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)

Until recently, racemic ketamine (S-ketamine/R-ketamine = 50:50) has been used to study NMDA receptor hypofunction in relation to pathophysiological models of schizophrenia. Ketamine given to normal humans in subanesthetic doses produces a model psychosis including both positive and negative symptoms of schizophrenia. More recently it has been shown that at subanesthetic doses the pure (S)- and (R)-ketamine enantiomeres interact differently with the NMDA and sigma receptor sites in human brain. It was found that (S)-ketamine binds with a 3-4 time higher affinity to the PCP binding site of the NMDA receptor than (R)-ketamine, and that at these concentrations (R)-ketamine interacts also weakly with the sigma receptor sites, where (S)-ketamine binds only negligibly. To further investigate the role of NMDA-receptor mediated neurotransmission in schizophrenic psychosis, the effects of pure (S)- and (R)-ketamine enantiomeres on brain energy metabolism in normal humans using positron emission tomography and [18F]fluorodeoxyglucose (FDG) are reported here. Psychotomimetic doses of (S)-ketamine increased cerebral metabolic rates of glucose (CMRglu) markedly in the frontal cortex including the anterior cingulate, parietal and left sensorimotor cortex, and in the thalamus. The metabolic changes in the frontal and left temporal cortex correlated with ego-disintegration and hallucinatory phenomena. Equimolar doses of (R)-ketamine tended to decrease CMRglu across brain regions and significantly suppressed CMRglu in the temporomedial cortex and left insula. (R)-ketamine did not produce psychotic symptoms, but a state of relaxation. The (S)-ketamine-induced metabolic hyperfrontality appears to parallel similar metabolic findings in acute psychotic schizophrenic patients and encourages further investigations of glutamatergic disturbances in schizophrenia.
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PMID:Differential psychopathology and patterns of cerebral glucose utilisation produced by (S)- and (R)-ketamine in healthy volunteers using positron emission tomography (PET). 908 82

1. The glucose and ATP dependence of exocytosis were investigated in single mouse pancreatic B-cells by monitoring changes in cell capacitance evoked by voltage-clamp depolarizations, infusion of high [Ca2+]i buffers or photorelease of caged Ca2+ or ATP. 2. In intact B-cells, using the perforated patch whole-cell technique, glucose (5 mM) increased exocytotic responses evoked by membrane depolarization 5-fold over that observed in the absence of the sugar. Increasing the glucose concentration to 20 mM produced a further doubling of exocytosis. The stimulatory action of glucose was attributable to glucose metabolism and abolished by mannoheptulose, an inhibitor of glucose phosphorylation. 3. Exocytosis triggered by infusion of high [Ca2+]i and ATP was reduced by 80% when ATP was replaced by its non-hydrolysable analogue adenosine 5'-[beta, gamma-methylene]triphosphate (AMP-PCP) in standard whole-cell experiments. Exocytosis elicited by GTP gamma S was similarly affected by replacement of ATP with the stable analogue. 4. Photoreleasing ATP in the presence of 170 nM [Ca2+]i, following the complete wash-out of endogenous ATP produced a prompt (latency, < 400 ms) and biphasic stimulation of exocytosis. 5. Elevation of [Ca2+]i to exocytotic levels by photorelease from Ca(2+)-nitrophenyl EGTA preloaded into the cell evoked a biphasic stimulation in the presence of Mg-ATP. The response consisted of an initial rapid (completed in < 200 ms) phase followed by a slower (lasting > or = 10 s) sustained component. Replacement of ATP with AMP-PCP abolished the late component but did not affect the initial phase. The latency between elevation of [Ca2+]i and exocytosis was determined as < 45 ms. Inclusion of N-ethylmaleimide (NEM; 0.5 mM for 3 min) in the intracellular solution exerted effects similar to those obtained by substituting AMP-PCP for ATP. 6. We conclude that the B-cell contains a small pool (40 granules) of primed granules which are immediately available for release and which are capable of undergoing exocytosis in an ATP-independent fashion. We propose that this pool of granules is preferentially released during first phase glucose-stimulated insulin secretion. The short latency between the application of ATP and the onset of exocytosis finally suggests that priming takes place with sufficient speed to participate in the rapid adjustment of the secretory capacity of the B-cell.
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PMID:Rapid ATP-dependent priming of secretory granules precedes Ca(2+)-induced exocytosis in mouse pancreatic B-cells. 930 81

1. The activity of Ca2+ channels is regulated by a number of mechanisms including direct allosteric modulation by intracellular ATP. Since ATP derived from glycolysis is preferentially used for membrane function, we hypothesized that glycolytic ATP also preferentially regulates cardiac L-type Ca2+ channels. 2. To test this hypothesis, peak L-type Ca2+ currents (ICa) were measured in voltage-clamped rabbit cardiomyocytes during glycolytic inhibition (2-deoxyglucose + pyruvate), oxidative inhibition (cyanide + glucose) or both (full metabolic inhibition; FMI). 3. A 10 min period of FMI resulted in a 40.0 % decrease in peak ICa at +10 mV (-5.1 +/- 0.6 versus -3.1 +/- 0.4 pA pF-1; n = 5, P < 0.01). Similar decreases in peak ICa were observed during glycolytic inhibition using 2-deoxyglucose (-6.2 +/- 0.2 versus -3.7 +/- 0.2 pA pF-1; n = 5, P < 0.01) or iodoacetamide (-6.7 +/- 0.3 versus -3.7 +/- 0.2 pA pF-1; n = 7, P < 0.01), but not following oxidative inhibition (-6.2 +/- 0.4 versus -6.4 +/- 0.3 pA pF-1; n = 5, n.s.). The reduction in ICa following glycolytic inhibition was not mediated by phosphate sequestration by 2-deoxyglucose or changes in intracellular pH. 4. Reductions in ICa were still observed when inorganic phosphate and creatine were included in the pipette, confirming a critical role for glycolysis in ICa regulation. 5. With 5 mM MgATP in the pipette during FMI, peak ICa decreased by only 18.4 % (-6.8 +/- 0.6 versus -5.5 +/- 0.3 pA pF-1; n = 4, P < 0.05), while inclusion of 5 mM MgAMP-PCP (beta,gamma-methyleneadenosine 5'-triphosphate, Mg2+ salt) completely prevented the decrease in peak ICa (-6.9 +/- 0.3 versus -6.5 +/- 0.3 pA pF-1; n = 5, n.s.). 6. Together, these results suggest that ICa is regulated by intracellular ATP derived from glycolysis and does not require hydrolysis of ATP. This regulation is expected to be energy conserving during periods of metabolic stress and myocardial ischaemia.
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PMID:Preferential regulation of rabbit cardiac L-type Ca2+ current by glycolytic derived ATP via a direct allosteric pathway. 967 64

Rats were given fixed-time, 1-min food-pellet delivery sessions, for 3 h every day, which resulted in over drinking (schedule-induced polydipsia). In previous research, groups of animals came to prefer solutions of cocaine or lidocaine to concurrently presented water, if the drugs were first offered in a glucose/saccharin vehicle, which was then gradually eliminated, so that the choice became a drug solution in water vehicle versus water. In the present experiment, the same procedure produced a preference for 0.025 mg/ml quinine solution to water, indicating that a bitter solution that was not a topical anesthetic agent could come to be preferred. After establishing preference for quinine solution, it was possible to gradually remove quinine while increasing phencyclidine (PCP) concentration to produce preference for 0.075 mg/ml PCP solution, and similarly to produce subsequent preference for 0.1 mg/ml caffeine solution, although not for all animals. For additional groups, drinking either 0.15 mg/ml PCP or 0.1 mg/ml caffeine, while gradually reducing the glucose/saccharin vehicle to water vehicle was a less successful procedure for establishing the respective drug preferences. The latter result suggests that first instituting a preference for quinine solution to water facilitated the later establishment of preferences for PCP and caffeine solutions.
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PMID:Establishing oral preference for quinine, phencyclidine and caffeine solutions in rats. 1078 Mar

Titanium dioxide (TiO2) photocatalysts were coated on hollow glass beads by sodium silicate (Na2SiO3.9H2O) solution. The coated catalysts were characterized by BET, XRD. Their photoactivity were examined using photocatalytic degradation of sodium pentachlorophenolate(PCP-Na) and glucose solution. The impact of catalysts dosage, PCP-Na initial concentration, initial pH and oxygen concentration on reaction kinetics were also studied in detail. The experiments illustrated that the performance of C3-type catalysts was satisfactory. Conditions of the experiments were following: The initial concentration of PCP-Na and CODCr were 10 mg.L-1 and 400 mg.L-1, respectively, and illumination time was 2 hours and catalysts dosage was 2 g.L-1, the removal rates of CODCr and PCP-Na were above 65% and 92% respectively. Optimum dosage of C3-type catalysts was 2-2.5 g.L-1, DO was no less than 3 mg.L-1.
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PMID:[Decomposition of aqueous sodium pentachlorophenolate (PCP-Na) by using TiO2 coating photocatalyst]. 1138 40

Stealth is an adulterant advertised as being undetectable by adulteration tests. It has been described as peroxidase and peroxide, which, when added to urine samples, are intended to prevent a positive drug test. Characterization of the effect of Stealth on urine samples and immunoassay results was undertaken to assist in detection of this adulterant. Stealth was added to a number of urine matrices, and various parameters were evaluated including pH, specific gravity, color, creatinine, chloride, urea, blood, glucose, and nitrite. Samples were spiked with THC acid metabolite, benzoylecgonine, morphine, secobarbital, PCP, amphetamine, and lysergic acid diethylamide (LSD) then tested by Roche OnLine and Microgenics CEDIA immunoassay reagents. Results of these analyses showed Stealth did not cause the urine sample to exceed any of the monitored parameters including those routinely used in drug-testing laboratories that would indicate adulteration of a sample. It did, however, cause samples positive for the marijuana metabolite (11-nor-delta9-tetrahydrocannibinol-9-carboxylic acid), LSD, and opiate (morphine) at 125-150% of cutoff to screen negative by immunoassay. Adulterating an authentic positive sample provided by a marijuana user caused that sample to screen negative using these immunoassay reagents as well.
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PMID:Effects of Stealth adulterant on immunoassay testing for drugs of abuse. 1155 Aug 22

Numerous human imaging studies have revealed an absolute or relative metabolic hypofunction within the prefrontal cortex, thalamus and temporal lobes of schizophrenic patients. The former deficit correlates with cognitive deficits and negative symptoms, whereas the latter correlates with positive symptomologies. There is also general consensus that schizophrenia is associated with decreased parvalbumin expression in the prefrontal cortex. Since the drug phencyclidine can induce a psychosis resembling schizophrenia in humans, we have examined whether repeated phencyclidine (PCP) treatment to rats could produce similar metabolic and neurochemical deficits to those occurring in schizophrenia and whether these deficits could be modulated by antipsychotic drugs. We demonstrate here that chronic intermittent exposure to PCP (2.58 mg kg(-1) i.p.) elicits a metabolic hypofunction, as demonstrated by reductions in the rates of glucose utilization, within the prefrontal cortex, reticular nucleus of thalamus and auditory system, key structures displaying similar changes in schizophrenia. Moreover, chronic PCP treatment according to this regime also decreases parvalbumin mRNA expression in the rat prefrontal cortex and reticular nucleus of the thalamus. Chronic coadministration of haloperidol (1 mg kg(-1) day(-1)) or clozapine (20 mg kg(-1) day(-1)) with PCP did not modulate PCP-induced reductions in metabolic activity in the rat prefrontal cortex, but reversed deficits in the structures of the auditory system. Clozapine, but not haloperidol, reversed PCP-induced decreases in parvalbumin expression in prefrontal cortex GABAergic interneurons, whereas both drugs reversed the deficits in the reticular nucleus of the thalamus. These data provide important new information, which strengthen the validity of chronic PCP as a useful animal model of schizophrenia, when administered according to this protocol. Furthermore, we propose that reversal of PCP-induced reductions in parvalbumin expression in the prefrontal cortex may be a potential marker of atypical antipsychotic activity in relation to amelioration of cognitive deficits and negative symptoms of schizophrenia.
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PMID:Induction of metabolic hypofunction and neurochemical deficits after chronic intermittent exposure to phencyclidine: differential modulation by antipsychotic drugs. 1258 79

Permeable spheroplasts were prepared from two strains of Saccharomyces cerevisiae by incubating with zymolyase without a permeabilizing agent. The loss of the plasma membrane barrier was confirmed by the nucleotide release, the activity of glucose 6-phosphate dehydrogenase with external substrates and by the effects on respiration of mitochondrial substrates and ADP. Mitochondrial integrity was maintained, as shown by respiration with lactate, pyruvate, glucose and ethanol, and its acceleration by ADP showed a coupled respiration. Potassium uptake into the vacuole was measured with a selective electrode and found to be taken up effectively by spheroplasts only in the presence of Mg-ATP; it was reverted by CCCP and PCP and inhibited by bafilomycin A1, but not by sodium vanadate or sodium azide. Potassium ions did not alter DeltaPsi of the vacuole, followed with oxonol V, but caused vacuolar alkalinization, as followed with pyranine. The increase of vacuolar pH was non-selective and observed at 50-200 mM of several monovalent cations. Isolated vacuoles with pyranine inside showed similar changes of the internal pH in the presence of KCl. Results indicate that some strains do not require a permeabilizing agent to directly access the vacuole in spheroplasts prepared with zymolyase. The hypothesis about the existence of a K+/H+ antiporter in the vacuolar membrane of S. cerevisiae is discussed.
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PMID:In situ study of K+ transport into the vacuole of Saccharomyces cerevisiae. 1603 2

The largely empirical dopamine theory has limited value in clarifying the pathogenesis of schizophrenia, due to its inability to explain consistent imaging findings, such as cortical grey matter loss, reduced frontal and thalamic activity, and, reduced D1 receptor load. Furthermore, the most effective drug for treating positive and negative symptoms - clozapine - has minimal dopaminergic activity. We present an alternative hypothesis centring on presumed deficits in membrane bound glucose transporter proteins GLUT 1 and GLUT 3, either in absolute numbers or functional capacity. In situations of high demand, intracellular hypoglycaemia in neurones and astrocytes will produce acute symptoms of misperceptions, misinterpretations, anxiety and irritability - the usual features of prodromal and first onset schizophrenia. Furthermore, reduced glucose uptake will disrupt production of glutamate--functionally similar to the schizophrenia-like syndrome produced by PCP, a glutamate antagonist. In the longer term, reduced neuronal growth and poor synaptic contacts will produce chronic cognitive difficulties and perpetuate acute symptoms. A backlog effect due to reduced brain uptake of glucose would produce systemic hyperglycaemia observed in drug nai ve subjects. Rat studies have shown that clozapine and similar compounds block GLUT proteins in the brain and peripherally, more so than selective dopamine blockers. By blocking GLUT proteins, clozapine would break malfunctioning circuits, resulting in the disappearance of cognitive and perceptual symptoms. Unfortunately, these drugs would also raise systemic glucose levels, increasing the risk of diabetes, as observed in longer term studies of clozapine in particular. We summarise potentially useful research strategies, including studying the genotype of GLUT proteins with respect to schizophrenia phenotypes, activation studies involving fMRI using deoxyglucose as a substrate, and investigating clinical features of schizophrenic patients prior to and following treatment for co-existing diabetes.
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PMID:Impaired neuronal glucose uptake in pathogenesis of schizophrenia - can GLUT 1 and GLUT 3 deficits explain imaging, post-mortem and pharmacological findings? 1612 30

The moderately halophilic strain Halomonas maura S-30 produces a high-molecular-mass acidic polymer (4.7 x 10(6) Da) composed of repeating units of mannose, galactose, glucose and glucuronic acid. This exopolysaccharide (EPS), known as mauran, has interesting functional properties that make it suitable for use in many industrial fields. Analysis of the flanking regions of a mini-Tn5 insertion site in an EPS-deficient mutant of H. maura, strain TK71, led to the identification of five ORFs (epsABCDJ), which form part of a gene cluster (eps) with the same structural organization as others involved in the biosynthesis of group 1 capsules and some EPSs. Conserved genetic features were found such as JUMPstart and ops elements, which are characteristically located preceding the gene clusters for bacterial polysaccharides. On the basis of their amino-acid-sequence homologies, their putative hydropathy profiles and the effect of their mutations, it is predicted that EpsA (an exporter-protein homologue belonging to the OMA family) and EpsC (a chain-length-regulator homologue belonging to the PCP family) play a role in the assembly, polymerization and translocation of mauran. The possibility that mauran might be synthesized via a Wzy-like biosynthesis system, just as it is for many other polysaccharides, is also discussed. This hypothesis is supported by the fact that EpsJ is homologous with some members of the PST-exporter-protein family, which seems to function together with each OMA-PCP pair in polysaccharide transport in Gram-negative bacteria, transferring the assembled lipid-linked repeating units from the cytoplasmic membrane to the periplasmic space. Maximum induction of the eps genes is reached during stationary phase in the presence of 5 % (w/v) marine salts.
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PMID:epsABCJ genes are involved in the biosynthesis of the exopolysaccharide mauran produced by Halomonas maura. 1615 Nov 97


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