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:3.1.4.1 (phosphodiesterase)
18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of K(+)-channel blockers on synaptic transmission in dunce (dnc), a Drosophila learning and memory mutant, were investigated. Larvae dnc mutants lack facilitation and post-tetanic potentiation (PTP) at their motor end-plates; dnc mutants are also deficient in a form of phosphodiesterase, and exhibit abnormally high levels of cyclic adenosine 3',5'-monophosphate (cAMP). A two-microelectrode voltage-clamp was used to record end-plate currents and spontaneous end-plate currents from longitudinal ventrolateral third-instar larval muscle. The K(+)-channel blockers 3,4-diaminopyridine (3,4-DAP) and tetraethylammonium (TEA), at micromolar concentrations, caused a reversible decrease in end-plate current amplitudes both in wild-type and mutant end-plates. In the presence of blockers, a period of high-frequency stimulation (tetanus) of the nerve gave way to a transient increase in the end-plate currents of dnc mutants resembling facilitation and PTP in normal end-plates; 3,4-DAP and TEA also restored facilitation and PTP in normal end-plates after incubation with a non-hydrolysable analogue of cAMP (8Br-cAMP). It is suggested that a specific K+ conductance might be relevant to the lack of synaptic plasticity at the dnc neuromuscular synapses.
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PMID:K(+)-channel blockers restore synaptic plasticity in the neuromuscular junction of dunce, a Drosophila learning and memory mutant. 136 88

In this report we describe the expression of Small Synaptic Bouton (SSB), an antigen that is selectively expressed in a specific subset of neuromuscular junction terminals in the body wall of Drosophila larva. The expression of SSB was studied with a polyclonal antibody raised against the cAMP phosphodiesterase of the Drosophila learning mutant dunce (Nighorn et al., 1991, Neuron 6:455-467); however, immunoreactivity was not abolished by the dunce (dnc) alleles dncM14 and dncM11 or deficiencies of the dnc gene, indicating that the antigen labelled could not be the dnc gene product, but another antigen that we termed SSB. Immunoreactivity was localized in the body wall muscles to a specific subset of neuromuscular junction terminals that have been implicated in activity-dependent plasticity. This demonstrates that these morphologically distinct terminals can be immunocytochemically distinguished and that they probably represent innervation by a distinct neuronal population. Confocal and electron microscopic examination demonstrated that staining was restricted to the synaptic boutons themselves, not to neurites or motor axons. Ultrastructural analysis showed label close to synaptic vesicles in the presynaptic terminal and in the surrounding subsynaptic reticulum. Central nervous system (CNS) staining was restricted to a segmentally repeated pattern of cell bodies in the ventral ganglion and to a few small groups of cells in the brain lobes.
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PMID:SSB, an antigen that selectively labels morphologically distinct synaptic boutons at the Drosophila larval neuromuscular junction. 146 Apr 64

The dunce gene, one of several genes critical for normal learning and memory in Drosophila, is organized in a complex and bizarre way, with enormous introns containing several other unrelated genes. Recent studies have focused on the spatial expression pattern of the product, cAMP phosphodiesterase, and have provisionally identified the mushroom bodies as important sites of action of dunce within adult brain. In addition, the recent cloning and characterization of dunce counterparts from mammals has revealed that these too may participate in animal behavior and, in particular, in the regulation of mood.
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PMID:The Drosophila dunce locus: learning and memory genes in the fly. 165 76

The dunce (dnc) gene of Drosophila melanogaster encodes cAMP phosphodiesterase (PDEase) and is required for learning/memory and female fertility. The gene is structurally complex, demonstrated in part by Northern blotting experiments which detected multiple RNAs ranging in size from 4.2 to 9.6 kb (1 kb = 10(3) bases or base-pairs). To characterize these RNAs and to understand their sequence heterogeneity, we isolated and analyzed 29 new and independent cDNA clones representing the dnc RNAs. Restriction mapping, hybridization analysis and sequence determination of these cDNA clones and the corresponding genomic exons resolved these into six different classes. Exons defined by the cDNA clones are distributed over more than 148 kb of genomic DNA, with some exons being used alternatively among the RNAs. The RNAs are transcribed from at least three initiation sites: two of these were mapped by parallel S1-nuclease and primer extension experiments. In addition, some of the heterogeneity is generated by using varying lengths of a 3'-untranslated trailer sequence. Altogether, the results indicate that the size and sequence heterogeneity of dnc transcripts results from transcription initiation at multiple sites, alternative splicing, and processes which generate different 3' ends. The existence of multiple protein products is suggested by the alternative use of exons which code for portions of the open reading frame. The protein variation potentially includes N-terminal differences coded for by transcript-specific 5' exons and internal differences arising from the optional inclusion of a 39 base-pair exon and from the alternative use of two 3' splice sites separated by six base-pairs. Expression of a cDNA clone in yeast containing a large portion of the open reading frame produced cAMP PDEase activity identical in properties to the Drosophila enzyme affected by the dnc mutation. The results suggest that the remarkable structural complexity of dnc may reflect an intricate control of the spatial and/or temporal expression of various isoforms of cAMP PDEase.
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PMID:Characterization of the memory gene dunce of Drosophila melanogaster. 166 Sep 26

Drosophila dunce (dnc) flies are defective in learning and memory as a result of lesions in the gene that codes for a cAMP-specific phosphodiesterase (PDE). Antibodies to the dnc PDE showed that the most intensely stained regions in the adult brain were the mushroom body neuropil--areas previously implicated in learning and memory. In situ hybridization demonstrated that dnc RNA was enriched in the mushroom body perikarya. The mushroom bodies of third instar larval brains were also stained intensely by the antibody, suggesting that the dnc PDE plays an important role in these neurons throughout their development. The role of the dnc PDE in mushroom body physiology is discussed, and a circuit model describing a possible role of the mushroom bodies in mediating olfactory learning and memory is presented.
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PMID:The cyclic AMP phosphodiesterase encoded by the Drosophila dunce gene is concentrated in the mushroom body neuropil. 184 82

The dunce locus of Drosophila melanogaster codes for a low Km, cAMP phosphodiesterase. The correct function of this gene is required for normal learning and memory activity in flies, because dunce mutants fail in tests of behavioral conditioning. These observations have indicated that cAMP regulation is an important aspect of the biochemistry underlying learning and memory processes in insects. To determine whether the locus is functionally conserved in mammals, we have expressed dunce gene homologs from the rat in a yeast expression system. We find that the rat homologs encode low Km, cAMP phosphodiesterases similar to that coded for by the Drosophila dunce+ gene and, more importantly, that the mammalian enzymes are inhibited by rolipram and RO 20-1724, drugs with antidepressant properties. Surprisingly, the dunce-encoded phosphodiesterase was not inhibited by rolipram or RO 20-1724. These findings suggest that the phosphodiesterases, through their regulation of cAMP levels, influence learning and memory in insects and mood in mammals.
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PMID:Rat homologs of the Drosophila dunce gene code for cyclic AMP phosphodiesterases sensitive to rolipram and RO 20-1724. 215 12

rutabaga1 (rut1), a Drosophila learning mutant, has adenylate cyclase (EC 4.6.1.1) with reduced basal activity and the absence of calcium/calmodulin-stimulated activity. A second learning mutant, dunce, is defective in cyclic AMP degradation due to decreased or absent phosphodiesterase activity. These opposing biochemical defects allow rut1 to partially suppress the female sterility caused by elevated cyclic AMP levels in dunce flies. Selection of mutations that suppress dunce sterility has led to the isolation of two rutabaga alleles. The alleles (rut2 and rut3) decrease basal adenylate cyclase activity [Bellen, H. J., Gregory, B. K., Olsson, C. L. & Kiger, J. A. (1987) Dev. Biol. 121, 432-444] but, unlike the original rutabaga mutation, leave the calcium/calmodulin-stimulated activity intact. Behaviorally, the two alleles also differ from rut1. One of the mutations partially rescues the dunce learning defect, and flies bearing both alleles learn. Calcium responsiveness may thus be the crucial component of adenylate cyclase activity required for associative learning.
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PMID:Rescue of the learning defect in dunce, a Drosophila learning mutant, by an allele of rutabaga, a second learning mutant. 215 13

We have isolated several genes expressed at abnormal levels in the memory mutant, dunce (dnc), of Drosophila melanogaster. These mutants have an elevated cyclic AMP (cAMP) content due to a mutation in the structural gene for cAMP phosphodiesterase, so the isolated genes are potentially ones regulated by cAMP. Here, we describe the characterization of a genomic clone and corresponding cDNA clones which contain sequences that are underexpressed in dnc mutants. Sequence analysis of portions of the genomic clone and representative cDNAs revealed the presence of two uninterrupted and complete open reading frames (SER1 and SER2) and part of a third (SER3). The predicted amino acid sequences of all of these were found to be homologous to the serine protease family of enzymes. The genomic clone was localized to the polytene chromosome region 99C-D, although genome-blotting experiments indicated the existence of several other genes related to the cloned serine protease-like genes. Hybridization experiments with probes representing each of the three sequenced genes showed that only the SER1-related genes were differentially expressed in dnc mutants. The putative serine protease genes were abundantly expressed in the larval gut, suggesting a major function in digestion. Feeding normal flies cAMP, isobutylmethylxanthine, or forskolin resulted in a decreased RNA level of the SER1-related genes. Thus, RNA levels of this serine protease gene family are negatively regulated by cAMP.
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PMID:Levels of RNA from a family of putative serine protease genes are reduced in Drosophila melanogaster dunce mutants and are regulated by cyclic AMP. 246 5

To study the structure and function of cyclic nucleotide phosphodiesterases (PDEs) involved in mammalian gametogenesis, a rat testis cDNA library was screened at low stringency with a cDNA clone coding for the Drosophila melanogaster dunce-encoded PDE as a probe. This screening resulted in the isolation of two groups of cDNA clones, differing in their nucleotide sequences (ratPDE1 and ratPDE2). In the rat testis, RNA transcripts corresponding to both groups of clones were expressed predominantly in germ cells. Additional screenings of a Sertoli cell cDNA library with a ratPDE2 clone as a probe led to the isolation of two more groups of clones (rat-PDE3 and ratPDE4). Unlike ratPDE1 and ratPDE2, these clones hybridized to transcripts present predominantly in the Sertoli cell. In the middle of the coding region, all four groups of clones were homologous to each other. The deduced amino acid sequences of part of this region were also homologous to the D. melanogaster dunce PDE and to PDEs from bovine and yeast. These data indicate that a family of genes homologous to the D. melanogaster dunce-encoded PDE is present in the rat and that these genes are differentially expressed in somatic and germ cells of the seminiferous tubule. These findings provide a molecular basis for the observed heterogeneity of cAMP PDEs.
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PMID:Molecular cloning of rat homologues of the Drosophila melanogaster dunce cAMP phosphodiesterase: evidence for a family of genes. 254 53

To elucidate the mechanisms by which hormones regulate cAMP phosphodiesterases (PDEs), a group of cDNA clones that had been isolated from a rat Sertoli cell library were characterized. These cDNAs are derived from a single gene (ratPDE3). The deduced amino acid sequence of the ratPDE3 cDNA corresponds to a 66,200-Da protein homologous to other testicular PDEs, to the Drosophila melanogaster dunce-encoded cAMP PDE, and to bovine and yeast PDEs. Expression of ratPDE3 in eukaryotic and prokaryotic cells leads to the appearance of a cAMP PDE with properties identical to the cAMP PDE purified from Sertoli cells. Although of different size, transcripts corresponding to ratPDE3 were present in all organs studied. In the immature Sertoli cell in culture, the level of mRNA transcripts of ratPDE3 was increased more than 100-fold by follicle-stimulating hormone or N6,O2'-dibutyryladenosine 3',5'-cyclic monophosphate treatment. Stimulation of ratPDE3 mRNA by N6,O2'-dibutyryladenosine 3',5'-cyclic monophosphate was also observed in a C6 glioma cell line. These data demonstrate that cAMP regulates the expression of one of its own degrading enzymes by an intracellular feedback mechanism that involves changes in mRNA levels.
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PMID:The mRNA encoding a high-affinity cAMP phosphodiesterase is regulated by hormones and cAMP. 255 3


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