A family of human phosphodiesterases homologous to the dunce learning and memory gene product of Drosophila melanogaster are potential targets for antidepressant drugs

We have isolated cDNAs for four human genes (DPDE1 through DPDE4) closely related to the dnc learning and memory locus of Drosophila melanogaster. The deduced amino acid sequences of the Drosophila and human proteins have considerable homology, extending beyond the putative catalytic region to include two novel, highly conserved, upstream conserved regions (UCR1 and UCR2). The upstream conserved regions are located in the amino-terminal regions of the proteins and appear to be unique to these genes. Polymerase chain reaction analysis suggested that these genes encoded the only homologs of dnc in the human genome. Three of the four genes were expressed in Saccharomyces cerevisiae and shown to encode cyclic AMP-specific phosphodiesterases. The products of the expressed genes displayed the pattern of sensitivity to inhibitors expected for members of the type IV, cyclic AMP-specific class of phosphodiesterases. Each of the four genes demonstrated a distinctive pattern of expression in RNA from human cell lines.

[1]  M. Wigler,et al.  Isolation and characterization of a previously undetected human cAMP phosphodiesterase by complementation of cAMP phosphodiesterase-deficient Saccharomyces cerevisiae. , 1993, The Journal of biological chemistry.

[2]  M. Mclaughlin,et al.  A low-Km, rolipram-sensitive, cAMP-specific phosphodiesterase from human brain. Cloning and expression of cDNA, biochemical characterization of recombinant protein, and tissue distribution of mRNA. , 1993, The Journal of biological chemistry.

[3]  M. Conti,et al.  Characterization of the structure of a low Km, rolipram-sensitive cAMP phosphodiesterase. Mapping of the catalytic domain. , 1992, The Journal of biological chemistry.

[4]  M. Mclaughlin,et al.  Coexpression of human cAMP-specific phosphodiesterase activity and high affinity rolipram binding in yeast. , 1992, The Journal of biological chemistry.

[5]  R. Davis,et al.  Characterization of the memory gene dunce of Drosophila melanogaster. , 1991, Journal of molecular biology.

[6]  D. Shoemaker,et al.  High-fidelity amplification using a thermostable DNA polymerase isolated from Pyrococcus furiosus. , 1991, Gene.

[7]  M. Conti,et al.  Properties and hormonal regulation of two structurally related cAMP phosphodiesterases from the rat Sertoli cell. , 1991, The Journal of biological chemistry.

[8]  M. Wigler,et al.  Expression of three mammalian cDNAs that interfere with RAS function in Saccharomyces cerevisiae. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[9]  G D Schuler,et al.  A workbench for multiple alignment construction and analysis , 1991, Proteins.

[10]  G. P. Livi,et al.  Expression of human recombinant cAMP phosphodiesterase isozyme IV reverses growth arrest phenotypes in phosphodiesterase-deficient yeast. , 1991, Molecular pharmacology.

[11]  Y. Zhong,et al.  Altered synaptic plasticity in Drosophila memory mutants with a defective cyclic AMP cascade. , 1991, Science.

[12]  R. Challiss,et al.  Differential modulation of tissue function and therapeutic potential of selective inhibitors of cyclic nucleotide phosphodiesterase isoenzymes. , 1991, TIPS - Trends in Pharmacological Sciences.

[13]  Taylor,et al.  Cloning and expression of cDNA for a human low-Km, rolipram-sensitive cyclic AMP phosphodiesterase , 1990, Molecular and cellular biology.

[14]  J. Beavo,et al.  Primary sequence of cyclic nucleotide phosphodiesterase isozymes and the design of selective inhibitors. , 1990, Trends in pharmacological sciences.

[15]  R. Davis,et al.  Rat homologs of the Drosophila dunce gene code for cyclic AMP phosphodiesterases sensitive to rolipram and RO 20-1724. , 1990, Molecular pharmacology.

[16]  E. Kandel,et al.  Long-term facilitation in Aplysia: persistent phosphorylation and structural changes. , 1990, Cold Spring Harbor symposia on quantitative biology.

[17]  M. Conti,et al.  The mRNA encoding a high-affinity cAMP phosphodiesterase is regulated by hormones and cAMP. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[18]  M. Conti,et al.  Molecular cloning of rat homologues of the Drosophila melanogaster dunce cAMP phosphodiesterase: evidence for a family of genes. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[19]  R. Davis,et al.  Cloning and characterization of mammalian homologs of the Drosophila dunce+ gene. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[20]  M. Wigler,et al.  Isolation and characterization of a mammalian gene encoding a high-affinity cAMP phosphodiesterase. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[21]  K. Mullis,et al.  Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase. , 1988, Science.

[22]  K. Fichte,et al.  Rolipram in major depression: results of a double-blind comparative study with amitriptyline , 1988 .

[23]  Y. Dudai.  Neurogenetic dissection of learning and short-term memory in Drosophila. , 1988, Annual review of neuroscience.

[24]  Gerald R. Fink,et al.  Methods in Yeast Genetics: A Laboratory Course Manual , 1987 .

[25]  J. Chirgwin,et al.  Isolation of RNA using guanidinium salts. , 1987, Methods in enzymology.

[26]  L. Stryer,et al.  Cyclic GMP cascade of vision. , 1986, Annual review of neuroscience.

[27]  C. Wermuth,et al.  Substituted carbostyrils as inhibitors of cyclic AMP phosphodiesterase , 1985 .

[28]  J. Sambrook,et al.  Molecular Cloning: A Laboratory Manual , 2001 .

[29]  M. Mumby,et al.  Purification and characterization of a cyclic GMP-stimulated cyclic nucleotide phosphodiesterase from bovine tissues. , 1982, The Journal of biological chemistry.

[30]  R. Davis,et al.  A partial characterization of the cyclic nucleotide phosphodiesterases of Drosophila melanogaster. , 1980, Archives of biochemistry and biophysics.

[31]  M. M. Bradford.  A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. , 1976, Analytical biochemistry.