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)

This study describes a novel action of morphine on adenylate cyclase activity in the rat locus coeruleus (LC). We have previously shown that acute in vitro morphine inhibits adenylate cyclase activity in isolated LC membranes, whereas chronic in vivo morphine treatment increases enzyme activity in this brain region. We now report that acute in vivo morphine treatment produces a 25-30% decrease in adenylate cyclase activity in the LC, which persists in in vitro assays in the absence of opiates. This in vivo effect is clearly distinct from the acute inhibition of adenylate cyclase observed during exposure of isolated LC membranes to opiates in vitro. The in vivo effect was not reversed by the inclusion of naloxone, an opiate receptor antagonist, in the assay, and acute in vitro opiate inhibition of the enzyme was the same in LC membranes isolated from control and morphine-treated rats. Thus, the in vivo effect does not appear to be due to residual morphine retained in the membrane preparation. This persistent decrease in adenylate cyclase was found to occur in a dose-dependent manner and to be mediated through the actions of morphine at opiate receptors, inasmuch as the inhibition was prevented by concomitant in vivo administration of naltrexone, a long-acting opiate receptor antagonist. This effect was also specific to the LC, in that it was not observed in the other brain regions examined, which included the dorsal raphe, neostriatum, and frontal cortex. Acute in vivo clonidine, an alpha 2-adrenergic receptor agonist known to have actions in the LC similar to those of morphine, produced a similar persistent decrease in adenylate cyclase activity in this brain region. In contrast, other drugs with different actions on the LC failed to produce this effect. This decrease in adenylate cyclase activity induced by acute in vivo morphine or clonidine, which persists in isolated membranes after the removal of the drugs, may be an early step in the sequence of events that leads to the development of opiate or clonidine addiction in the LC.
Mol Pharmacol 1989 May
PMID:A novel action of morphine in the rat locus coeruleus: persistent decrease in adenylate cyclase. 249 35

We have studied a possible role for cyclic AMP-dependent protein kinase in mediating opiate addiction in the central nervous system by focusing on the rat locus coeruleus. This brain region is well suited for these studies because it is relatively homogeneous and because a wealth of electrophysiological and behavioral data indicate that it plays an important role in mediating the chronic effects of opiates in animals, including humans. It was found that chronic, but not acute, in vivo treatment of rats with morphine increased cyclic AMP-dependent protein kinase activity in the locus coeruleus with a time course that closely paralleled the time course by which locus coeruleus neurons become tolerant to and dependent on opiates, based on electrophysiological studies. Concomitant administration of the opiate receptor antagonist naltrexone was found to block the effect of chronic morphine treatment on protein kinase activity, indicating that the effect is mediated via specific activation of opiate receptors. In contrast, chronic morphine treatment did not alter protein kinase activity in several other brain regions studied, including the neostriatum, frontal cortex, and dorsal raphe. We propose that the observed increase in cyclic AMP-dependent protein kinase activity in the locus coeruleus contributes to the biochemical basis of opiate addiction.
Mol Pharmacol 1988 Feb
PMID:Chronic morphine treatment increases cyclic AMP-dependent protein kinase activity in the rat locus coeruleus. 334 78

The cyclic AMP-phosphodiesterase assay was used to quantitate the amount of calmodulin activity in various brain areas of male rats treated acutely or chronically for 5 days with morphine. The acute treatment with morphine decreased calmodulin activity in the mitochondrial-synaptosomal P2 fraction of the striatum, midbrain, and thalamus but had no effect on the cerebellum, which contains a low density of opiate receptors. The decrease in calmodulin activity by morphine was dose-dependent and was blocked by the opiate antagonist naloxone. In contrast, chronic treatment of rats with morphine increased calmodulin activity in the mitochondrial-synaptosomal P2 of the striatum, midbrain, cerebral cortex, and thalamus. A highly sensitive Ca2+/Mg2+-ATPase assay was also used to quantitate the amount of calmodulin activity in subcellular fractions obtained from the striatum. Chronic morphine treatment caused a significant increase in calmodulin activity in the membrane containing microsomal, synaptosomal, and mitochondrial layers but only a small change in the layer that contained the soluble proteins and the synaptic vesicles. It is suggested that alteration of the content of calmodulin in specific subcellular sites may have a central role in opiate action and addiction via regulation of multiple calmodulin-sensitive biochemical pathways.
Mol Pharmacol 1982 Sep
PMID:Effects of acute and chronic morphine treatment of calmodulin activity of rat brain. 612 69

Bacterial plasmids are stabilized by a number of different mechanisms. Here we describe the molecular aspects of a group of plasmid-encoded gene systems called the proteic killer gene systems. These systems mediate plasmid maintenance by selectively killing plasmid-free cells (post-segregational killing or plasmid addiction). The group includes ccd of F, parD/pem of R1/R100, parDE of RP4/RK2, and phd/doc of P1. All of these systems encode a stable toxin and an unstable antidote. The antidotes prevent the lethal action of their cognate toxins by forming tight complexes with them. The antidotes are degraded by cellular proteases. Thus, the different decay rates of the toxins and antidotes seem to be the molecular basis of toxin activation in plasmid-free cells. The operons encoding the toxins and antidotes are autoregulated at the level of transcription either by a complex formed by the toxins and the cognate antidotes or by the antidote alone. The cellular targets of the killer proteins have been determined to be DNA gyrase in the case of ccd of F and DnaB in the case of parD of R1. Surprisingly, the Escherichia coli chromosome encodes at least two of these peculiar gene systems.
Mol Microbiol 1995 Jul
PMID:Programmed cell death in bacteria: proteic plasmid stabilization systems. 749 69

A number of plasmid-encoded gene systems are thought to stabilize plasmids by killing plasmid-free cells (also termed post-segregational killing or plasmid addiction). Here we analyse the mechanisms of plasmid stabilization by ccd of F, parDE of RP4 and parD of R1, and compare them to hok/sok of R1. To induce synchronous plasmid loss we constructed a novel plasmid replication-arrest system, which possesses the advantage that plasmid replication can be completely arrested by the addition of IPTG, a non-metabolizable inducer. Using isogenic plasmid constructions we have found, for the first time, consistent correlation between the effect on steady-state loss rates and the effect on cell proliferation in the plasmid replication-arrest assay for all three systems. The parDE system had the most pronounced effect both on plasmid stabilization and on plasmid retention after replication arrest. In contrast, ccd and parD both exhibited weaker effects than anticipated from previously published results. Thus, our results indicate that the function and efficiencies of some of the systems should be reconsidered. Our results are consistent with the previously postulated hypothesis that ccd and parDE act by killing plasmid-free segregants, whereas parD seems to act by inhibiting cell division of plasmid-free segregants.
Mol Microbiol 1995 Jul
PMID:Comparison of ccd of F, parDE of RP4, and parD of R1 using a novel conditional replication control system of plasmid R1. 749 70

With chronic opiate use, opioid receptor desensitization may be one of the important mechanisms underlying the development of opiate tolerance and addiction. Opioid receptors belong to the G protein-coupled receptor superfamily. In this study, the mouse delta-opioid receptor (delta OR) was used in a model system to investigate the role of opioid receptor phosphorylation in receptor desensitization. When expressed in 293 cells and exposed to agonist, the delta OR underwent receptor-specific desensitization within 10 min. This agonist-induced desensitization corresponded temporally to a 3-fold increase in receptor phosphorylation. Phorbol ester, but not forskolin, also stimulated phosphorylation of the delta OR in 293 cells. Although down-regulation of protein kinase C failed to affect agonist-induced receptor phosphorylation, it abolished phorbol ester-induced receptor phosphorylation. Agonist-induced delta OR phosphorylation must therefore involve kinases other than protein kinase C. Whereas overexpression of a dominant negative mutant (K220R) of beta-adrenergic receptor kinase-1 (beta ARK1) in 293 cells significantly reduced agonist-dependent phosphorylation of the delta OR, overexpression of beta ARK1 or G protein-coupled receptor kinase-5 significantly enhanced this phosphorylation. Concordantly, beta ARK1-K220R overexpression reduced agonist-dependent delta OR desensitization, whereas beta ARK1 overexpression enhanced this densensitization. We conclude that short term desensitization of the delta OR involves phosphorylation of the receptor by one or more G protein-coupled receptor kinases.
Mol Pharmacol 1995 Aug
PMID:Agonist-dependent phosphorylation of the mouse delta-opioid receptor: involvement of G protein-coupled receptor kinases but not protein kinase C. 765 49

P1 lysogens of Escherichia coli carry the prophage as a stable low copy number plasmid. The frequency with which viable cells cured of prophage are produced is about 10(-5) per cell per generation. Here we show that a significant part of this remarkable stability can be attributed to a plasmid-encoded mechanism that causes death of cells that have lost P1. In other words, the lysogenic cells appear to be addicted to the presence of the prophage. The plasmid withdrawal response depends on a gene named doc (death on curing), encoding a 126 amino acid protein. Expression of doc is not SOS-inducing and killing by Doc is recA-independent. In cells that retain P1 the killing is prevented by the product of a gene named phd (prevent host death), encoding a 73 amino acid protein. The genes phd and doc have been cloned and expressed from a 0.7 kb segment of P1 DNA. The two genes constitute an operon and the synthesis of Doc appears to be translationally coupled to that of Phd. Homologs of the P1 addiction genes are found elsewhere, but phd and doc are unrelated to previously described genes of other plasmids that also cause an apparent increase in plasmid stability by post-segregational killing.
J Mol Biol 1993 Oct 05
PMID:Plasmid addiction genes of bacteriophage P1: doc, which causes cell death on curing of prophage, and phd, which prevents host death when prophage is retained. 841 Nov 53

We have initiated studies to characterize the predominant subtypes of HIV-1 which account for infections in a defined cohort of intravenous (IV) drug addicts. A region of ENV encoding the C2 to the V5 regions was amplified from the leukocytes of two subjects currently enrolled in a methadone maintenance program at the Addiction Research and Treatment Corporation (ARTC), in Brooklyn, New York. This region of the viral genome encodes the principal neutralizing determinant (PND) located in the V3 loop, the immunogenic CD4-binding site, and six other linear antigenic epitopes in the envelope glycoprotein, gp120. Phylogenetic tree analysis of the nucleotide sequences showed that the sibling clones RT1.4, RT1.15, RT1.17, RT1.21 and RT3.6, RT3.10, RT3.11, RT3.12 and RT3.15 derived from the isolates, RT1 and RT3, respectively, cluster with "group B" viruses at 99% confidence level. Marked intra-patient and inter-patient sequence variation was apparent in the V3 loop. The divergence included the presence of a previously unreported hexapeptide GPWGTF at the cap of the loop in the clones from RT1. The North American consensus hexapeptide, GPGRAF, was identified in the cap of the loop from the clones of RT3. Four of the five sibling clones from RT3 were closely related whereas the other clone, RT3.15, displayed five amino acid mutations downstream of the V3 cap. To assess the effect of sequence variation on the distribution of linear antigenic epitopes, complementary computer software programs, were used to analyze the gp120 residues. Eight analogous antigenic epitopes were identified in the clones from both isolates despite the marked divergence in the primary sequences.(ABSTRACT TRUNCATED AT 250 WORDS)
Cell Mol Biol (Noisy-le-grand) 1995
PMID:Distribution of linear antigenic epitopes on GP120 encoded in sibling clones of novel New York HIV-1 subtype B isolates. 857 51

Chronic opiate administration leads to a selective regulation of several cellular proteins and mRNAs. This phenomenon has been viewed as a compensatory mechanism to the opiate signaling leading to the development of opiate addiction. In this study, in situ hybridization histochemistry experiments were employed to investigate the effect of chronic morphine treatment on synapsin I gene expression. We show here for the first time that prolonged morphine exposure causes a selective increase in the mRNA levels of synapsin I in several brain regions which are considered to be important for opiate action. Quantitative analysis of the signals, obtained by hybridization of digoxigenin-labeled antisense RNA probe, revealed a 5.8- and 7-fold increase of synapsin I mRNA levels in the locus coeruleus and the amygdala of morphine-treated rats, respectively, as compared with control untreated rats. Increased expression of synapsin I mRNA was also observed in the spinal cord of morphine-treated rats (by 3.8-fold). Since opiates were shown to attenuate neurotransmitter release and reduce synapsin I phosphorylation, it is suggested that the increase in synapsin I levels would lead to the requirement of higher amounts of opiate agonists to obtain the opiate physiological effects. These results suggest that the increases in mRNA levels of synapsin I in these specific areas can be part of the molecular mechanism(s) underlying opiate tolerance and withdrawal.
Brain Res Mol Brain Res 1995 Dec 28
PMID:Increased expression of synapsin I mRNA in defined areas of the rat central nervous system following chronic morphine treatment. 875 Aug 25

The biochemical and cellular mechanisms involved in the development and/or maintenance of morphine tolerance remain unclear. In the adult central nervous system (CNS) results are contradictory. For the neonate, a variety of drug induced deficits have been observed following prenatal addiction to opioids, although very little work on the biochemical and molecular level has been done. Therefore, the present study was carried out to investigate the effects of prenatal morphine treatment on the levels and expression of endogenous opioid peptides in brain regions of newborns. Dams were implanted with one morphine pellet (75 mg each) 1 week prior to the birth of pups. Changes in mRNA levels for the opioid peptides were determined by Northern blot analysis. Alterations in opioid peptide levels were determined by radioimmunoassays. Prenatal morphine treatment significantly increased proenkephalin mRNA levels and decreased met-enkephalin levels in striatum of newborns. These data are in contrast to what is observed in the adult CNS. These data indicate that prenatal morphine treatment may increase met-enkephalin release and/or cause inhibition at the level of translation. In addition, increased transcription may be necessary to maintain equilibrium in the system when there is an increase in met-enkephalin release.
Brain Res Mol Brain Res 1995 Nov
PMID:Prenatal morphine exposure differentially alters expression of opioid peptides in striatum of newborns. 875 Aug 81


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