportional to the amount of glycosphingolipid accumulated in the neuronal membranes. The ganglioside concentration (30-60 microM) that blocks glutamate-elicited neuronal death also prevents glutamate- and kainate-induced protein kinase C translocation from cytosol to neuronal membranes.
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PMID:Gangliosides prevent glutamate and kainate neurotoxicity in primary neuronal cultures of neonatal rat cerebellum and cortex. 290 28

Rats were trained to discriminate phencyclidine (PCP) from saline at doses of 2 and 4 mg/kg, using a two-lever food reinforced operant technique. +/- N-allylnormetazocine (+/- SKF 10047), +5-methyl-10,11-dihydro-5H-dibenzo[A,D]cyclohepten-5,10-imine MK 801), 3-(2-carboxypiperazin-4-yl) propyl-1-phosphonic acid (CPP) and ifenprodil, which have been shown to antagonise the effects of N-methyl-D-aspartate (NMDA), were tested for their ability to give rise to PCP-appropriate responding. In rats trained at both doses of PCP, +/- SKF 10047 (2-12 mg/kg) and MK 801 (0.0125-0.2 mg/kg) produced dose-related responding on the lever associated with PCP injection. The relative potency of these two compounds was the same in the two groups of animals, but their absolute potencies to produce a PCP-like discriminative stimulus were dependent on the training dose of PCP. In contrast, neither the competitive NMDA antagonist CPP (4-20 mg/kg) nor the non-competitive antagonist ifenprodil (2-12 mg/kg) produced PCP-appropriate responding and ifenprodil (4 mg/kg) neither potentiated nor antagonised PCP. These findings are discussed in the light of the hypothesis that the behavioural effects of PCP are mediated via a reduction of neurotransmission at the NMDA-subtype of glutamate receptors.
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PMID:Is the discriminative stimulus produced by phencyclidine due to an interaction with N-methyl-D-aspartate receptors? 290 45

Phencyclidine (PCP) and some of its pharmacological congeners inhibit the signal transduction at specific excitatory amino acid receptors of cerebellar granule cells in primary cultures. These drugs do not bind to the transmitter recognition sites, and affinity of this specific binding site is increased by the presence of the transmitter bound to its recognition sites. PCP inhibits phosphatidylinositol phosphate hydrolysis mediated by Mg2+-sensitive glutamate receptors (GP1) but not that mediated by Mg2+-insensitive glutamate receptors (GP2). In addition, PCP inhibits Ca2+ influx and cGMP formation mediated by the activation of Mg2+-sensitive glutamate receptors (GC1) but not that mediated by Mg2+-insensitive glutamate receptors (GC2). In this cell culture the activation of phosphatidylinositol phosphate hydrolysis by muscarinic receptor agonists is not affected by PCP. Since PCP inhibits noncompetitively GP1 and GC1 signal transduction it may act as a negative allosteric modulator of signal transduction at both receptors. The pharmacological profile of PCP and its congeners delimits a class of drugs modulating allosterically the action of the primary transmitter at GP1 and GC1 receptors. These drugs need the presence of the transmitter to act and they cannot be termed inverse agonists because they are devoid of activity in the absence of the transmitter; moreover, they do not bind to the transmitter recognition site nor do they prevent the transmitter binding to its recognition sites.
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PMID:Phencyclidine is a negative allosteric modulator of signal transduction at two subclasses of excitatory amino acid receptors. 303 32

It has been reported that glutamate can increase the binding of [3H]TCP to phencyclidine (PCP) receptors by an action on receptors which are selective for N-methyl-D-aspartate (NMDA). Recently this laboratory has reported that glycine and magnesium can amplify this effect of NMDA agonists in well-washed, lysed cortical membranes. Here we report that maximally effective concentrations of glutamate (10 microM), NMDA (300 microM), MgCl2 (300 microM) and glycine (10 microM) increase the affinity of the PCP receptor for [3H]TCP by approximately 4-fold in the absence of any change in the density of PCP receptors. However, in combination with glutamate, magnesium had the further effect of increasing the Bmax by about 75%. Finally, a synaptosomal P2 preparation, which had not been washed to minimize the concentration of endogenous effectors had a Bmax value similar to the well-washed preparation, but had a KD value 8-fold lower. These data indicate that the primary effect of NMDA agonists, glycine, and low concentrations of magnesium ions is to convert the PCP receptor from a low-affinity to a high-affinity state. These data are discussed in relation to the functional regulation of the NMDA ionophore.
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PMID:Equilibrium analysis of [3H]TCP binding: effects of glycine, magnesium and N-methyl-D-aspartate agonists. 306 29


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