Brain distribution of four rat homologues of the drosophila <i>dunce</i> cAMP phosphodiesterase

Engels, Peter; Abdel'Al, Samir; Hulley, P A; Lübbert, Hermann

doi:10.1002/jnr.490410204

Cited by 61 publications

(34 citation statements)

References 49 publications

(46 reference statements)

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“…Because no full-length PDE4C cDNAs were available, the cross-reactivity of the antisera against this PDE form could not be assessed; however, transcripts corresponding to this form have been detected in the rat kidney (Swinnen et al, 1989), rat meiotic germ cells (Welch et al, 1992), and a rat thyroid cell line (FRTL-5) but not in the rat brain (Bolger et al, 1994;Engels et al, 1995;Iwahashi et al, 1996;Swinnen et al, 1989), Sertoli cells , or MA-10 cells (Swinnen JV and Conti M, unpublished observations). Therefore, interpretation of the current data would not be affected by cross-reactivity with PDE4C.…”

Section: Resultsmentioning

confidence: 99%

“…Despite many reports identifying different mRNAs expressed in any given tissue (Bolger et al, 1994;Engels et al, 1994Engels et al, , 1995Iwahashi et al, 1996;Swinnen et al, 1989;Torphy et al, 1992;Verghese et al, 1995), little information is available on whether this multiplicity of genes is translated in the presence of multiple proteins with similar catalytic properties. The data reported herein demonstrate the presence of several PDE4 proteins of different molecular Fig.…”

Section: Discussionmentioning

confidence: 99%

“…In the rat testis, for instance, somatic cells express predominantly PDE4D and PDE4B mRNAs (Swinnen et al, 1989) and germ cells express preferentially PDE4C and PDE4A mRNAs (Welch et al, 1992). In the rat brain, transcripts have been detected corresponding to PDE4A, PDE4B, and PDE4D but not to PDE4C (Bolger et al, 1994;Davis et al, 1989;Engels et al, 1995;Iwahashi et al, 1996;Swinnen et al, 1989). Despite the established presence of multiple genes and of cognate mRNAs, it remains unclear whether different cAMP-PDE proteins are in fact expressed in a cell.…”

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confidence: 99%

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Characterization of the Rolipram-Sensitive, Cyclic AMP-Specific Phosphodiesterases: Identification and Differential Expression of Immunologically Distinct Forms in the Rat Brain

et al. 1998

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To determine the properties of the cAMP-specific, rolipramsensitive phosphodiesterases (cAMP-PDEs) that are expressed in different organs, monoclonal and polyclonal antibodies were raised against different epitopes present in the cAMP-PDE sequences. Of the several antibodies generated against peptides and fusion proteins, one monoclonal and four polyclonal antibodies recognized both the native cAMP-PDEs as well as the denatured proteins on Western immunoblot analysis. An immunoprecipitation assay demonstrated that these antibodies recognized the recombinant rat PDE4A, PDE4B, and PDE4D proteins with different avidity. The polyclonal antibody K118 and the monoclonal M3S1 were most specific for rat PDE4B and PDE4D forms, respectively, whereas the AC55 antiserum displayed the highest affinity for PDE4A forms. This selectivity was confirmed by Western blot analysis using recombinant rat PDE4A, PDE4B, and PDE4D proteins expressed in a heterologous system. These antibodies were used to characterize the cAMP-PDEs expressed in the rat brain. An immunoblot of extract of cortex and cerebellum demonstrated that at least seven different polypeptides specifically cross-reacted with the different antibodies, indicating that multiple cAMP-PDEs are expressed in this tissue. On the basis of cross-reactivity with PDE4D but not PDE4A or PDE4B antibodies, 93-and 105-kDa PDE4D species were detected in the cortex and cerebellum extract. These forms are different from the 68-kDa PDE4D form expressed in endocrine cells after hormonal stimulation. Although the 93-kDa form was recovered in both the soluble and particulate fractions, the 105-kDa polypeptide was mostly particulate in the cortex and cerebellum extracts. PDE4B forms of 90 -87 kDa were recovered in both soluble and particulate compartments of the brain extract. These forms were different from the previously identified PDE4A variants of 110 and 75 kDa. These data demonstrate that the presence of multiple cAMP-PDE genes is translated into cAMP-PDE proteins of different sizes and distinct immunological properties and that multiple variants derived from these cAMP-PDE genes are expressed in different regions of the brain and different subcellular compartments. These immunological tools will be useful to identify different cAMP-PDE forms expressed in organs targeted for pharmacological intervention with PDE4 inhibitors.The high affinity, cAMP-specific phosphodiesterases [type 4 according to the nomenclature proposed by Beavo et al. (1994)] are a class of enzymes with similar kinetic properties that are inhibited by the antidepressant rolipram and structurally related compounds. Although the presence of these forms has long been recognized, their distinctive properties are becoming evident only recently (Conti et al., 1995b). Early attempts to purify these forms have been hampered by their low abundance and instability (Conti and Swinnen, 1990). The molecular mass attributed to this group of enzymes ranges between 29 and 89 kDa (Conti and Swinnen, 1990). The definition of th...

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Characterization of the Rolipram-Sensitive, Cyclic AMP-Specific Phosphodiesterases: Identification and Differential Expression of Immunologically Distinct Forms in the Rat Brain

et al. 1998

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“…A differential expression of cAMP-PDEs was also described for the rat testis [9,10] where rPDE IV-A and -C are expressed in germ cells whereas rPDE IV-B and -D were found in somatic cells. Furthermore, in rat brain distinct expression patterns of the four isogenes were shown by in situ hybridization with overlapping expression in hippocampus and cerebellum but differences in midbrain and cortex [26]. In human neuronal tissue it was demonstrated that no expression of hPDE IV-C occurred in temporal cortex and glioblastoma cells whereas in SH-N-SK neu-…”

Section: Discussionmentioning

confidence: 97%

Expression and regulation of human and rat phosphodiesterase type IV isogenes

1994

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Type IV phosphodiesterases (PDE IV) specifically hydrolyze cAMP and are inhibited by rolipram. RT-PCR was applied to analyze the expression patterns of mRNAs for four cloned human and rat phosphodiesterase type IV isogenes (PDE IV-A, -B, -C and -D). Although these patterns were mostly coincident for the human and rat PDE IV genes, some differences were found between the two species. PDE IV-A expression was detectable in human blood but not in rat blood, suggesting a species-specific difference in the expression of this PDE IV isogene. PDE IV-C was neither detected in human or rat blood nor in different cell populations of the human immune system. It is further demonstrated that the PDE IV isogene expression is differentially regulated by cAMP in different cell types.

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“…Indeed, we have recently exploited this technique to identify interaction sites that define the interaction of the PDE4D5 isoform with the signaling scaffold proteins ␤arrestin and RACK1 (Bolger et al, 2006;Baillie et al, 2007) and between PDE4D3 and the PKA scaffold AKAP18␦ (Stefan et al, 2007). Taking PDE4D3 and PDE4B1, which are both expressed in brain (Engels et al, 1995;Bolger et al, 1997;Thompson et al, 2000;Miro et al, 2002;Richter et al, 2005), as paradigms for classes of PDE4 isoforms that show profound differences in susceptibility to release from fl-DISC1 after elevation of intracellular cAMP, we set out to see whether they showed differences in interaction with a scanning peptide array of fl-DISC1. In this strategy, a library of overlapping peptides (25-mers), sequentially shifted by 5 aa across the entire sequence of fl-DISC1, was immobilized on cellulose membranes.…”

Section: Coimmunoprecipitation Of Pde4 With Fl-disc1mentioning

confidence: 99%

Isoform-Selective Susceptibility of DISC1/Phosphodiesterase-4 Complexes to Dissociation by Elevated Intracellular cAMP Levels

Murdoch¹,

Mackie²,

Collins³

et al. 2007

J. Neurosci.

145

164

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Disrupted-in-schizophrenia 1 (DISC1) is a genetic susceptibility factor for schizophrenia and related severe psychiatric conditions. DISC1 is a multifunctional scaffold protein that is able to interact with several proteins, including the independently identified schizophrenia risk factor phosphodiesterase-4B (PDE4B). Here we report that the 100 kDa full-length DISC1 isoform (fl-DISC1) can bind members of each of the four gene, cAMP-specific PDE4 family. Elevation of intracellular cAMP levels, so as to activate protein kinase A, caused the release of PDE4D3 and PDE4C2 isoforms from fl-DISC1 while not affecting binding of PDE4B1 and PDE4A5 isoforms. Using a peptide array strategy, we show that PDE4D3 binds fl-DISC1 through two regions found in common with PDE4B isoforms, the interaction of which is supplemented because of the presence of additional PDE4B-specific binding sites. We propose that the additional binding sites found in PDE4B1 underpin its resistance to release during cAMP elevation. We identify, for the first time, a functional distinction between the 100 kDa long DISC1 isoform and the short 71 kDa isoform. Thus, changes in the expression pattern of DISC1 and PDE4 isoforms offers a means to reprogram their interaction and to determine whether the PDE4 sequestered by DISC1 is released after cAMP elevation. The PDE4B-specific binding sites encompass point mutations in mouse Disc1 that confer phenotypes related to schizophrenia and depression and that affect binding to PDE4B. Thus, genetic variation in DISC1 and PDE4 that influence either isoform expression or docking site functioning may directly affect psychopathology.

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Brain distribution of four rat homologues of the drosophila dunce cAMP phosphodiesterase

Cited by 61 publications

References 49 publications

Characterization of the Rolipram-Sensitive, Cyclic AMP-Specific Phosphodiesterases: Identification and Differential Expression of Immunologically Distinct Forms in the Rat Brain

Characterization of the Rolipram-Sensitive, Cyclic AMP-Specific Phosphodiesterases: Identification and Differential Expression of Immunologically Distinct Forms in the Rat Brain

Expression and regulation of human and rat phosphodiesterase type IV isogenes

Isoform-Selective Susceptibility of DISC1/Phosphodiesterase-4 Complexes to Dissociation by Elevated Intracellular cAMP Levels

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