Disease relevance of PDE3A

• This may be mediated via a protein kinase A-dependent mechanism, as treatment of cells with Br-cAMP (100 microM) mimicked chronic hypoxia in increasing PDE3A expression, while the PKA inhibitor, H8 peptide (50 microM) abolished the hypoxic-dependent increase in PDE3A transcript [1].
• To obtain structural information on platelet PDE3A, we cloned the enzyme cDNA from a human erythroleukemia cell (HEL) library since the cell line expresses many platelet proteins [2].
• A functional truncated recombinant PDE3A containing the catalytic domain (PDE3Atriangle up1) and mutant proteins were expressed in a baculovirus/Sf9 cell system [3].
• The differences in PDE3A expression and responses may be the result of hypertension rather than the cause [4].

Psychiatry related information on PDE3A

• The data obtained indicate that neither the expression levels nor the sequence deviations of PDE3A are the main reasons for erectile dysfunction in men [5].

High impact information on PDE3A

• We believe that these findings provide the first genetic evidence indicating that resumption of meiosis in vivo and in vitro requires PDE3A activity [6].
• cGMP-inhibited cAMP phosphodiesterase 3A (PDE3A) is expressed in mouse oocytes, and its function is indispensable for meiotic maturation as demonstrated by genetic ablation [7].
• Protein kinase B/Akt phosphorylation of PDE3A and its role in mammalian oocyte maturation [7].
• This effect is greatly decreased by mutation of any of the PDE3A serines 290-292 to alanine in both Xenopus and mouse [7].
• Here, we demonstrate that ICER induction repressed PDE3A gene transcription [8].

Biological context of PDE3A

• Of the 11 human PDEs, only PDE3A and 3B have 44-amino acid inserts in the catalytic domain [9].
• 5. RT - PCR using specific primers for PDE3B, but not for PDE3A, amplified, from BRIN - BD11 cell total RNA, a 351 base pair product that was >97% homologous with rat adipose tissue PDE3B [10].
• The most distal transcription initiation site of the PDE3A gene is approximately 1071 bases upstream of the ATG site, suggesting that exon 1 consists of 1071 and 960 bp of untranslated and translated sequences, respectively [11].
• Here, we describe PDE3A gene structure, which comprises 16 exons spanning over 130 kb on chromosome 12p12 [11].
• We have cloned the coding region of a human gene, whose predicted amino acid sequence shows 88% homology and higher correspondence in functional domains to the rat cGMP inhibited phosphodiesterase gene (PDE3A) [12].

Anatomical context of PDE3A

• 2. PDE3A/B gene transcript levels were increased in the main, first, intrapulmonary and resistance pulmonary arteries by chronic hypoxia. mRNA transcript and protein levels of PDE5A2 in the main and first branch pulmonary arteries were also increased by chronic hypoxia, with no effect on PDE5A1/A2 in the intra-pulmonary and resistance vessels [1].
• Cardiac type cGMP-inhibited phosphodiesterase (PDE3A) gene structure: similarity and difference to adipocyte type PDE3B gene [11].
• In a genome-wide DNA microarray analysis, PDE3A and PDE2A were found to be significantly increased in HeLa cells compared to the other cell lines [13].
• Isoforms of cyclic nucleotide phosphodiesterase PDE3A in cardiac myocytes [14].
• Presence of cyclic nucleotide phosphodiesterases PDE1A, existing as a stable complex with calmodulin, and PDE3A in human spermatozoa [15].

Associations of PDE3A with chemical compounds

• The major PDE activity in platelets is PDE3A (cyclic guanosine monophosphate [cGMP]-inhibited PDE) [2].
• Binding of PDE3A to 14-3-3 proteins was also blocked by the DNA replication inhibitors aphidicolin and mimosine, but the PDE3A-14-3-3 interaction was not cell-cycle-regulated [16].
• We further show that the PDE3A-ICER feedback loop is essential for Ang II-induced cardiomyocyte apoptosis [8].
• Angiotensin II (Ang II) and the beta-adrenergic receptor agonist isoproterenol (ISO) also induced persistent PDE3A down-regulation and concomitant ICER up-regulation in vitro, which is important in Ang II- and ISO-induced cardiomyocyte apoptosis [8].
• We have used a newly discovered inhibitor of phosphodiesterase 3A (PDE3A) and the well-characterized PDE3A inhibitor, cilostazol, to modulate 3',5'-cyclic adenosine monophosphate (cAMP) levels in an in vivo model that enables the kinetic analysis of platelet accumulation [17].
• CAMP-elevating agents such as PGE(1) and forskolin-induced phosphorylation of Ser(312) and increased PDE3A activity, but did not stimulate 14-3-3 binding [18].

Physical interactions of PDE3A

• An additional observation was that the cytoskeletal cross-linker protein plectin-1 coimmunoprecipitated with PDE3A independently of 14-3-3 binding [16].

Other interactions of PDE3A

• Platelets contain two cAMP phosphodiesterases (PDEs) which regulate intracellular cAMP levels, cGMP-inhibited cAMP PDE (PDE3A) and cGMP-stimulated PDE (PDE2A) [19].
• As revealed by reverse transcriptase polymerase chain reaction, of all tissues of the urogenital tract analyzed the expression of the PDE3A gene was highest in the corpus cavernosum [5].
• Our findings may provide a therapeutic paradigm to prevent cardiomyocyte apoptosis and the progression of heart failure by inhibiting the PDE3A-ICER feedback loop [8].
• These findings are compatible with elevation of cGMP by NO in a compartment close to PDE3A, PKA, and VASP, leading to a local increase of cAMP able to block thrombin-induced shape change [20].
• To identify amino acid residues involved in PDE3-selective inhibitor binding, we selected eight presumed interacting residues in the substrate-binding pocket of PDE3A using a model created on basis of homology to the PDE4B crystal structure [21].

Analytical, diagnostic and therapeutic context of PDE3A

• High pressure liquid chromatography (HPLC) analysis of a tryptic digest yielded an octapeptide within the insert of PDE3A ((K)T(806)YNVTDDK(813)), suggesting that a substrate-binding site exists within the insert [9].
• In concordance with the expression data of the rat PDE3A gene, a 5.3-kb transcript of the human cGMP-inhibited phosphodiesterase gene is shown in Northern blot analysis to be highly expressed in adipose tissue [12].
• Immunoblotting confirmed the presence of PDE1A and PDE3A isoforms in spermatozoa [15].
• RT-PCR yields the expected size fragment for the primer pair PDE3B and not for PDE3A [22].
• Microinjection of myr-Akt in mouse oocytes causes in vitro meiotic maturation and this effect requires PDE3A [7].

References