Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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The relaxant action of adenine nucleotides was studied in isolated rabbit trachealis to assess the presence of P2-purinoceptors in the airways, their cellular location, and pharmacologic properties. Strips of tracheal smooth muscle with intact epithelium were incubated in tissue baths and contracted with 1 microM acetylcholine. Over a dose range of 0.1 microM to 1 mM, ATP and ADP were significantly more potent than adenosine in relaxing tracheal smooth muscle. Significant relaxations were also elicited by AMP-PCP, AMP-CPP, and AMP-PNP, three ATP analogs stable to enzymatic hydrolysis to adenosine. In the absence of acetylcholine, neither ATP nor AMP-CPP exerted any contractile effect on the tracheal strips. In tissues selectively denuded of epithelium, ATP-, ADP-, and AMP-PCP-induced relaxations were markedly reduced. ATP-induced relaxation was also inhibited by the P2y-purinoceptor antagonist Reactive Blue 2 (RB2) (50 to 300 microM) and partially reduced by the cyclooxygenase inhibitor indomethacin (10 microM), whereas adenosine-induced relaxation was not significantly affected by these agents. These results suggest that ATP can induce smooth muscle relaxation in acetylcholine-contracted tracheal strips through a distinct P2-purinoceptor. This receptor appears to be located on the epithelium where its relaxant effect is mediated in part by release of one or more cyclooxygenase products. Additional relaxation at high ATP concentrations may occur through enzymatic hydrolysis of ATP to adenosine and interaction at P1-purinoceptors.
Am J Respir Cell Mol Biol 1994 Feb
PMID:Relaxation of rabbit tracheal smooth muscle by adenine nucleotides: mediation by P2-purinoceptors. 811 Apr 78

Drugs of abuse, such as phencyclidine (PCP), methamphetamine (METH), and cocaine (COC) are known to affect several behaviors in rats, such as motor activity, stereotypy, and circling. In this study, we evaluated whether these drugs produce circling preferences in the presence or absence of unilateral 6-hydroxydopamine (6-OHDA)-induced lesions of the caudate nucleus. Adult male CD rats were lesioned with 10 micrograms 6-OHDA/site. Animals were dosed with PCP (15 mg/kg, ip) its congener (+) MK-801 (0.15 mg/kp, ip), METH (2 mg/kg, ip) COC (60 mg/kp, ip), or apomorphine (0.2 mg/kg, ip). Circling preference was recorded in control and lesioned rats for 2 h before animals were sacrificed to determined monoamine levels by HPLC/EC. In control animals, administration of these drugs produced 60-70% left circling. In lesioned animals, these drugs produced 78-90% ipsilateral (toward the lesion) circling, except apomorphine, which produced 60-80% contralateral (away from the lesion) circling. Dopamine (DA) and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) concentrations significantly decreased ipsilaterally in lesioned caudate nucleus (CN) and substantia nigra (SN). However, no significant changes were observed in nucleus accumbens (NA) and olfactory tubercles (OT). These data demonstrate that drugs of abuse like PCP, its congener (+) MK-801, METH, and COC produce a greater preference to turn toward the left than the right, a finding similar to that found in human psychosis. Since 6-OHDA lesions enhanced the circling bias and depleted DA and its metabolites DOPAC and HVA, it also suggests that the dopaminergic system may be involved in the circling behavior.
Mol Neurobiol
PMID:Drug-induced circling preference in rats. Correlation with monoamine levels. 856 58

The present study was designed to determine the effects of chronic neonatal exposure to the NMDA receptor antagonist phencyclidine (PCP) on [3H]MK-801 binding and on gene expression of NMDA receptor subunits in juvenile male rats. Rat pups were injected daily with PCP from day 5 to 15 and killed on day 21. [3H]MK-801 binding was measured by quantitative autoradiography. A sensitive RNase protection assay was employed to determine simultaneously the mRNA levels of NR1 subunit (comprising all different splice variants) and three NR2 subunits (NR2A-NR2C). The relative distribution profile of NMDA receptor subunits in the cerebral cortex was NR2B > NR1 > NR2A > NR2C and in the cerebellum NR2C = NR1 > NR2A = NR2B. Chronic PCP administration in postnatal rats produced significant reduction in both [3H]MK-801 binding and mRNA level of the NR2B subunit in the cerebral cortex. Expression of the other NMDA receptor subunits in the cerebral cortex did not change following the drug treatment. In the cerebellum, neither [3H]MK-801 binding nor any of the NMDA receptor subunit expression levels showed any alteration. Together, these data provide a molecular correlate for chronic postnatal PCP-induced down-regulation of [3H]MK-801 binding in rat cerebral cortex and suggest that the NR2B subunit plays an important role in developmental plasticity.
Brain Res Mol Brain Res 1996 Sep 01
PMID:Postnatal phencyclidine treatment differentially regulates N-methyl-D-aspartate receptor subunit mRNA expression in developing rat cerebral cortex. 887 5

Tubulin carboxypeptidase, the enzyme which releases the COOH terminal tyrosine from the alpha-chain of tubulin, remains associated with microtubules through several cycles of assembly/disassembly (Arce CA, Barra HS: FEBS Lett 157: 75-78, 1983). Here, we present evidence indicating that in rat brain extract the carboxypeptidase/microtubules association is regulated by the relative activities of endogenous protein kinase(s) and phosphatase(s) which seem to determine the phosphorylation state of the enzyme (or another entity) and in some way the affinity of the enzyme for microtubules. The presence of 2.5 mM ATP during the in vitro microtubule formation resulted in a low recovery of carboxypeptidase activity in the microtubule fraction. This ATP-induced effect was not due to alteration of the enzyme activity or to inhibition of microtubule assembly but to a decrease of the association of the enzyme with microtubules. We found that the ATP-induced effect was not mediated by modifications on the microtubules but, presumably, on the enzyme molecule. The non-hydrolyzable ATP analogue, AMP-PCP, did not reproduce the effect of ATP. The inclusion of phosphatase inhibitors in the homogenization buffer also led to a decrease in the amount of tubulin carboxypeptidase associated with microtubules. Finally, we found that, in concordance with the mechanism hypothesized, the magnitude of the carboxypeptidase/microtubule association correlated well with the different incubation conditions created to favor maximal, minimal or intermediate protein phosphorylation states.
Mol Cell Biochem 1997 May
PMID:The association of tubulin carboxypeptidase activity with microtubules in brain extracts is modulated by phosphorylation/dephosphorylation processes. 914 13

Aromatic L-amino acid decarboxylase (AADC) is rate limiting in the production of 2-phenylethylamine (2PE). AADC activity and 2PE serum concentrations have been found to be increased in schizophrenic patients. Both antipsychotic and psychotogenic drugs, including amphetamine, affect the activity and encoding mRNA levels of AADC. Amphetamine is an analogue of 2PE and has a similar physiological effect. We have looked at the effects of chronic (32 day) treatment of rats with LSD (0.12 microg/kg/day) and phencyclidine (PCP; 10 mg/kg/day) on AADC mRNA levels. Both drugs up-regulated AADC mRNA levels in striatum, nucleus accumbens, hippocampus and cerebellum by between 50% and 150%. A splicing variant of AADC, present in human brain, which lacks the 3rd exon does not appear to be present in rat brain. These results are consistent with the hypothesis that over activity of AADC leading to increased production of 2PE is involved in endogenous psychosis such as schizophrenia.
Brain Res Mol Brain Res 1997 Oct 03
PMID:Does phenylethylamine have a role in schizophrenia?: LSD and PCP up-regulate aromatic L-amino acid decarboxylase mRNA levels. 938 86

Multidrug-resistant strains of Vibrio cholerae (the causative agent of the diarrhoeal disease cholera) have recently been described. In an attempt to identify a homologue of the Escherichia coli TolC in V. cholerae, we isolated a DNA fragment (pVC) that enabled an E. coli tolC mutant to grow in the presence of 0.05% deoxycholate (DOC). However, other TolC defects were not complemented. Nucleotide sequence analysis of this fragment revealed the presence of two open reading frames (ORF1 and ORF2) separated by 9 bp and encoding 42.4 and 55.8 kDa proteins respectively. The translational products of these two ORFs correlated closely with the molecular weights of the predicted proteins. The deduced amino acid sequences of ORF1 and ORF2 showed a high degree of similarity with conserved regions of the E. coli efflux pump proteins, EmrA and EmrB. The presence of pVC2 within the E. coli efflux pump mutants defective in either the emrAB or the acrAB genes provided the mutants with resistance against several antibiotics. A V. cholerae isogenic mutant defective in ORF2 was constructed by gene replacement. Characterization of this mutant has shown it to be more sensitive to CCCP, PMA, PCP, nalidixic acid and DOC than the parent strain. These results suggest that ORF1 and ORF2 constitute an operon encoding two components of a putative multidrug resistance pump in V. cholerae. In addition, the presence of both structural and functional similarities between VceAB and EmrAB suggests that VceAB is a homologue of EmrAB.
Mol Microbiol 1998 Jan
PMID:Isolation and characterization of a putative multidrug resistance pump from Vibrio cholerae. 946 56

Striatopallidal output neurons, which coexpress D2-dopamine receptors and NMDA receptors, are logically a potential site of interaction between corticostriatal glutamatergic input and dopaminergic systems. Recent hypotheses about the etiology of schizophrenia have implicated both excitatory amino acid and dopamine systems. The present study was designed to examine, in vivo, the interaction between D2-dopamine receptors and NMDA receptors in the regulation of the expression of the early immediate genes (IEGs), zif 268 and jun B, in striatopallidal neurons. We tested whether coadministration of NMDA antagonists interacted with the actions of the D2 agonist, quinpirole, on IEG expression following dopamine depletion with reserpine. When rats were pretreated with the non-competitive NMDA receptor antagonists, MK 801 (1 mg/kg) or PCP (20 mg/kg), together with quinpirole, the quinpirole reversal of reserpine induction of zif 268 mRNA was potentiated in all regions examined. MK 801 alone had no significant effect on reserpine induction of zif 268 mRNA. Pretreatment with the competitive NMDA receptor antagonist, CPP (5 mg/kg), did not significantly alter the dose response of zif 268 mRNA expression to quinpirole in any region. There was no significant effect of MK 801 on jun B mRNA expression, either on the response to quinpirole or when administered alone with reserpine. Our findings provide evidence of an interaction between the NMDA receptor channel system and the D2-dopamine system on a molecular level in striatopallidal neurons carrying output from the basal ganglia.
Brain Res Mol Brain Res 1998 Aug 15
PMID:Potentiation of D2-dopamine receptor-mediated suppression of zif 268 by non-competitive NMDA receptor antagonists in reserpinized rats. 972 66

Geometric and vibrational spectroscopic data (bond distances and angles, vibrational frequencies, infrared intensities) of pentachlorophenol-OH (PCP-OH) and pentachlorophenol-OD (PCP-OD) are calculated by density functional theory (B3LYP) using the 6-311G(d, p) basis set. Except for the vibrations involving the OH bond, the agreement between the experimental and calculated fundamental frequencies between 3600 and 400 cm-1 is very good. The theoretical method failed, however, to reproduce quantitatively the experimental intensities. The infrared spectra between 3600 and 10 000 cm-1 are studied, and the overtones or combination bands are assigned by comparing the spectra of PCP-OH and PCP-OD. The difference between the experimental and theoretical frequencies of the nu(OH) and nu(OD) frequencies can be mainly accounted for by the neglect of the anharmonicities of these vibrations in calculations. The binary or ternary combinations characterized by the highest coupling constants and the highest intensities are those involving the nu(OH), delta(OH), gamma(OH), and nu(C-O) vibrations. Copyright 1999 Academic Press.
J Mol Spectrosc 1999 Jun
PMID:Theoretical and Experimental (400-10 000 cm-1) Study of the Vibrational Spectrum of Pentachlorophenol. 1032 74

We describe the cloning and characterization of PCP, a novel calcium-binding protein that is expressed predominantly in the pistils and anthers of Brassica flowers late in flower development. A PCP cDNA - isolated from a subtracted cDNA library enriched in transcripts present in the pistil late in flower development - potentially encodes a 175 amino acid protein with a calculated molecular weight of 19.1 kDa. Other than limited homology to a repetitive C-terminal polyacidic region of PCP, none of the sequences in the GenBank database shares identity to PCP. This unique protein was purified from an Escherichia coli expression system and shown to bind calcium in a specific manner, both in a protein blot assay and by equilibrium dialysis. PCP binds 29 mol of calcium per mol of PCP protein with an apparent affinity constant of 3.2 x 10(2)/M, values consistent with the presence of a high capacity/low-affinity calcium-binding domain. PCP-specific mRNAs are detected predominantly in the stigma and style of pistils excised from open flowers; much lower levels of expression are seen in anthers of open flowers and in root and leaf tissue. Expression in the pistil steadily increases during flower development and peaks at flower opening. A PCP-specific antibody first detects the protein in pistils at one day prior to flowering, with higher levels of the protein seen in the pistils of open flowers. A low level of the protein is present in anthers of open flowers; however, PCP is not detected in either root or leaf extracts. The pattern of PCP expression is consistent with a possible role for PCP in pollen-pistil interactions or in pistil development. The results are also discussed in light of the central role calcium maintains in pollen tube growth and fertilization.
Plant Mol Biol 1999 Mar
PMID:A novel calcium-binding protein is expressed in Brassica pistils and anthers late in flower development. 1035 87

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


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