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 dunce gene of Drosophila melanogaster codes for a cyclic adenosine-3',5'-monophosphate-specific phosphodiesterase. Mutations of dunce alter or abolish the activity of this enzyme, produce elevated cAMP levels, cause recessive female sterility, and produce learning deficiencies in both sexes. Aberrant male sexual behavior has also been associated with the memory defects of dunce mutants. Here we show that the longevity of dunce mutant females, homozygous for null-enzyme alleles, is reduced by 50% in the presence of males compared to control dunce females kept without males. Mutant dunce females, mate every 22-24 hr. We propose a cause-effect relationship between mating and reduced longevity. Pheromones or peptides transferred during mating may activate adenylate cyclase and create an increase in cAMP levels that cannot be damped in dunce females. This increase may affect basic physiological functions and lead to reduced longevity.
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PMID:Sexual hyperactivity and reduced longevity of dunce females of Drosophila melanogaster. 303 Aug 81

The dunce locus of Drosophila melanogaster is considered to house a gene involved in memory, because flies carrying lesions at the locus have shortened memory of several different conditioned behaviours. Our recent partial characterization of the gene at the molecular level, along with prior genetic and biochemical evidence, recently provides compelling evidence that the gene codes for the enzyme cAMP phosphodiesterase. The observation that the gene encodes at least six overlapping poly(A)+ RNA molecules ranging in size from 4.2 to 9.5 kilobases (kb) (ref. 8), suggests that the gene is extraordinarily complex. Here we provide the sequence of a dunce complementary DNA clone and the corresponding genomic coding regions which show that the organization of the gene is elaborate. The cDNA clone defines dunce exons which are separated by a large intron of 79 kb. More importantly, at least two other genes are shown to reside within the large intron, including the well-defined glue protein gene, Sgs-4. The location of dunce exons relative to the molecular breakpoints of chromosomal aberrations with defined cytological positions indicates that the dunce gene extends over more than five polytene chromosome bands.
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PMID:At least two genes reside within a large intron of the dunce gene of Drosophila. 311 8

A detailed characterization of the cyclic nucleotide phosphodiesterase (PDEs) from normal Drosophila melanogaster was made, including purification of the two major enzymes to near homogeneity. A third more labile phosphodiesterase also was identified in crude homogenates. The total activity per fly of one of these three enzymes, PDE-II, is strongly influenced by the dunce locus. Two independently derived dunce mutants produce variations of PDE-II with modified intrinsic properties: a marked decrease of thermal stability in dunce and a 10-fold increase in the Michaelis kinetic constant in dunce. These defects, which persisted in purified preparations of PDE-II, were mapped genetically to dunce. The results support the identification of dunce as the structural locus for PDE-II. The tight connection between the dunce gene and the PDE-II enzyme indicates that defective cyclic adenosine 3':5'-monophosphate metabolism is the primary lesion which leads to failure of dunce flies to learn in the olfactory associative conditioning paradigm of Quinn et al. (Quinn, W. G., W. A. Harris, and S. Benzer (1974) Proct. Natl. Acad. Sci. U. S. A. 71: 708-712).
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PMID:Defective cyclic adenosine 3':5'-monophosphate phosphodiesterase in the Drosophila memory mutant dunce. 628 93

Drosophila carrying the X-linked mutation dunce (dnc) showed poor learning in a negative reinforcement olfactory conditioning paradigm (Dudai, Y., Y.-N. Jan, D. Byers, W.G. Quinn, and S. Benzer (1976) Proc. Natl. Acad. Sci. U.S.A. 73: 1684-1688). More recently, dnc flies were shown to have reduced activity for one of two cAMP phosphodiesterases (PDEs) present in normal flies, PDE II, whereas PDE form I was unaffected (Byers, D., R. L. Davis, and J. A. Kiger, Jr. (1981) Nature 289: 79-81). A micro-assay technique is described that allows the separate measurement of PDE I and PDE II in crude extracts, based on specific inhibition of PDE I [3H]cAMP hydrolysis by cGMP. Using this technique, PDE II is shown to occur normally at high specific activity in the nervous system, consistent with the hypothesis that this enzyme plays a role in neuronal function. Reduced PDE II activity correlates with poor learning in dnc flies at three developmental stages (first and third instar larva and adult), as well as in response to genetic modification of dnc gene activity. Biochemical and genetic experiments fail to reveal any abnormal regulation of PDE II in dnc. The specific activity of PDE II is shown to correlate in a one to one fashion with the level of normal dnc gene (dnc+) activity at five different doses of dnc+. These results support the hypothesis that PDE II represents the primary product of the dnc gene, indicating a role for this enzyme in Drosophila learning.
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PMID:Cyclic adenosine 3':5'-monophosphate phosphodiesterase and its role in learning in Drosophila. 630 Mar 56

Two genetically distinct forms of cyclic nucleotide phosphodiesterases are present in adult Drosophila melanogaster. Form II, which specifically hydrolyzes adenosine 3':5'-cyclic monophosphate (cAMP), is controlled by the dunce+ gene. Mutants of this gene either eliminate this enzyme form entirely or alter its kinetic and thermal properties, suggesting that dunce+ is the structural gene for this enzyme. These mutants are defective in memory formation, habituation, and sensitization and exhibit elevated cAMP levels, implicating cAMP in these neurological processes. The other phosphodiesterase, Form I, which hydrolyzes both cAMP and guanosine 3':5'-cyclic monophosphate (cGMP), is not affected by dunce mutations. Because both cAMP and Ca2+ serve as intracellular second messengers in mediating the effects of neurotransmitters, the effects of Ca2+ on each form of phosphodiesterase have been investigated. Previous work has suggested that Form I is activated by calmodulin in a Ca2+-dependent manner. We confirm this activation and demonstrate that the activation involves the Ca2+-dependent association of two molecules of calmodulin with one Form I molecule. Under conditions permitting activation and association of Form I with calmodulin, we observe no interaction of Ca2+/calmodulin with Form II. Our studies suggest that the primary physiological defect, associated with a defective or absent Form II cAMP-specific phosphodiesterase and leading to the dunce neurological phenotype, is due to a direct failure to regulate the cAMP level in nerve cells rather than to a failure to mediate a signal resulting from a cAMP-induced Ca2+ influx, associated with presynaptic facilitation.
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PMID:The Dunce gene of Drosophila: roles of Ca2+ and calmodulin in adenosine 3':5'-cyclic monophosphate-specific phosphodiesterase activity. 632 97

The dunce (dnc) gene of Drosophila melanogaster codes for cAMP phosphodiesterase (PDE) and is required for normal learning/memory and for female fertility. The expression of the gene is elevated in mushroom bodies, brain structures implicated in olfactory learning and memory. In this study several chromosomal deletions and inversions that remove increasingly larger portions of the dnc gene from its 5' end and progressively more of the five known transcription start sites (tss) were used to assess the functions of the various transcriptional units. Surprisingly, the dnc PDE activity, female fertility, mushroom body expression, learning, and memory were unaffected by the removal of tss1 and tss2. tss3 was required for elevated mushroom body expression but not for female fertility nor initial learning. tss4 contributed to learning and the female fertility function, whereas tss5 contributed to female fertility. The results indicate that the structural complexity of the gene is of biological significance, with individual transcriptional units serving different biological functions.
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PMID:Genetic dissection of the learning/memory gene dunce of Drosophila melanogaster. 768 28

Mutations in the Drosophila dunce gene, the structural gene for a cAMP-specific phosphodiesterase (PDE), disrupt normal learning and memory and lead to female sterility. Our experiments address a long-standing question in the genetic dissection of learning and memory of whether dnc is involved in physiological processes underlying learning. Conditional expression of dunce transgenes in dnc adults shortly before training significantly improves learning over nontransgenic controls. Remarkably, behavioral rescue was also observed after induction of a transgene carrying a rat counterpart of dunce. Induction of the transgenes in adult dnc females confers partial rescue of the female sterility phenotype. These data are consistent with a major physiological requirement for the gene's activity in the learning process and show that a rat counterpart can substitute functionally for the Drosophila gene.
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PMID:Conditional rescue of the dunce learning/memory and female fertility defects with Drosophila or rat transgenes. 775 24

A novel plasmid was generated which allowed the expression of the cytosolic bacterial enzyme chloramphenicol acetyl transferase (CAT) in COS-7 cells. Upon transfection, the majority of the novel CAT activity was found in the cytosol fraction of COS cells. Chimeric molecules were made between N-terminal portions of the type IVA cyclic AMP-specific rat 'dunce-like' phosphodiesterase (RD1) (RNPDE4A1A; rPDE-IVA1) fused to CAT at its N-terminus. Expression in COS-7 cells of chimeras formed from 1-100RD1-CAT and 1-25RD1-CAT now showed CAT activity associated with the membrane fraction. In contrast, a chimera formed from 26-100RD1-CAT showed an identical expression pattern to native CAT, with the major fraction of CAT activity occurring in the cytosol fraction. Membrane-bound CAT activity provided by 1-100RD1-CAT and 1-25RD1-CAT was not released by either high-salt or washing treatments but was solubilized in a dose-dependent fashion by the non-ionic detergent Triton X-100. Subcellular fractionation of COS-7 cells showed that, as with RD1, the membrane-bound activity of the RD1-CAT chimera followed that of the plasma membrane marker 5'-nucleotidase. Plasmids containing chimeric cDNAs were exposed to a coupled transcription-translation system that, in addition to the full-length chimeras, was found to generate a range of N-terminal truncated species due to initiation at different methionine residues. Incubation of the mature protein products formed in this system with a COS cell membrane fraction showed that only those chimeric CAT constructs containing the first 25 amino acids of RD1 became membrane-associated. The unique 25 amino acid N-terminal domain of RD1 contains structural information that can confer membrane association upon an essentially soluble protein.
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PMID:Chimeric constructs show that the unique N-terminal domain of the cyclic AMP phosphodiesterase RD1 (RNPDE4A1A; rPDE-IVA1) can confer membrane association upon the normally cytosolic protein chloramphenicol acetyltransferase. 777 57

Long-term scotopic (rod-mediated) visual deficits following developmental lead exposure occur in monkeys and hooded rats. This report describes and summarizes previous ERG and biochemical findings, presents new biochemical data aimed at determining the mechanism of inhibition of lead on rod cGMP-PDE, presents an integratory framework for understanding the ERG and cGMP results and speculates on the implications of the present data. A- and b-wave voltage-log intensity and latency-log intensity functions, generated from single-flash ERGs in fully dark-adapted rats, revealed that low and moderate level lead exposure caused decreases in absolute sensitivity and amplitude, and increases in latency. Rod- and cone-mediated flicker fusion frequency measures revealed selective rod deficits in temporal resolution. In addition, the slope of the increment threshold function was decreased, but only at scotopic adapting backgrounds, and dark adaptation was delayed. Prior exposure to lead produced a dose-response inhibition of retinal cGMP-phosphodiesterase (PDE) resulting in an increase in cGMP in dark-adapted and light-adapted states and an increase in the calcium content of rods. In vitro experiments with adult rat retinas incubated with 10(-9) to 10(-4) M Pb2+ revealed a concentration-dependent inhibition of cGMP-PDE which suggested that Pb2+ directly inhibited the rod cGMP-PDE. This was confirmed in experiments conducted with isolated, purified, trypsin-activated bovine rod cGMP-specific PDE exposed to 5 x 10(-8) to 10(-4) M Pb2+. The cGMP data are entirely consistent with the observed ERG changes. The ERG data is relevant to low level pediatric lead poisoning since rat rods are similar to human rods. Finally, since a lesion in the gene that codes for a cAMP-PDE leads to defective learning and memory in the Drosophila dunce flies, it is possible that lead-induced alterations in cyclic nucleotide phosphodiesterases contribute to the long-term CNS deficits produced by developmental lead exposure.
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PMID:Lead-induced alterations in rod-mediated visual functions and cGMP metabolism: new insights. 785 84

Neural circadian pacemakers can be reset by light, and the resetting mechanism may involve cyclic nucleotide second messengers. We have examined pacemaker resetting and free-running activity rhythms in Drosophila dunce (dnc) and DC0 mutants, which identify a cAMP specific phosphodiesterase and the catalytic subunit of cAMP-dependent protein kinase, respectively. dnc mutants exhibit augmented light-induced phase delays and shortened circadian periods, which indicate altered pacemaker function. Interestingly, however, light-induced phase advances are normal in dnc, suggesting a selective effect on one component of the pacemaker resetting response. Furthermore, we demonstrate the presence of circadian rhythms in cAMP content in head tissues and show that dnc mutations increase the amplitude of daily cAMP peaks. These results show that cAMP levels are not chronically elevated in the dnc mutant. A role for cAMP signaling in circadian processes is also suggested by an analysis of DC0 mutants, which have severe kinase deficits and display arrhythmic locomotor activity.
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PMID:Altered circadian pacemaker functions and cyclic AMP rhythms in the Drosophila learning mutant dunce. 794 40


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