Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Phencyclidine (PCP) is a potent psychotomimetic drug of abuse and has profound effect on the functioning of the central nervous system (CNS). Many of the CNS functions are known to be mediated by calcium (Ca2+). In the present study we have investigated the effects of PCP on Ca2+ ATPase activity in rat brain both in vitro and in vivo. For in vitro studies, synaptic membrane fractions prepared from normal rat brain were incubated with PCP at different concentrations (25-100 microM) before the addition of substrate. For in vivo studies, rats were treated with a single moderate dose of PCP (10 mg/kg, i.p.) and animals were sacrificed at 1,2, 6 and 12 h after treatment. Ca2+ ATPase activity in synaptic membrane fractions was assayed by estimation of inorganic phosphate. PCP inhibited the Ca2+ ATPase in vitro in a concentration dependent manner with significant effect at 50 and 100 microM. A significant time-dependent reduction of the Ca2+ ATPase activity was evident in vivo. As early as 2 h after the treatment of rats with PCP the ATPase activity was significantly reduced. The reduction of Ca2+ ATPase observed even at 12 h after treatment suggesting a prolonged presence of the drug in the brain tissue. Further, kinetic studies in vitro indicated PCP to be a competitive inhibitor of Ca2+ ATPase with respect to the substrate, ATP. The present findings indicate that PCP inhibits synaptic membrane Ca2+ ATPase thus altering cellular Ca2+ homeostasis in CNS which may partially explain the pharmacological effects of the drug and/or its neurotoxicity.
Mol Cell Biochem 1999 Apr
PMID:Inhibition of calcium ATPase by phencyclidine in rat brain. 1039 Nov 37

Atovaquone represents a class of antimicrobial agents with a broad-spectrum activity against various parasitic infections, including malaria, toxoplasmosis and Pneumocystis pneumonia. In malaria parasites, atovaquone inhibits mitochondrial electron transport at the level of the cytochrome bc1 complex and collapses mitochondrial membrane potential. In addition, this drug is unique in being selectively toxic to parasite mitochondria without affecting the host mitochondrial functions. A better understanding of the structural basis for the selective toxicity of atovaquone could help in designing drugs against infections caused by mitochondria-containing parasites. To that end, we derived nine independent atovaquone-resistant malaria parasite lines by suboptimal treatment of mice infected with Plasmodium yoelii; these mutants exhibited resistance to atovaquone-mediated collapse of mitochondrial membrane potential as well as inhibition of electron transport. The mutants were also resistant to the synergistic effects of atovaquone/ proguanil combination. Sequencing of the mitochondrially encoded cytochrome b gene placed these mutants into four categories, three with single amino acid changes and one with two adjacent amino acid changes. Of the 12 nucleotide changes seen in the nine independently derived mutants 11 replaced A:T basepairs with G:C basepairs, possibly because of reactive oxygen species resulting from atovaquone treatment. Visualization of the resistance-conferring amino acid positions on the recently solved crystal structure of the vertebrate cytochrome bc1 complex revealed a discrete cavity in which subtle variations in hydrophobicity and volume of the amino acid side-chains may determine atovaquone-binding affinity, and thereby selective toxicity. These structural insights may prove useful in designing agents that selectively affect cytochrome bc1 functions in a wide range of eukaryotic pathogens.
Mol Microbiol 1999 Aug
PMID:Resistance mutations reveal the atovaquone-binding domain of cytochrome b in malaria parasites. 1044 80

1. Phencyclidine (PCP) is an inhibitor of the nicotinic acetylcholine receptor (AChR) with characteristics of an open-channel blocker. The location of PCP binding site on the AChR molecule is unknown. 2. PCP inhibits the AChR from electric organ with a higher potency than muscle AChR. To find the molecular basis of this difference, we expressed the two native and six hybrid receptors, and two receptors containing mutated mouse gamma subunits in Xenopus laevis oocytes. The inhibition of ACh-induced current in these receptors by PCP was studied using whole-cell voltage-clamp. All hybrid receptors generated robust ACh-induced currents, while incomplete receptors (gamma-less or delta-less) did not. 3. PCP potency was higher on hybrids containing Torpedo beta and gamma subunits regardless of the alpha and delta subunit origin. A mouse gamma subunit containing the asparagine 6' to the serine mutation in the M2 segment conferred a high sensitivity to PCP. 4. These results support the conclusion that the amino acid residues at the position 6' of the M2 segments contribute to the PCP potency difference between Torpedo and mouse receptors. 5. Another noncompetitive inhibitor of the AChR, the cembranoid eupalmerin acetate (EUAC), also inhibited the electric organ receptor with a somewhat higher potency than muscle AChR. However, the IC50 values for EUAC inhibition of hybrid receptors did not follow the pattern observed for PCP. Therefore, these two inhibitors interact differently with the AChR molecule.
Cell Mol Neurobiol 1999 Dec
PMID:Determinants of phencyclidine potency on the nicotinic acetylcholine receptors from muscle and electric organ. 1045 35

N-methyl-D-aspartate (NMDA) glutamate (Glu) receptor antagonists (eg MK-801, ketamine, phencyclidine [PCP]) injure cerebrocortical neurons in the posterior cingulate and retrosplenial cortex (PC/RSC). We have proposed that the neurotoxic action of these agents is mediated in part by a complex polysynaptic mechanism involving an interference in GABAergic inhibition resulting in excessive release of acetylcholine (ACh). Previously we have found that the systemic injection of GABAergic agents and alpha2-adrenergic agonists can block this neurotoxicity. In the present study we tested the hypothesis that NMDA antagonists trigger release of ACh in PC/RSC and that this action of NMDA antagonists is suppressed by GABAergic agents or alpha2-adrenergic agonists. The effect of MK-801 and ketamine on PC/RSC ACh output (and the ability of pentobarbital, diazepam and clonidine to modify MK-801-induced ACh release) was studied in adult female rats using in vivo microdialysis. Both MK-801 and ketamine caused a significant rise in PC/RSC ACh output compared to basal levels. Pentobarbital, diazepam and clonidine suppressed MK-801's effect on ACh release. Exploratory studies indicated that the site of action of these agents was outside of the PC/RSC. The microdialysis results are consistent with several aspects of the circuitry proposed to mediate the neurotoxic action of NMDA antagonists.
Mol Psychiatry 1999 Jul
PMID:Excessive cerebrocortical release of acetylcholine induced by NMDA antagonists is reduced by GABAergic and alpha2-adrenergic agonists. 1048 51

Haloperidol augmented a trend of an increase in the heat shock protein (hsp70) mRNA levels induced by phencyclidine (PCP) in rat medial prefrontal cortex, nucleus accumbens and striatum, while the atypical antipsychotic drugs such as clozapine, olanzapine and risperidone decreased it. When administered alone, clozapine, but not haloperidol, decreased hsp70 mRNA levels. Haloperidol and the atypical antipsychotic drugs may thus have differential effects on hsp70 expression in some brain regions of PCP-treated rats.
Brain Res Mol Brain Res 1999 Nov 10
PMID:Effects of atypical antipsychotic drugs vs. haloperidol on expression of heat shock protein in the discrete brain regions of phencyclidine-treated rats. 1058 14

Our recent studies demonstrating the expression of fibrinogen (FBG) by an alveolar type II cell line stimulated with proinflammatory mediators and also in the inflamed pulmonary epithelium of animals with Pneumocystis carinii pneumonia suggest that extrahepatic FBG participates in the local acute phase response (APR) to infection and subsequent wound repair. However, the mechanisms that regulate extrahepatic FBG expression are poorly understood. This study compares the regulation of hepatic and pulmonary FBG expression by mediators of the APR, interleukin (IL)-6, IL-1beta, and dexamethasone (DEX), a synthetic glucocorticoid. Northern blotting and metabolic labeling studies revealed that IL-6 with or without DEX upregulates gammaFBG messenger RNA and protein, whereas IL-1beta inhibits gammaFBG expression in human lung (A549) and liver (HepG2) epithelial cells. In contrast, the addition of DEX relieved the IL-1beta-mediated inhibition of FBG expression in lung epithelial cells only; this response is termed "DEX rescue." Studies with cycloheximide indicate that only DEX rescue required de novo protein synthesis. Nuclear run-on analysis revealed no increase in gammaFBG transcription by DEX treatment. Although DEX treatment alone increased the stability of gammaFBG transcripts in lung cells, this effect was not observed in the presence of IL-1beta. Together, these results suggest that pre-existing transcription factors mediate the effects of IL-6 with or without DEX, DEX, and IL-1beta on gammaFBG gene expression in lung and liver cells. Also, the data suggest that DEX induces new protein synthesis of an inhibitor of IL-1beta signal transduction to effectively "rescue" FBG production in lung but not liver epithelial cells. This cell type-specific stimulation of FBG production by glucocorticoids to overcome IL-1beta inhibition may promote pulmonary wound repair mechanisms.
Am J Respir Cell Mol Biol 2000 Feb
PMID:Cell type-specific regulation of fibrinogen expression in lung epithelial cells by dexamethasone and interleukin-1beta. 1065 42

Adenosine kinase (AK) is a key purine metabolic enzyme from the opportunistic parasitic protozoan Toxoplasma gondii and belongs to the family of carbohydrate kinases that includes ribokinase. To understand the catalytic mechanism of AK, we determined the structures of the T. gondii apo AK, AK:adenosine complex and the AK:adenosine:AMP-PCP complex to 2.55 A, 2.50 A and 1.71 A resolution, respectively. These structures reveal a novel catalytic mechanism that involves an adenosine-induced domain rotation of 30 degrees and a newly described anion hole (DTXGAGD), requiring a helix-to-coil conformational change that is induced by ATP binding. Nucleotide binding also evokes a coil-to-helix transition that completes the formation of the ATP binding pocket. A conserved dipeptide, Gly68-Gly69, which is located at the bottom of the adenosine-binding site, functions as the switch for domain rotation. The synergistic structural changes that occur upon substrate binding sequester the adenosine and the ATP gi phosphate from solvent and optimally position the substrates for catalysis. Finally, the 1.84 A resolution structure of an AK:7-iodotubercidin:AMP-PCP complex reveals the basis for the higher affinity binding of this prodrug over adenosine and thus provides a scaffold for the design of new inhibitors and subversive substrates that target the T. gondii AK.
J Mol Biol 2000 Feb 18
PMID:Crystal structures of Toxoplasma gondii adenosine kinase reveal a novel catalytic mechanism and prodrug binding. 1066 8

Studies of Pneumocystis carinii pneumonia (PCP) suggest an important role for the surfactant system in the pathogenesis of the hypoxemic respiratory insufficiency associated with this infection. We hypothesized that PCP induces selective alterations in alveolar surfactant component expression and resultant biophysical properties. PCP was induced by intratracheal inoculation of 2 x 10(5) P. carinii organisms into C.B-17 scid/scid mice. Six weeks after inoculation, large (LA)- and small (SA)-aggregate surfactant fractions were prepared from bronchoalveolar lavage fluids and analyzed for expression of surfactant components and for biophysical activity. Total phospholipid content was significantly reduced in LA surfactant fractions from mice infected with PCP (53 +/- 15% of uninfected mice; P < 0.05). Quantitation of hydrophobic surfactant protein (SP) content demonstrated significant reductions of alveolar SP-B and SP-C protein levels in mice with PCP compared with those in uninfected mice (46 +/- 7 and 19 +/- 6%, respectively; P < 0.05 for both). The reductions in phospholipid, SP-B, and SP-C in LA fractions measured during PCP were associated with an increase in the minimum surface tension of LAs as measured by pulsating bubble surfactometer (13.1 +/- 1.1 vs. 5.4 +/- 1.8 mN/m; P < 0.05). In contrast to decreases in the hydrophobic SPs, SP-D content in the SA fraction was markedly increased (343 +/- 30% of control value; P < 0. 05) and SP-A levels in LA surfactant were maintained (93 +/- 26% of control value) during P. carinii infection. In all cases, the changes in SP content were reflected by commensurate changes in the levels of mRNA. We conclude that PCP induces selective alterations in surfactant component expression, including profound decreases in hydrophobic protein contents and resultant increases in surface tension. These changes, demonstrated in an immunologically relevant animal model, suggest that alterations in surfactant could contribute to the hypoxemic respiratory insufficiency observed in PCP.
Am J Physiol Lung Cell Mol Physiol 2000 Mar
PMID:P. carinii induces selective alterations in component expression and biophysical activity of lung surfactant. 1071 May 33

Molecular mechanics calculations using MM3-92 and ab initio quantum mechanical calculations using SPARTAN 5.0 were performed on the structurally similar PCP and BTCP, in which only the latter has a cocaine-like pharmacological profile as a dopamine reuptake blocker. Calculations were also performed on BTCP analogs with a methyl group in various positions of the cyclohexane ring. The results for the cis-2-methyl compound, which retains good pharmacological activity, allowed us to determine that an aryl-axial conformer is the biologically active form for at least some of the compounds in this series. However, an aryl-equatorial conformer presents the identical pharmacophore, as shown by superposition of the two conformers. X-ray crystallographic structures were also obtained for BTCP and related compounds with a 2-methyl group on the cyclohexane ring, with reasonable agreement between the computational and experimental results. Superposition studies were performed with two rigid analogs of cocaine which illustrate the optimal orientations of the ammonium hydrogen for monoamine transporters. There is excellent agreement between a 'back-bridged' cocaine analog that is optimal as a dopamine reuptake blocker and the previously proposed biologically active conformer of methylphenidate. However, BTCP is found to be a better fit to the 'front-bridged' cocaine analog that is optimal for a serotonin reuptake blocker.
J Comput Aided Mol Des 2000 Feb
PMID:Conformational preferences of the potent dopamine reuptake blocker BTCP and its analogs and their incorporation into a pharmacophore model. 1072 2

In cerebellar Purkinje neurons, the degree of dendritic segregation of the Purkinje cell-specific mRNA L7/pcp-2 is correlated with their development and synaptic investment. This developmental pattern is also observed in Purkinje cells in primary dissociated culture. Short-term (12-48 h) stimulation of cultured Purkinje cells by potassium-induced depolarization or blockade of their inhibitory GABAergic input results in an increased incidence of Purkinje cells with L7/pcp-2 mRNA-positive dendrites and increased levels of L7 protein expression, the latter by a posttranscriptional mechanism. None of these treatments affected the localization of the mRNA encoding calbindin D28k nor the level of this protein in Purkinje neurons. Protracted exposure to depolarizing levels of potassium or elimination of GABAergic transmission resulted in conspicuous changes of Purkinje cell dendritic morphology. These data suggest a scenario in which activity-driven translation of subcellularly segregated mRNAs may contribute to the developmental and functional plasticity of nerve cells.
Mol Cell Neurosci 2000 Mar
PMID:Changing subcellular distribution and activity-dependent utilization of a dendritically localized mRNA in developing Purkinje cells. 1073 4


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