Isolation, Expression and Analysis of Splice Variants of a Human Ca2+/Calmodulin-Stimulated Phosphodiesterase (PDE1A)

Snyder, Peter B.; Florio, Vincent A.; Ferguson, K.; Loughney, Kate

doi:10.1016/s0898-6568(99)00027-3

Cited by 33 publications

(14 citation statements)

References 38 publications

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“…We found differences in the relative V max and in the sensitivity to PDE inhibitors of PDE11A3 and PDE11A4, suggesting that the N-terminal region of PDE11A affects the conformation of the protein, leading to the change of enzymatic profile. Similar effects of N-terminal splicing variability have been demonstrated for some PDEs including PDE1A, PDE1C, PDE4A, PDE4B, and PDE7A (15,16,18,20,47). For example, rat PDE4A isoforms have been reported to exhibit 2-5-fold differences in their V max values and in their sensitivity to the PDE4-specific inhibitor, rolipram (16).…”

Section: ϫ7mentioning

confidence: 57%

Isolation and Characterization of Two Novel Phosphodiesterase PDE11A Variants Showing Unique Structure and Tissue-specific Expression

Yuasa

Kotera

Fujishige

et al. 2000

Journal of Biological Chemistry

144

164

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cDNAs encoding a novel phosphodiesterase, phosphodiesterase 11A (PDE11A), were isolated by a combination of reverse transcriptase-polymerase chain reaction using degenerate oligonucleotide primers and rapid amplification of cDNA ends. Their catalytic domain was identical to that of PDE11A1 (490 amino acids) reported during the course of this study. However, the cDNAs we isolated had N termini distinct from PDE11A1, indicating two novel N-terminal variants of PDE11A. PDE11A3 cDNA encoded a 684-amino acid protein including one complete and one incomplete GAF domain in the Nterminal region. PDE11A4 was composed of 934 amino acids including two complete GAF domains and shared 630 C-terminal amino acids with PDE11A3 but had a distinct N terminus containing the putative phosphorylation sites for cAMP-and cGMP-dependent protein kinases. PDE11A3 transcripts were specifically expressed in testis, whereas PDE11A4 transcripts were particularly abundant in prostate. Recombinant PDE11A4 expressed in COS-7 cells hydrolyzed cAMP and cGMP with K m values of 3.0 and 1.4 M, respectively, and the V max value with cAMP was almost twice that with cGMP. Although PDE11A3 showed the same K m values as PDE11A4, the relative V max values of PDE11A3 were approximately one-sixth of those of PDE11A4. PDE11A4, but not PDE11A3, was phosphorylated by both cAMPand cGMP-dependent protein kinases in vitro. Thus, the PDE11A gene undergoes tissue-specific alternative splicing that generates structurally and functionally distinct gene products. Cyclic nucleotide phosphodiesterases (PDEs)1 metabolize cAMP and cGMP, which are second messengers regulating many functions in various cells and tissues. Based on their amino acid sequence homology, biochemical properties, and inhibitor profiles, many kinds of PDEs have been identified in mammalian tissues (1-3). The PDE1 family is Ca 2ϩ /calmodulindependent and hydrolyzes both cAMP and cGMP. PDE2 is stimulated by cGMP and hydrolyzes cAMP and cGMP, while PDE3 is cGMP-inhibited. The cAMP-specific and rolipram-sensitive PDEs belong to the PDE4 family. PDE5 is a cGMPbinding, cGMP-specific PDE. The photoreceptor cGMP PDEs are in the PDE6 family. PDE7 is cAMP-specific and rolipraminsensitive. PDE8 is a cAMP-specific PDE, and PDE9 is a cGMP-specific PDE (3-8). Recently, we revealed a new member of the PDE group, PDE10A, which hydrolyzes both cAMP and cGMP (9). Some of these PDEs constitute subfamilies encoded by distinct genes. In each PDE family, alternative splice variants have been reported (1, 10, 11). In many cases, different gene products and alternative splice variants in each PDE family show different expression patterns in tissues and different subcellular localization (1,(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22). PDEs encoded by alternatively spliced mRNAs have been reported to differ in their regulation by some kinases including cAMP-dependent protein kinase (cAK) and cGMP-dependent kinase (cGK) and associated proteins (19, 23). Thus, cyclic nucleotide levels are controlled by a complex system. Each ...

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Section: ϫ7mentioning

confidence: 57%

Isolation and Characterization of Two Novel Phosphodiesterase PDE11A Variants Showing Unique Structure and Tissue-specific Expression

Yuasa

Kotera

Fujishige

et al. 2000

Journal of Biological Chemistry

144

164

View full text Add to dashboard Cite

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“…Fidock et al (28) found that the N-terminal sequences of PDE1A1 and PDE1B2 align well, whereas the N termini of PDE1A2 and PDE1B1 are homologous. As with the two PDE1B forms described here, sequence variation at the N terminus of PDE1A did not affect V max or K m for cAMP and cGMP (43). Because PDE1A1 had been found to have a 10-fold higher affinity for calmodulin than PDE1A2 (18)(19)(20), the authors logically predicted that PDE1B2 might have a higher affinity for calmodulin than PDE1B1.…”

Section: Pde1b1 and Pde1b2 Have Separate Transcriptional Start Sites Andmentioning

confidence: 62%

Selective up-regulation of PDE1B2 upon monocyte-to-macrophage differentiation

Bender

Ostenson

Wang

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a major regulator of monocyte to macrophage differentiation. In both humans and mice, the main phenotype of decreased GM-CSF function is pulmonary proteinosis due to aberrant function of alveolar macrophages. Recently, this cytokine has been shown to up-regulate a cyclic nucleotide phosphodiesterase, PDE1B. Two PDE1B variants with unique N-terminal sequences, PDE1B1 and PDE1B2, have been identified. Here, we report that the previously uncharacterized PDE1B2 is selectively increased by GM-CSF by stimulation of transcription at a previously unknown transcriptional start site. Analysis of the exon and intron organization of the PDE1B gene reveals that PDE1B2 has a different N-terminal sequence because of a separate first exon that is located 11.5 kb downstream from the PDE1B1 first exon. By using 5 -RACE, alignment of EST sequences, and a luciferase-reporter system, we provide evidence that PDE1B2 has a separate transcriptional start site from PDE1B1 that can be activated by monocyte differentiation. Furthermore, IL-4 treatment in the presence of GM-CSF, which shifts the differentiation from a macrophage to a dendritic cell phenotype, suppresses the up-regulation of PDE1B2. Induction of PDE1B2 is also found in T cells upon activation by PHA. Therefore, PDE1B2 may have a regulatory role in multiple immune cell types. Last, characterization of the catalytic properties of recombinant PDE1B2 shows that it prefers cGMP over cAMP as a substrate and, thus, is likely to regulate cGMP in macrophages. Also, PDE1B2 has a nearly 3-fold lower EC50 for activation by calmodulin than PDE1B1.cAMP ͉ cGMP ͉ phosphodiesterase

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“…14,[18][19][20][21][22][23][24][25] The PDE1A is known to be highly expressed in canine, bovine, and human hearts as a major form in cardiac tissue. 14,23,24) PDE1C transcripts are also documented to be weakly expressed in the rat heart.…”

Section: Discussionmentioning

confidence: 99%

cGMP-Phosphodiesterase Activity Is Up-regulated in Response to Pressure Overload of Rat Ventricles

Yanaka

Kurosawa

Minami

et al. 2003

Bioscience, Biotechnology, and Biochemistry

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Isolation, Expression and Analysis of Splice Variants of a Human Ca2+/Calmodulin-Stimulated Phosphodiesterase (PDE1A)

Cited by 33 publications

References 38 publications

Isolation and Characterization of Two Novel Phosphodiesterase PDE11A Variants Showing Unique Structure and Tissue-specific Expression

Isolation and Characterization of Two Novel Phosphodiesterase PDE11A Variants Showing Unique Structure and Tissue-specific Expression

Selective up-regulation of PDE1B2 upon monocyte-to-macrophage differentiation

cGMP-Phosphodiesterase Activity Is Up-regulated in Response to Pressure Overload of Rat Ventricles

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