Journal articles: 'PDE2A'

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Skryabin, Egor B., Kirstie A. De Jong, Hariharan Subramanian, Nadja I. Bork, Alexander Froese, Boris V. Skryabin, and Viacheslav O. Nikolaev. "CRISPR/Cas9 Knock-Out in Primary Neonatal and Adult Cardiomyocytes Reveals Distinct cAMP Dynamics Regulation by Various PDE2A and PDE3A Isoforms." Cells 12, no. 11 (June 4, 2023): 1543. http://dx.doi.org/10.3390/cells12111543.

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Cyclic nucleotide phosphodiesterases 2A (PDE2A) and PDE3A play an important role in the regulation of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP)-to-cAMP crosstalk. Each of these PDEs has up to three distinct isoforms. However, their specific contributions to cAMP dynamics are difficult to explore because it has been challenging to generate isoform-specific knock-out mice or cells using conventional methods. Here, we studied whether the CRISPR/Cas9 approach for precise genome editing can be used to knock out Pde2a and Pde3a genes and their distinct isoforms using adenoviral gene transfer in neonatal and adult rat cardiomyocytes. Cas9 and several specific gRNA constructs were cloned and introduced into adenoviral vectors. Primary adult and neonatal rat ventricular cardiomyocytes were transduced with different amounts of Cas9 adenovirus in combination with PDE2A or PDE3A gRNA constructs and cultured for up to 6 (adult) or 14 (neonatal) days to analyze PDE expression and live cell cAMP dynamics. A decline in mRNA expression for PDE2A (~80%) and PDE3A (~45%) was detected as soon as 3 days post transduction, with both PDEs being reduced at the protein level by >50–60% in neonatal cardiomyocytes (after 14 days) and >95% in adult cardiomyocytes (after 6 days). This correlated with the abrogated effects of selective PDE inhibitors in the live cell imaging experiments based on using cAMP biosensor measurements. Reverse transcription PCR analysis revealed that only the PDE2A2 isoform was expressed in neonatal myocytes, while adult cardiomyocytes expressed all three PDE2A isoforms (A1, A2, and A3) which contributed to the regulation of cAMP dynamics as detected by live cell imaging. In conclusion, CRISPR/Cas9 is an effective tool for the in vitro knock-out of PDEs and their specific isoforms in primary somatic cells. This novel approach suggests distinct regulation of live cell cAMP dynamics by various PDE2A and PDE3A isoforms in neonatal vs. adult cardiomyocytes.

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Ivey, F. Douglas, Lili Wang, Didem Demirbas, Christina Allain, and Charles S. Hoffman. "Development of a Fission Yeast-Based High-Throughput Screen to Identify Chemical Regulators of cAMP Phosphodiesterases." Journal of Biomolecular Screening 13, no. 1 (November 26, 2007): 62–71. http://dx.doi.org/10.1177/1087057107312127.

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Cyclic nucleotide phosphodiesterases (PDEs) comprise a superfamily of enzymes that serve as drug targets in many human diseases. There is a continuing need to identify high-specificity inhibitors that affect individual PDE families or even subtypes within a single family. The authors describe a fission yeast-based high-throughput screen to detect inhibitors of heterologously expressed adenosine 3′,5′-cyclic monophosphate (cAMP) PDEs. The utility of this system is demonstrated by the construction and characterization of strains that express mammalian PDE2A, PDE4A, PDE4B, and PDE8A and respond appropriately to known PDE2A and PDE4 inhibitors. High-throughput screens of 2 bioactive compound libraries for PDE inhibitors using strains expressing PDE2A, PDE4A, PDE4B, and the yeast PDE Cgs2 identified known PDE inhibitors and members of compound classes associated with PDE inhibition. The authors verified that the furanocoumarin imperatorin is a PDE4 inhibitor based on its ability to produce a PDE4-specific elevation of cAMP levels. This platform can be used to identify PDE activators, as well as genes encoding PDE regulators, which could serve as targets for future drug screens. ( Journal of Biomolecular Screening 2008:62-71)

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Manns, J. M., K. J. Brennan, S. B. Sheth, and R. W. Colman. "Differential Regulation of Human Platelet Responses by cGMP Inhibited and Stimulated cAMP Phosphodiesterases." Thrombosis and Haemostasis 87, no. 05 (2002): 873–79. http://dx.doi.org/10.1055/s-0037-1613099.

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SummaryPlatelets contain two cAMP phosphodiesterases (PDEs) which regulate intracellular cAMP levels, cGMP-inhibited cAMP PDE (PDE3A) and cGMP-stimulated PDE (PDE2A). Using the PDE3 inhibitor, milrinone and the PDE2 inhibitor, erythro-9-(2-hydroxyl-3-nonyl)adenine (EHNA), we have explored the contribution of each PDE to the regulation of platelet function. Inhibition of PDE2 resulted in higher levels of intracellular cAMP than inhibition of PDE3A suggesting this PDE may be the more important regulator of cAMP in human platelets. However, a concentration-dependent inhibition of agonist-induced aggregation was observed with milrinone while little effect was seen with EHNA. In addition, we observed a concentration-dependent inhibition in the increase of intracellular Ca2+ with PDE3 inhibition and significantly less with PDE2 inhibition. PDE3 inhibition also resulted in a concentration-dependent increase in cAMP-mediated phosphorylation of the vasodilator-stimulated phospho-protein (VASP) whereas there was no significant increase with PDE2 inhibition. In each of these experiments, synergism was noted with the combination of milrinone and EHNA. These results suggest that cAMP pools may be localized and the various PDEs regulate specific pools. These data also suggest that inhibitors of PDE3A may be more effective antiplatelet agents.

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Carvalho, Thays Maria da Conceição Silva, Silvia Cardarelli, Mauro Giorgi, Andrea Lenzi, Andrea M. Isidori, and Fabio Naro. "Phosphodiesterases Expression during Murine Cardiac Development." International Journal of Molecular Sciences 22, no. 5 (March 5, 2021): 2593. http://dx.doi.org/10.3390/ijms22052593.

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3′-5′ cyclic nucleotide phosphodiesterases (PDEs) are a large family of enzymes playing a fundamental role in the control of intracellular levels of cAMP and cGMP. Emerging evidence suggested an important role of phosphodiesterases in heart formation, but little is known about the expression of phosphodiesterases during cardiac development. In the present study, the pattern of expression and enzymatic activity of phosphodiesterases was investigated at different stages of heart formation. C57BL/6 mice were mated and embryos were collected from 14.5 to 18.5 days of development. Data obtained by qRT-PCR and Western blot analysis showed that seven different isoforms are expressed during heart development, and PDE1C, PDE2A, PDE4D, PDE5A and PDE8A are modulated from E14.5 to E18.5. In heart homogenates, the total cAMP and cGMP hydrolytic activity is constant at the evaluated times, and PDE4 accounts for the majority of the cAMP hydrolyzing ability and PDE2A accounts for cGMP hydrolysis. This study showed that a subset of PDEs is expressed in developing mice heart and some of them are modulated to maintain constant nucleotide phosphodiesterase activity in embryonic and fetal heart.

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Chen, Ling, Suying Cui, Haiyang Yu, Gaowen Li, Na Liu, Qiang Wu, Han-Ting Zhang, James M. O’Donnell, Gang Wang, and Ying Xu. "Reduced phosphodiesterase-2 activity in the amygdala results in anxiolytic-like effects on behavior in mice." Journal of Psychopharmacology 33, no. 5 (March 5, 2019): 568–76. http://dx.doi.org/10.1177/0269881119832753.

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Background: Phosphodiesterase-2 (PDE2) is a cyclic nucleotide phosphodiesterase and is highly expressed in the amygdala, which suggests its important role in anxiety-like behavior. Aims: The present study examined whether reduced PDE2A expression in the central nucleus of the amygdala (CeA) produces anxiolytic-like effects in mice. Methods: PDE2A knockdown in amygdaloid (AR5) cells or the CeA was established using a lentiviral vector-based siRNA system. The anxiety-like behaviors were detected by the elevated plus maze (EPM) and hole-board tests in mice. The related proteins involved in cAMP/cGMP-dependent signaling, such as specific marker VASPser239, CREBser133 and BDNF were detected by immunoblot analysis. Results: PDE2A inhibition in AR-5 cells resulted in increases in cAMP/cGMP-related pVASPser239 and pCREBser133. Behavioral tests showed that PDE2A knockdown in the CeA induced anxiolytic-like effects as evidenced by the increases in percentages of open-arm entries and time spent in the open arms in the EPM test, and the increases in head dips and time spent in head dipping in the hole-board test. However, these anxiolytic-like effects were antagonized by pre-treatment of soluble guanylyl cyclase inhibitor ODQ or adenylate cyclase inhibitor SQ. Furthermore, PDE2A knockdown significantly increased pVASPSer239, pCREBSer133 and decreased BDNF expression in the amygdala. Pre-intra-CeA of ODQ or SQ reversed or partially prevented the eﬀects of PDE2A knockdown on these proteins. Conclusions: The results suggest that PDE2A plays a crucial role in the regulation of anxiety by the cGMP/cAMP-dependent pVASP-pCREB-BDNF signaling pathway.

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Chen, Lin, Jinchi Zhou, Zifeng Zhao, Yuhan Zhu, Jinliang Xing, Jiaze An, and Xu Guo. "Low Expression of Phosphodiesterase 2 (PDE2A) Promotes the Progression by Regulating Mitochondrial Morphology and ATP Content and Predicts Poor Prognosis in Hepatocellular Carcinoma." Cells 12, no. 1 (December 23, 2022): 68. http://dx.doi.org/10.3390/cells12010068.

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Phosphodiesterase 2 (PDE2A) modulates the levels of cAMP/cGMP and was recently found to be involved in mitochondria function regulation, closely related to multiple types of tumor progression. This study aimed to estimate the prognostic significance and biological effects of PDE2A on hepatocellular carcinoma (HCC). We comprehensively analyzed the PDE2A mRNA expression in HCC based on The Cancer Genome Atlas (TCGA) database and investigated the effects of PDE2A on the proliferation and metastatic capacity of HCC cells. PDE2A was downregulated in 25 cancer types, including HCC. Lower PDE2A expression was a protective factor in HCC and was negatively associated with serum AFP levels, tumor status, vascular invasion, histologic grade, and pathologic stage of HCC. Moreover, tumors with low PDE2A expression displayed a decreased immune function. Then, the ROC curve was used to assess the diagnostic ability of PDE2A in HCC (AUC = 0.823 in TCGA and AUC = 0.901 in GSE76427). Patients with low PDE2A expression exhibited worse outcomes compared with those with high PDE2A expression. Additionally, GO functional annotations demonstrated the involvement of PDE2A in the ECM organization, systems development, and ERK-related pathways, indicating that PDE2A might regulate HCC growth and metastasis. The in vitro experiments confirmed that overexpression of PDE2A inhibited proliferation, colony formation, migration, and invasion in two HCC cell lines (HLF and SNU-368), while inhibition of PDE2A has the opposite results. The mechanism of PDE2A’s effect on HCC cells is attributed to the change of mitochondrial morphology and ATP content. These data demonstrated that PDE2A closely participated in the regulation of HCC proliferation and metastasis and can be used as a predictive marker candidate and a potential therapeutic target for HCC.

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Barbagallo, Federica, Valentina Rotilio, Maria Rita Assenza, Salvatore Aguanno, Tiziana Orsini, Sabrina Putti, Andrea M. Isidori, et al. "PDE2A Is Indispensable for Mouse Liver Development and Hematopoiesis." International Journal of Molecular Sciences 21, no. 8 (April 21, 2020): 2902. http://dx.doi.org/10.3390/ijms21082902.

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Phosphodiesterase 2A (PDE2A) is a cAMP-cGMP hydrolyzing enzyme essential for mouse development and the PDE2A knockout model (PDE2A−/−) is embryonic lethal. Notably, livers of PDE2A−/− embryos at embryonic day 14.5 (E14.5) have extremely reduced size. Morphological, cellular and molecular analyses revealed loss of integrity in the PDE2A−/− liver niche that compromises the hematopoietic function and maturation. Hematopoietic cells isolated from PDE2A−/− livers are instead able to differentiate in in vitro assays, suggesting the absence of blood cell-autonomous defects. Apoptosis was revealed in hepatoblasts and at the endothelial and stromal compartments in livers of PDE2A−/− embryos. The increase of the intracellular cAMP level and of the inducible cAMP early repressor (ICER) in liver of PDE2A−/− embryos might explain the impairment of liver development by downregulating the expression of the anti-apoptotic gene Bcl2. In summary, we propose PDE2A as an essential gene for integrity maintenance of liver niche and the accomplishment of hematopoiesis.

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Matthiesen, Karina, and Jacob Nielsen. "Binding of cyclic nucleotides to phosphodiesterase 10A and 11A GAF domains does not stimulate catalytic activity." Biochemical Journal 423, no. 3 (October 12, 2009): 401–9. http://dx.doi.org/10.1042/bj20090982.

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To date eleven human PDE (3′,5′-cyclic nucleotide phosphodiesterase) families have been identified. Of these, five families contain non-catalytic tandem GAF (cGMP-specific and -stimulated phosphodiesterases, Anabaenaadenylate cyclases and Escherichia coliFhlA) domains, GAFa and GAFb, in the N-terminal part of the enzyme. For PDE2A, PDE5A and PDE6 the GAF domains have been shown to bind cGMP with high affinity. For PDE2A and PDE5A this ligand binding has been shown to stimulate the catalytic activity of the enzyme. PDE10A and PDE11A are the two most recently described PDEs and it has been suggested that their GAF domains bind to cAMP and cGMP respectively. We have developed a scintillation proximity-based assay to directly measure cyclic nucleotide binding to the PDE2A, PDE10A and PDE11A GAF domains, and in the present study we demonstrate binding of cyclic nucleotides to the PDE10A and PDE11A GAF domains. We show that these non-catalytic sites bind cAMP and cGMP respectively with much higher affinity than has previously been suggested using indirect assessment of the interaction. The GAFb domain of PDE10A binds cAMP with a Kd of 48 nM and the GAFa domain of PDE11A binds cGMP with a Kd of 110 nM. The effect of cyclic nucleotides binding to the GAF domains on the enzyme activity was investigated through the use of modified cyclic nucleotides. In contrast with other GAF domain-containing PDEs, and with what has previously been predicted, ligand binding to the GAF domains of PDE10A and PDE11A does not stimulate catalytic activity.

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Ritawidya, Ludwig, Briel, Brust, and Scheunemann. "Synthesis and In Vitro Evaluation of 8-Pyridinyl-Substituted Benzo[e]imidazo[2,1-c][1,2,4]triazines as Phosphodiesterase 2A Inhibitors." Molecules 24, no. 15 (July 31, 2019): 2791. http://dx.doi.org/10.3390/molecules24152791.

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Phosphodiesterase 2A (PDE2A) is highly expressed in distinct areas of the brain, which are known to be related to neuropsychiatric diseases. The development of suitable PDE2A tracers for Positron Emission Tomography (PET) would permit the in vivo imaging of the PDE2A and evaluation of disease-mediated alterations of its expression. A series of novel fluorinated PDE2A inhibitors on the basis of a Benzoimidazotriazine (BIT) scaffold was prepared leading to a prospective inhibitor for further development of a PDE2A PET imaging agent. BIT derivatives (BIT1–9) were obtained by a seven-step synthesis route, and their inhibitory potency towards PDE2A and selectivity over other PDEs were evaluated. BIT1 demonstrated much higher inhibition than other BIT derivatives (82.9% inhibition of PDE2A at 10 nM). BIT1 displayed an IC50 for PDE2A of 3.33 nM with 16-fold selectivity over PDE10A. This finding revealed that a derivative bearing both a 2-fluoro-pyridin-4-yl and 2-chloro-5-methoxy-phenyl unit at the 8- and 1-position, respectively, appeared to be the most potent inhibitor. In vitro studies of BIT1 using mouse liver microsomes (MLM) disclosed BIT1 as a suitable ligand for 18F-labeling. Nevertheless, future in vivo metabolism studies are required.

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Rentsendorj, Otgonchimeg, Mahendra Damarla, Neil R. Aggarwal, Ji-Young Choi, Laura Johnston, Franco R. D'Alessio, Michael T. Crow, and David B. Pearse. "Knockdown of lung phosphodiesterase 2A attenuates alveolar inflammation and protein leak in a two-hit mouse model of acute lung injury." American Journal of Physiology-Lung Cellular and Molecular Physiology 301, no. 2 (August 2011): L161—L170. http://dx.doi.org/10.1152/ajplung.00073.2011.

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Phosphodiesterase 2A (PDE2A) is stimulated by cGMP to hydrolyze cAMP, a potent endothelial barrier-protective molecule. We previously found that lung PDE2A contributed to a mouse model of ventilator-induced lung injury (VILI). The purpose of the present study was to determine the contribution of PDE2A in a two-hit mouse model of 1-day intratracheal (IT) LPS followed by 4 h of 20 ml/kg tidal volume ventilation. Compared with IT water controls, LPS alone (3.75 μg/g body wt) increased lung PDE2A mRNA and protein expression by 6 h with a persistent increase in protein through day 4 before decreasing to control levels on days 6 and 10. Similar to the PDE2A time course, the peak in bronchoalveolar lavage (BAL) neutrophils, lactate dehydrogenase (LDH), and protein concentration also occurred on day 4 post-LPS. IT LPS (1 day) and VILI caused a threefold increase in lung PDE2A and inducible nitric oxide synthase (iNOS) and a 24-fold increase in BAL neutrophilia. Compared with a control adenovirus, PDE2A knockdown with an adenovirus expressing a short hairpin RNA administered IT 3 days before LPS/VILI effectively decreased lung PDE2A expression and significantly attenuated BAL neutrophilia, LDH, protein, and chemokine levels. PDE2A knockdown also reduced lung iNOS expression by 53%, increased lung cAMP by nearly twofold, and improved survival from 47 to 100%. We conclude that in a mouse model of LPS/VILI, a synergistic increase in lung PDE2A expression increased lung iNOS and alveolar inflammation and contributed significantly to the ensuing acute lung injury.

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Jiang, Lei, and Shenghu Yan. "Prokaryotic Expression, Purification and Activity Detection of Phosphodiesterase 2A Protein." Journal of Biology and Life Science 11, no. 2 (April 16, 2020): 1. http://dx.doi.org/10.5296/jbls.v11i2.16650.

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Depression is associated with changes in cyclic guanosine monophosphate (cGMP) levels. Depression can be improved by increasing the cGMP concentration through the cGMP/PKG pathway with PDE2A inhibitors. This study is aimed to improve the expression of a highly active PDE2A protein with an Escherichia coli vector ST6 for the screening of PDE2A inhibitors. PDE2A gene was obtained through polymerase chain reaction. A recombinant plasmid of ST6-PDE2A was built by seamless cloning and then introduced into E. coli BL21 (DE3). The cultivation conditions were optimized to increase target protein expression. The expressed protein was purified with Ni-NTA affinity chromatography. Its purified activity was measured by a PDE-GloTM phosphodiesterase kit. An maximized protein expression was obtained by cultivating E. coli BL21 with ST6-PDE2A in the YT medium at 37 °C till OD600 reached to 0.6-0.8 and then by inducible expressing with 1 mM IPTG at 16 °C for 40 hours. The resultant active protein has an EC50 of 0.1196 mg/ml.

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Kubacka, Monika, Szczepan Mogilski, Marek Bednarski, Krzysztof Pociecha, Artur Świerczek, Noemi Nicosia, Jakub Schabikowski, et al. "Antiplatelet Effects of Selected Xanthine-Based Adenosine A2A and A2B Receptor Antagonists Determined in Rat Blood." International Journal of Molecular Sciences 24, no. 17 (August 29, 2023): 13378. http://dx.doi.org/10.3390/ijms241713378.

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The platelet aggregation inhibitory activity of selected xanthine-based adenosine A2A and A2B receptor antagonists was investigated, and attempts were made to explain the observed effects. The selective A2B receptor antagonist PSB-603 and the A2A receptor antagonist TB-42 inhibited platelet aggregation induced by collagen or ADP. In addition to adenosine receptor blockade, the compounds were found to act as moderately potent non-selective inhibitors of phosphodiesterases (PDEs). TB-42 showed the highest inhibitory activity against PDE3A along with moderate activity against PDE2A and PDE5A. The antiplatelet activity of PSB-603 and TB-42 may be due to inhibition of PDEs, which induces an increase in cAMP and/or cGMP concentrations in platelets. The xanthine-based adenosine receptor antagonists were found to be non-cytotoxic for platelets. Some of the compounds showed anti-oxidative properties reducing lipid peroxidation. These results may provide a basis for the future development of multi-target xanthine derivatives for the treatment of inflammation and atherosclerosis and the prevention of heart infarction and stroke.

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Wenzel, Barbara, Stefan R. Fritzsche, Magali Toussaint, Detlef Briel, Klaus Kopka, Peter Brust, Matthias Scheunemann, and Winnie Deuther-Conrad. "Radiosynthesis and Preclinical Evaluation of an 18F-Labeled Triazolopyridopyrazine-Based Inhibitor for Neuroimaging of the Phosphodiesterase 2A (PDE2A)." Pharmaceuticals 15, no. 10 (October 15, 2022): 1272. http://dx.doi.org/10.3390/ph15101272.

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The cyclic nucleotide phosphodiesterase 2A is an intracellular enzyme which hydrolyzes the secondary messengers cAMP and cGMP and therefore plays an important role in signaling cascades. A high expression in distinct brain areas as well as in cancer cells makes PDE2A an interesting therapeutic and diagnostic target for neurodegenerative and neuropsychiatric diseases as well as for cancer. Aiming at specific imaging of this enzyme in the brain with positron emission tomography (PET), a new triazolopyridopyrazine-based derivative (11) was identified as a potent PDE2A inhibitor (IC50, PDE2A = 1.99 nM; IC50, PDE10A ~2000 nM) and has been radiofluorinated for biological evaluation. In vitro autoradiographic studies revealed that [18F]11 binds with high affinity and excellent specificity towards PDE2A in the rat brain. For the PDE2A-rich region nucleus caudate and putamen an apparent KD value of 0.24 nM and an apparent Bmax value of 16 pmol/mg protein were estimated. In vivo PET-MR studies in rats showed a moderate brain uptake of [18F]11 with a highest standardized uptake value (SUV) of 0.97. However, no considerable enrichment in PDE2A-specific regions in comparison to a reference region was detectable (SUVcaudate putamen = 0.51 vs. SUVcerebellum = 0.40 at 15 min p.i.). Furthermore, metabolism studies revealed a considerable uptake of radiometabolites of [18F]11 in the brain (66% parent fraction at 30 min p.i.). Altogether, despite the low specificity and the blood–brain barrier crossing of radiometabolites observed in vivo, [18F]11 is a valuable imaging probe for the in vitro investigation of PDE2A in the brain and has potential as a lead compound for further development of a PDE2A-specific PET ligand for neuroimaging.

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Kallenborn-Gerhardt, Wiebke, Ruirui Lu, Aaron Bothe, Dominique Thomas, Jessica Schlaudraff, Jana E. Lorenz, Nancy Lippold, et al. "Phosphodiesterase 2A Localized in the Spinal Cord Contributes to Inflammatory Pain Processing." Anesthesiology 121, no. 2 (August 1, 2014): 372–82. http://dx.doi.org/10.1097/aln.0000000000000270.

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Abstract Background: Phosphodiesterase 2A (PDE2A) is an evolutionarily conserved enzyme that catalyzes the degradation of the cyclic nucleotides, cyclic adenosine monophosphate, and/or cyclic guanosine monophosphate. Recent studies reported the expression of PDE2A in the dorsal horn of the spinal cord, pointing to a potential contribution to the processing of pain. However, the functions of PDE2A in spinal pain processing in vivo remained elusive. Methods: Immunohistochemistry, laser microdissection, and quantitative real-time reverse transcription polymerase chain reaction experiments were performed to characterize the localization and regulation of PDE2A protein and messenger RNA in the mouse spinal cord. Effects of the selective PDE2A inhibitor, BAY 60–7550 (Cayman Chemical, Ann Arbor, MI), in animal models of inflammatory pain (n = 6 to 10), neuropathic pain (n = 5 to 6), and after intrathecal injection of cyclic nucleotides (n = 6 to 8) were examined. Also, cyclic adenosine monophosphate and cyclic guanosine monophosphate levels in spinal cord tissues were measured by liquid chromatography tandem mass spectrometry. Results: The authors here demonstrate that PDE2A is distinctly expressed in neurons of the superficial dorsal horn of the spinal cord, and that its spinal expression is upregulated in response to hind paw inflammation. Administration of the selective PDE2A inhibitor, BAY 60–7550, increased the nociceptive behavior of mice in animal models of inflammatory pain. Moreover, BAY 60–7550 increased the pain hypersensitivity induced by intrathecal delivery of cyclic adenosine monophosphate, but not of cyclic guanosine monophosphate, and it increased the cyclic adenosine monophosphate levels in spinal cord tissues. Conclusion: Our findings indicate that PDE2A contributes to the processing of inflammatory pain in the spinal cord.

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Maurin, Thomas, Francesca Melancia, Marielle Jarjat, Liliana Castro, Lara Costa, Sébastien Delhaye, Anouar Khayachi, et al. "Involvement of Phosphodiesterase 2A Activity in the Pathophysiology of Fragile X Syndrome." Cerebral Cortex 29, no. 8 (August 23, 2018): 3241–52. http://dx.doi.org/10.1093/cercor/bhy192.

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Abstract The fragile X mental retardation protein (FMRP) is an RNA-binding protein involved in translational regulation of mRNAs that play key roles in synaptic morphology and plasticity. The functional absence of FMRP causes the fragile X syndrome (FXS), the most common form of inherited intellectual disability and the most common monogenic cause of autism. No effective treatment is available for FXS. We recently identified the Phosphodiesterase 2A (Pde2a) mRNA as a prominent target of FMRP. PDE2A enzymatic activity is increased in the brain of Fmr1-KO mice, a recognized model of FXS, leading to decreased levels of cAMP and cGMP. Here, we pharmacologically inhibited PDE2A in Fmr1-KO mice and observed a rescue both of the maturity of dendritic spines and of the exaggerated hippocampal mGluR-dependent long-term depression. Remarkably, PDE2A blockade rescued the social and communicative deficits of both mouse and rat Fmr1-KO animals. Importantly, chronic inhibition of PDE2A in newborn Fmr1-KO mice followed by a washout interval, resulted in the rescue of the altered social behavior observed in adolescent mice. Altogether, these results reveal the key role of PDE2A in the physiopathology of FXS and suggest that its pharmacological inhibition represents a novel therapeutic approach for FXS.

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Xu, Ying, Jianchun Pan, Ling Chen, Chong Zhang, Jiao Sun, Jianxin Li, Linda Nguyen, Neetu Nair, Hanting Zhang, and James M. O'Donnell. "Phosphodiesterase-2 inhibitor reverses corticosterone-induced neurotoxicity and related behavioural changes via cGMP/PKG dependent pathway." International Journal of Neuropsychopharmacology 16, no. 4 (May 1, 2013): 835–47. http://dx.doi.org/10.1017/s146114571200065x.

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Abstract Phosphodiesterase 2 (PDE2) is an enzyme responsible for hydrolysis of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) to restrict intracellular signalling of these second messenger molecules. This study investigated how PDE2 inhibitor Bay 60-7550 affects the dysregulated glucocorticoid signalling in neuronal cells and regulates depressive behaviours after chronic stress in mice. We found that exposure of hippocampal neurons to corticosterone resulted in time- and concentration-dependent increases in PDE2 expression. These intriguing findings were confirmed in the hippocampal cell line HT-22. After corticosterone exposure for 24 h, HT-22 cells showed a concentration-dependent increase in mRNA levels for PDE2 subtypes, PDE2A1 and 2A3, as well as for the total PDE2A protein expression. Bay 60-7550 was found to reverse the cell lesion induced by corticosterone (50 µm). This neuroprotective effect was blocked by pretreatment with protein kinase G inhibitor KT5823, but not protein kinase A inhibitor H89, suggesting the involvement of cGMP-dependent signalling. Although Bay 60-7550 treatment for 24 h did not change the levels of phosphorylated mitogen-activated protein kinases ERK1/2 (pERK) and phosphorylated cAMP response element-binding protein (pCREB), it down-regulated pERK at 2 h and up-regulated a CREB co-activator, CREB-binding protein, at 24 h. Both of these effects were blocked by KT 5823. Furthermore, Bay 60-7550 reversed corticosterone-induced down-regulation of brain-derived neurotrophic factor protein levels 24 h after corticosterone exposure. In behavioural testing, Bay 60-7550 produced antidepressant-like effects and reduced corticosterone levels in stressed mice, further supporting the involvement of a PDE2-dependent pathway in mediating Bay 60-7550's effect during stress hormone insults.

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Rassi-Cruz, Marcela, Andrea G. Maria, Fabio R. Faucz, Edra London, Leticia A. P. Vilela, Lucas S. Santana, Anna Flavia F. Benedetti, et al. "Phosphodiesterase 2A and 3B variants are associated with primary aldosteronism." Endocrine-Related Cancer 28, no. 1 (January 2021): 1–13. http://dx.doi.org/10.1530/erc-20-0384.

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Abstract Familial primary aldosteronism (PA) is rare and mostly diagnosed in early-onset hypertension (HT). However, ‘sporadic’ bilateral adrenal hyperplasia (BAH) is the most frequent cause of PA and remains without genetic etiology in most cases. Our aim was to investigate new genetic defects associated with BAH and PA. We performed whole-exome sequencing (paired blood and adrenal tissue) in six patients with PA caused by BAH that underwent unilateral adrenalectomy. Additionally, we conducted functional studies in adrenal hyperplastic tissue and transfected cells to confirm the pathogenicity of the identified genetic variants. Rare germline variants in phosphodiesterase 2A (PDE2A) and 3B (PDE3B) genes were identified in three patients. The PDE2A heterozygous variant (p.Ile629Val) was identified in a patient with BAH and early-onset HT at 13 years of age. Two PDE3B heterozygous variants (p.Arg217Gln and p.Gly392Val) were identified in patients with BAH and HT diagnosed at 18 and 33 years of age, respectively. A strong PDE2A staining was found in all cases of BAH in zona glomerulosa and/or micronodules (that were also positive for CYP11B2). PKA activity in frozen tissue was significantly higher in BAH from patients harboring PDE2A and PDE3B variants. PDE2A and PDE3B variants significantly reduced protein expression in mutant transfected cells compared to WT. Interestingly, PDE2A and PDE3B variants increased SGK1 and SCNN1G/ENaCg at mRNA or protein levels. In conclusion, PDE2A and PDE3B variants were associated with PA caused by BAH. These novel genetic findings expand the spectrum of genetic etiologies of PA.

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Nakashima, Kosuke, and Hideki Matsui. "A Novel Inhibition Modality for Phosphodiesterase 2A." SLAS DISCOVERY: Advancing the Science of Drug Discovery 25, no. 5 (April 28, 2020): 498–505. http://dx.doi.org/10.1177/2472555220913241.

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Phosphodiesterase type 2A (PDE2A) has received considerable interest as a molecular target for treating central nervous system diseases that affect memory, learning, and cognition. In this paper, the authors present the discovery of small molecules that have a novel modality of PDE2A inhibition. PDE2A possesses GAF-A and GAF-B domains and is a dual-substrate enzyme capable of hydrolyzing both cGMP and cAMP, and activation occurs through cGMP binding to the GAF-B domain. Thus, positive feedback of the catalytic activity to hydrolyze cyclic nucleotides occurs in the presence of appropriate concentrations of cGMP, which binds to the GAF-B domain, resulting in a “brake” that attenuates downstream cyclic nucleotide signaling. Here, we studied the inhibitory effects of some previously reported PDE2A inhibitors, all of which showed impaired inhibitory effects at a lower concentration of cGMP (70 nM) than a concentration effective for the positive feedback (4 μM). This impairment depended on the presence of the GAF domains but was not attributed to binding of the inhibitors to these domains. Notably, we identified PDE2A inhibitors that did not exhibit this behavior; that is, the inhibitory effects of these inhibitors were as strong at the lower concentration of cGMP (70 nM) as they were at the higher concentration (4 μM). This suggests that such inhibitors are likely to be more effective than previously reported PDE2A inhibitors in tissues of patients with lower cGMP concentrations.

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Li, Dan, Kun Liu, Harvey Davis, Calum Robertson, Oliver C. Neely, Adib Tarafdar, Ni Li, Konstantinos Lefkimmiatis, Manuela Zaccolo, and David J. Paterson. "Abnormal Cyclic Nucleotide Signaling at the Outer Mitochondrial Membrane In Sympathetic Neurons During the Early Stages of Hypertension." Hypertension 79, no. 7 (July 2022): 1374–84. http://dx.doi.org/10.1161/hypertensionaha.121.18882.

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Background: Disruption of cyclic nucleotide signaling in sympathetic postganglionic neurons contributes to impaired intracellular calcium handling (Ca 2+ ) and the development of dysautonomia during the early stages of hypertension, although how this occurs is poorly understood. Emerging evidence supports the uncoupling of signalosomes in distinct cellular compartments involving cyclic nucleotide–sensitive PDEs (phosphodiesterases), which may underpin the autonomic phenotype in stellate neurons. Methods: Using a combination of single-cell RNA sequencing together with Forster resonance energy transfer–based sensors to monitor cyclic adenosine 3’,5’-monophosphate, PKA (protein kinase A)-dependent phosphorylation and cGMP (cyclic guanosine 3’,5’-monophosphate), we tested the hypothesis that dysregulation occurs in a sub-family of PDEs in the cytosol and outer mitochondrial membrane of neurons from the stellate ganglion. Results: PDE2A, 6D, 7A, 9A genes were highly expressed in young Wistar neurons and also conserved in neurons from spontaneously hypertensive rats (SHRs). In stellate neurons from prehypertensive SHRs, we found the levels of cyclic adenosine 3’,5’-monophosphate and cGMP at the outer mitochondrial membrane were decreased compared with normal neurons. The reduced cyclic adenosine 3’,5’-monophosphate response was due to the hydrolytic activity of overexpressed PDE2A2 located at the mitochondria. Normal cyclic adenosine 3’,5’-monophosphate levels were re-established by inhibition of PDE2A. There was also a greater PKA-dependent phosphorylation in the cytosol and at the outer mitochondrial membrane in spontaneously hypertensive rat neurons, where this response was regulated by protein phosphatases. The cGMP response was only restored by inhibition of PDE6. Conclusions: When taken together, these results suggest that site-specific inhibition of PDE2A and PDE6D at the outer mitochondrial membrane may provide a therapeutic target to ameliorate cardiac sympathetic impairment during the onset of hypertension.

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Ritawidya, Wenzel, Teodoro, Toussaint, Kranz, Deuther-Conrad, Dukic-Stefanovic, Ludwig, Scheunemann, and Brust. "Radiosynthesis and Biological Investigation of a Novel Fluorine-18 Labeled Benzoimidazotriazine- Based Radioligand for the Imaging of Phosphodiesterase 2A with Positron Emission Tomography." Molecules 24, no. 22 (November 15, 2019): 4149. http://dx.doi.org/10.3390/molecules24224149.

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A specific radioligand for the imaging of cyclic nucleotide phosphodiesterase 2A (PDE2A) via positron emission tomography (PET) would be helpful for research on the physiology and disease-related changes in the expression of this enzyme in the brain. In this report, the radiosynthesis of a novel PDE2A radioligand and the subsequent biological evaluation were described. Our prospective compound 1-(2-chloro-5-methoxy phenyl)-8-(2-fluoropyridin-4-yl)-3- methylbenzo[e]imidazo[5,1-c][1,2,4]triazine, benzoimidazotriazine (BIT1) (IC50 PDE2A = 3.33 nM; 16-fold selectivity over PDE10A) was fluorine-18 labeled via aromatic nucleophilic substitution of the corresponding nitro precursor using the K[18F]F‐K2.2.2‐carbonate complex system. The new radioligand [18F]BIT1 was obtained with a high radiochemical yield (54 ± 2%, n = 3), a high radiochemical purity (≥99%), and high molar activities (155–175 GBq/μmol, n = 3). In vitro autoradiography on pig brain cryosections exhibited a heterogeneous spatial distribution of [18F]BIT1 corresponding to the known pattern of expression of PDE2A. The investigation of in vivo metabolism of [18F]BIT1 in a mouse revealed sufficient metabolic stability. PET studies in mouse exhibited a moderate brain uptake of [18F]BIT1 with a maximum standardized uptake value of ~0.7 at 5 minutes p.i. However, in vivo blocking studies revealed a non-target specific binding of [18F]BIT1. Therefore, further structural modifications are needed to improve target selectivity.

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Gong, Wei, Lei Yang, Yuanyuan Wang, Jianfeng Xian, Fuman Qiu, Li Liu, Mingzhu Lin, Yingyi Feng, Yifeng Zhou, and Jiachun Lu. "Analysis of Survival-Related lncRNA Landscape Identifies A Role for LINC01537 in Energy Metabolism and Lung Cancer Progression." International Journal of Molecular Sciences 20, no. 15 (August 1, 2019): 3713. http://dx.doi.org/10.3390/ijms20153713.

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Many long non-coding RNAs (lncRNAs) have emerged as good biomarkers and potential therapeutic targets for various cancers. We aimed to get a detailed understanding of the lncRNA landscape that is associated with lung cancer survival. A comparative analysis between our RNA sequencing (RNA-seq) data and TCGA datasets was conducted to reveal lncRNAs with significant correlations with lung cancer survival and then the association of the most promising lncRNA was validated in a cohort of 243 lung cancer patients. Comparing RNA-seq data with TCGA ones, 84 dysregulated lncRNAs were identified in lung cancer tissues, among which 10 lncRNAs were significantly associated with lung cancer survival. LINC01537 was the most significant one (p = 2.95 × 10−6). Validation analysis confirmed the downregulation of LINC01537 in lung cancer. LINC01537 was observed to inhibit tumor growth and metastasis. It also increased cellular sensitivity to nilotinib. PDE2A (phosphodiesterase 2A) was further identified to be a target of LINC01537 and it was seen that LINC01537 promoted PDE2A expression via RNA–RNA interaction to stabilize PDE2A mRNA and thus echoed effects of PDE2A on energy metabolism including both Warburg effect and mitochondrial respiration. Other regulators of tumor energy metabolism were also affected by LINC01537. These results elucidate a suppressed role of LINC01537 in lung cancer development involving tumor metabolic reprogramming, and we believe that it might be a biomarker for cancer survival prediction and therapy.

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Lu, Jia Yang, and Marion B. Sewer. "p54nrb/NONO Regulates Cyclic AMP-Dependent Glucocorticoid Production by Modulating Phosphodiesterase mRNA Splicing and Degradation." Molecular and Cellular Biology 35, no. 7 (January 20, 2015): 1223–37. http://dx.doi.org/10.1128/mcb.00993-14.

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Glucocorticoid production in the adrenal cortex is activated in response to an increase in cyclic AMP (cAMP) signaling. The nuclear protein p54nrb/NONO belongs to theDrosophilabehavior/human splicing (DBHS) family and has been implicated in several nuclear processes, including transcription, splicing, and RNA export. We previously identified p54nrb/NONO as a component of a protein complex that regulates the transcription of CYP17A1, a gene required for glucocorticoid production. Based on the multiple mechanisms by which p54nrb/NONO has been shown to control gene expression and the ability of the protein to be recruited to the CYP17A1 promoter, we sought to further define the molecular mechanism by which p54nrb/NONO confers optimal cortisol production. We show here that silencing p54nrb/NONO expression in H295R human adrenocortical cells decreases the ability of the cells to increase intracellular cAMP production and subsequent cortisol biosynthesis in response to adrenocorticotropin hormone (ACTH) stimulation. Interestingly, the expression of multiple phosphodiesterase (PDE) isoforms, including PDE2A, PDE3A, PDE3B, PDE4A, PDE4D, and PDE11A, was induced in p54nrb/NONO knockdown cells. Investigation of the mechanism by which silencing of p54nrb/NONO led to increased expression of select PDE isoforms revealed that p54nrb/NONO regulates the splicing of a subset of PDE isoforms. Importantly, we also identify a role for p54nrb/NONO in regulating the stability of PDE transcripts by facilitating the interaction between the exoribonuclease XRN2 and select PDE transcripts. In summary, we report that p54nrb/NONO modulates cAMP-dependent signaling, and ultimately cAMP-stimulated glucocorticoid biosynthesis by regulating the splicing and degradation of PDE transcripts.

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Keefer, Christopher E., and George Chang. "The use of matched molecular series networks for cross target structure activity relationship translation and potency prediction." MedChemComm 8, no. 11 (2017): 2067–78. http://dx.doi.org/10.1039/c7md00465f.

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Tanaka, Saori, Rina Tanaka, Saeko Harada, Yuka Kohda, Hitoshi Matsumura, Chikao Shimamoto, Yukinori Sawabe, et al. "A PKG inhibitor increases Ca2+-regulated exocytosis in guinea pig antral mucous cells: cAMP accumulation via PDE2A inhibition." American Journal of Physiology-Gastrointestinal and Liver Physiology 304, no. 9 (May 1, 2013): G773—G780. http://dx.doi.org/10.1152/ajpgi.00281.2012.

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In antral mucous cells, acetylcholine (ACh, 1 μM) activates Ca2+-regulated exocytosis, consisting of an initial peak that declines rapidly (initial transient phase) followed by a second slower decline (late phase) lasting during ACh stimulation. The addition of 8-bromo-cGMP (8-BrcGMP) enhanced the initial phase, which was inhibited by the protein kinase G (PKG) inhibitor guanosine 3′,5′-cyclic monophosphorothoiate, β-phenyl-1, N2-etheno-8-bromo, Rp-isomer, sodium salt (Rp-8-BrPETcGMPS, 100 nM). However, Rp-8-BrPETcGMPS produced a delayed, but transient, increase in the exocytotic frequency during the late phase that was abolished by a protein kinase A (PKA) inhibitor (PKI-amide), suggesting that Rp-8-BrPETcGMPS accumulates cAMP. The cGMP-dependent phosphodiesterase 2 (PDE2), which degrades cAMP, may exist in antral mucous cells. The PDE2 inhibitor BAY-60-7550 (250 nM) mimicked the effect of Rp-8-BrPETcGMPS on ACh-stimulated exocytosis. Measurement of the cGMP and cAMP contents in antral mucosae revealed that ACh stimulates the accumulation of cGMP and that BAY-60-7550 accumulates cAMP similarly to Rp-8-BrPETcGMPS during ACh stimulation. Analyses of Western blot and immunohistochemistry demonstrated that PDE2A exists in antral mucous cells. In conclusion, Rp-8-BrPETcGMPS accumulates cAMP by inhibiting PDE2 in ACh-stimulated antral mucous cells, leading to the delayed, but transient, increase in the frequency of Ca2+-regulated exocytosis. PDE2 may prevent antral mucous cells from excessive mucin secretion caused by the cAMP accumulation.

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Ding, Hao, Xiao-Xing Xiong, Guan-Lan Fan, Yue-Xiong Yi, Yu-Rou Chen, Jing-Tao Wang, and Wei Zhang. "The New Biomarker for Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma (CESC) Based on Public Database Mining." BioMed Research International 2020 (April 13, 2020): 1–9. http://dx.doi.org/10.1155/2020/5478574.

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To reconstruct the ceRNA biological network of cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) and to select an appropriate mRNA as a biomarker that could be used for CESC early diagnosis and prognosis evaluation. We downloaded CESC data from the TCGA public database, and statistical analysis was conducted with the R software to find out differential expressed genes encoding for lncRNAs, miRNAs, and mRNAs. The differentially expressed mRNAs (DEmRNAs) screened in the ceRNA network were analyzed for survival to find the mRNAs with significantly linked to the survival prognosis. These mRNAs were searched in the Pathological Atlas to identify the final appropriate mRNAs. Differential expression analysis revealed 773 lncRNAs, 94 miRNAs, and 2466 mRNAs. Survival analysis of DEmRNAs in the ceRNA network indicated that ADGRF4, ANXA8L1, HCAR3, IRF6, and PDE2A (P<0.05) were negatively correlated with survival time. Verification of these six DEmRNAs in the Pathology Atlas indicated that PDE2A was a possible biomarker for CESC patients. PDE2A might be a biomarker for early diagnosis and prognosis evaluation of CESC patients, but due to the lack of available data, further studies may be needed for confirmation.

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Russwurm, Corina, Georg Zoidl, Doris Koesling, and Michael Russwurm. "Dual Acylation of PDE2A Splice Variant 3." Journal of Biological Chemistry 284, no. 38 (July 24, 2009): 25782–90. http://dx.doi.org/10.1074/jbc.m109.017194.

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Wang, Jianjie, Susan Bingaman, and Virginia H. Huxley. "Intrinsic sex-specific differences in microvascular endothelial cell phosphodiesterases." American Journal of Physiology-Heart and Circulatory Physiology 298, no. 4 (April 2010): H1146—H1154. http://dx.doi.org/10.1152/ajpheart.00252.2009.

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The importance of gonadal hormones in the regulation of vascular function has been documented. An alternate and essential contribution of the sex chromosomes to sex differences in vascular function is poorly understood. We reported previously sex differences in microvessel permeability ( Ps) responses to adenosine that were mediated by the cAMP signaling pathway (Wang J, PhD thesis, 2005; Wang J and Huxley V, Proceedings of the VIII World Congress of Microcirculation, 2007 ; Wang J and Huxley VH, Am J Physiol Heart Circ Physiol 291: H3094–H3105, 2006). The two cyclic nucleotides, cAMP and cGMP, central to the regulation of vascular barrier integrity, are hydrolyzed by phosphodiesterases (PDE). We hypothesized that microvascular endothelial cells (EC) would retain intrinsic and inheritable sexually dimorphic genes with respect to the PDEs modulating EC barrier function. Primary cultured microvascular EC from skeletal muscles isolated from male and female rats, respectively, were used. SRY (a sex-determining region Y gene) mRNA expression was observed exclusively in male, not female, cells. The predominant isoform among PDE1–5, present in both XY and XX EC, was PDE4. Expression mRNA levels of PDE1A (male > female) and PDE3B (male < female) were sex dependent; PDE2A, PDE4D, and PDE5A were sex independent. Barrier function, Ps, was determined from measures of albumin flux across confluent primary cultured microvessel XY and XX EC monolayers. Consistent with intact in situ microvessels, basal monolayer Ps did not differ between XY (1.7 ± 0.2 × 10−6 cm/s; n = 8) and XX (1.8 ± 0.1 × 10−6 cm/s; n = 10) EC. Cilostazol, a PDE3 inhibitor, reduced (11%, P < 0.05) Ps in XX, not XY, cells. These findings demonstrate the presence and maintenance of intrinsic sex-related differences in gene expression and cellular phenotype by microvascular EC in a gonadal-hormone-free environment. Furthermore, intrinsic cell-sex likely contributes significantly to sexual dimorphism in cardiovascular function.

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Schmidt, Eric P., Mahendra Damarla, Otgonchimeg Rentsendorj, Laura E. Servinsky, Bing Zhu, Aigul Moldobaeva, Alfredo Gonzalez, Paul M. Hassoun, and David B. Pearse. "Soluble guanylyl cyclase contributes to ventilator-induced lung injury in mice." American Journal of Physiology-Lung Cellular and Molecular Physiology 295, no. 6 (December 2008): L1056—L1065. http://dx.doi.org/10.1152/ajplung.90329.2008.

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High tidal volume (HVT) ventilation causes pulmonary endothelial barrier dysfunction. HVT ventilation also increases lung nitric oxide (NO) and cGMP. NO contributes to HVT lung injury, but the role of cGMP is unknown. In the current study, ventilation of isolated C57BL/6 mouse lungs increased perfusate cGMP as a function of VT. Ventilation with 20 ml/kg VT for 80 min increased the filtration coefficient ( Kf), an index of vascular permeability. The increased cGMP and Kf caused by HVT were attenuated by nitric oxide synthase (NOS) inhibition and in lungs from endothelial NOS knockout mice. Inhibition of soluble guanylyl cyclase (sGC) in wild-type lungs (10 μM ODQ) also blocked cGMP generation and inhibited the increase in Kf, suggesting an injurious role for sGC-derived cGMP. sGC inhibition also attenuated lung Evans blue dye albumin extravasation and wet-to-dry weight ratio in an anesthetized mouse model of HVT injury. Additional activation of sGC (1.5 μM BAY 41-2272) in isolated lungs at 40 min increased cGMP production and Kf in lungs ventilated with 15 ml/kg VT. HVT endothelial barrier dysfunction was attenuated with a nonspecific phosphodiesterase (PDE) inhibitor (100 μM IBMX) as well as an inhibitor (10 μM BAY 60-7550) specific for the cGMP-stimulated PDE2A. Concordantly, we found a VT-dependent increase in lung cAMP hydrolytic activity and PDE2A protein expression with a decrease in lung cAMP concentration that was blocked by BAY 60-7550. We conclude that HVT-induced endothelial barrier dysfunction resulted from a simultaneous increase in NO/sGC-derived cGMP and PDE2A expression causing decreased cAMP.

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Wang, Junnan, Mingyi Wu, Xiaowen Lin, Yun Li, and Zhijian Fu. "Low-Concentration Oxygen/Ozone Treatment Attenuated Radiculitis and Mechanical Allodynia via PDE2A-cAMP/cGMP-NF-κB/p65 Signaling in Chronic Radiculitis Rats." Pain Research and Management 2018 (December 13, 2018): 1–8. http://dx.doi.org/10.1155/2018/5192814.

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Background. Oxygen/ozone therapy is a minimally invasive technique for the treatment of radiculitis from lumbar disc herniation. This study aimed at investigating whether intrathecal administration of low-concentration oxygen/ozone could attenuate chronic radiculitis and mechanical allodynia after noncompressive lumbar disc herniation and at elucidating the underlying mechanisms. Methods. First, we transplanted autologous nucleus pulposus into dorsal root ganglions to establish chronic radiculitis in rats. Then, filtered oxygen or oxygen/ozone (10, 20, or 30 μg/mL) was intrathecally injected on day 1 after surgery. The ipsilateral paw withdrawal thresholds (PWTs) to mechanical stimuli were tested daily with von Frey filaments. The expression of the tumor necrosis factor- (TNF-) α, interleukin- (IL-) 1β, IL-6, cyclic adenosine monophosphate (cAMP), cyclic guanosine monophosphate (cGMP), phosphodiesterase 2A (PDE2A), and nuclear factor- (NF-) κB/p65 in spinal dorsal horns was measured by enzyme-linked immunosorbent assay, polymerase chain reaction, and western blot on day 7 after surgery. Results. Chronic radiculitis was established in rats. Intrathecal administration of 10 μg/mL, 20 μg/mL, or 30 μg/mL oxygen/ozone significantly attenuated the decreased mechanical PWTs, downregulated the overexpression of spinal TNF-α, IL-1β, and IL-6, and increased the expression of cGMP and cAMP in chronic radiculitis rats. In addition, the effects of treatment with 20 μg/mL oxygen/ozone were greater than the effects of the 10 μg/mL or 30 μg/mL doses. Moreover, intrathecal administration of 20 μg/mL oxygen/ozone reversed the increased levels of spinal PDE2A and NF-κB/p65 mRNA and protein expressions in rats with chronic radiculitis. Conclusion. Intrathecal administration of low-concentration oxygen/ozone alleviated mechanical allodynia and attenuated radiculitis, likely by a PDE2A-cGMP/cAMP-NF-κB/p65 signaling pathway in chronic radiculitis rats.

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Durand, Julien, Antoine Lampron, Tania L. Mazzuco, Audrey Chapman, and Isabelle Bourdeau. "Characterization of Differential Gene Expression in Adrenocortical Tumors Harboring β-Catenin (CTNNB1) Mutations." Journal of Clinical Endocrinology & Metabolism 96, no. 7 (July 1, 2011): E1206—E1211. http://dx.doi.org/10.1210/jc.2010-2143.

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Abstract Background: Mutations of β-catenin gene (CTNNB1) are frequent in adrenocortical adenomas (AA) and adrenocortical carcinomas (ACC). However, the target genes of β-catenin have not yet been identified in adrenocortical tumors. Objective: Our objective was to identify genes deregulated in adrenocortical tumors harboring CTNNB1 genetic alterations and nuclear accumulation of β-catenin. Methods: Microarray analysis identified a dataset of genes that were differently expressed between AA with CTNNB1 mutations and wild-type (WT) tumors. Within this dataset, the expression profiles of five genes were validated by real time-PCR (RT-PCR) in a cohort of 34 adrenocortical tissues (six AA and one ACC with CTNNB1 mutations, 13 AA and four ACC with WT CTNNB1, and 10 normal adrenal glands) and two human ACC cell lines. We then studied the effects of suppressing β-catenin transcriptional activity with the T-cell factor/β-catenin inhibitors PKF115-584 and PNU74654 on gene expression in H295R and SW13 cells. Results: RT-PCR analysis confirmed the overexpression of ISM1, RALBP1, and PDE2A and the down-regulation of PHYHIP in five of six AA harboring CTNNB1 mutations compared with WT AA (n = 13) and normal adrenal glands (n = 10). RALBP1 and PDE2A overexpression was also confirmed at the protein level by Western blotting analysis in mutated tumors. ENC1 was specifically overexpressed in three of three AA harboring CTNNB1 point mutations. mRNA expression and protein levels of RALBP1, PDE2A, and ENC1 were decreased in a dose-dependent manner in H295R cells after treatment with PKF115-584 or PNU74654. Conclusion: This study identified candidate genes deregulated in CTNNB1-mutated adrenocortical tumors that may lead to a better understanding of the role of the Wnt-β-catenin pathway in adrenocortical tumorigenesis.

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Fryknäs, Mårten, Linda Rickardson, Malin Wickström, Sumeer Dhar, Henrik Lövborg, Joachim Gullbo, Peter Nygren, Mats G. Gustafsson, Anders Isaksson, and Rolf Larsson. "Phenotype-Based Screening of Mechanistically Annotated Compounds in Combination with Gene Expression and Pathway Analysis Identifies Candidate Drug Targets in a Human Squamous Carcinoma Cell Model." Journal of Biomolecular Screening 11, no. 5 (April 28, 2006): 457–68. http://dx.doi.org/10.1177/1087057106288048.

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The squamous cell carcinoma HeLa cell line and an epithelial cell line hTERT-RPE with a nonmalignant phenotype were interrogated for HeLa cell selectivity in response to 1267 annotated compounds representing 56 pharmacological classes. Selective cytotoxic activity was observed for 14 of these compounds dominated by cyclic adenosine monophosphate (cAMP) selective phosphodiesterase (PDE) inhibitors, which tended to span a representation of the chemical descriptor space of the library. The PDE inhibitors induced delayed cell death with features compatible with classical apoptosis. The PDE inhibitors were largely inactive when tested against a cell line panel consisting of hematological and nonsquamous epithelial phenotypes. 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. The pathway analysis software PathwayAssist was subsequently used to extract a list of proteins and small molecules retrieved from Medline abstracts associated with the hit compounds. The resulting list consisted of major parts of the cAMP–protein kinase A pathway linking to ERK, P38, and AKT. This molecular network may provide a basis for further exploitation of novel candidate targets for the treatment of squamous cell carcinoma.

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Juilfs, D. M., W. K. Sonnenburg, S. Seraji, H.-I. Fülle, D. L. Garbers, M. D. Houslay, and J. A. Beavo. "IDENTIFICATION OF A NEW PDE2A ISOFORM AND EXPRESSION OF PDE2 IN A SUBSET OF OLFACTORY NEURONS & GASTROINTESTINAL CELLS." Biochemical Society Transactions 24, no. 4 (November 1, 1996): 624S. http://dx.doi.org/10.1042/bst024624s.

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Montoya-Durango, Diego, Mary Nancy Walter, Walter Rodriguez, Yali Wang, Julia H. Chariker, Eric C. Rouchka, Claudio Maldonado, Shirish Barve, Craig J. McClain, and Leila Gobejishvili. "Dysregulated Cyclic Nucleotide Metabolism in Alcohol-Associated Steatohepatitis: Implications for Novel Targeted Therapies." Biology 12, no. 10 (October 10, 2023): 1321. http://dx.doi.org/10.3390/biology12101321.

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Background: Cyclic nucleotides are second messengers, which play significant roles in numerous biological processes. Previous work has shown that cAMP and cGMP signaling regulates various pathways in liver cells, including Kupffer cells, hepatocytes, hepatic stellate cells, and cellular components of hepatic sinusoids. Importantly, it has been shown that cAMP levels and enzymes involved in cAMP homeostasis are affected by alcohol. Although the role of cyclic nucleotide signaling is strongly implicated in several pathological pathways in liver diseases, studies describing the changes in genes regulating cyclic nucleotide metabolism in ALD are lacking. Methods: Male C57B/6 mice were used in an intragastric model of alcohol-associated steatohepatitis (ASH). Liver injury, inflammation, and fibrogenesis were evaluated by measuring plasma levels of injury markers, liver tissue cytokines, and gene expression analyses. Liver transcriptome analysis was performed to examine the effects of alcohol on regulators of cyclic AMP and GMP levels and signaling. cAMP and cGMP levels were measured in mouse livers as well as in livers from healthy human donors and patients with alcohol-associated hepatitis (AH). Results: Our results show significant changes in several phosphodiesterases (PDEs) with specificity to degrade cAMP (Pde4a, Pde4d, and Pde8a) and cGMP (Pde5a, Pde6d, and Pde9a), as well as dual-specificity PDEs (Pde1a and Pde10a) in ASH mouse livers. Adenylyl cyclases (ACs) 7 and 9, which are responsible for cAMP generation, were also affected by alcohol. Importantly, adenosine receptor 1, which has been implicated in the pathogenesis of liver diseases, was significantly increased by alcohol. Adrenoceptors 1 and 3 (Adrb), which couple with stimulatory G protein to regulate cAMP and cGMP signaling, were significantly decreased. Additionally, beta arrestin 2, which interacts with cAMP-specific PDE4D to desensitize G-protein-coupled receptor to generate cAMP, was significantly increased by alcohol. Notably, we observed that cAMP levels are much higher than cGMP levels in the livers of humans and mice; however, alcohol affected them differently. Specifically, cGMP levels were higher in patients with AH and ASH mice livers compared with controls. As expected, these changes in liver cyclic nucleotide signaling were associated with increased inflammation, steatosis, apoptosis, and fibrogenesis. Conclusions: These data strongly implicate dysregulated cAMP and cGMP signaling in the pathogenesis of ASH. Future studies to identify changes in these regulators in a cell-specific manner could lead to the development of novel targeted therapies for ASH.

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Petersen, Tonny Studsgaard, Martin Stahlhut, and Claus Yding Andersen. "Phosphodiesterases in the rat ovary: effect of cAMP in primordial follicles." REPRODUCTION 150, no. 1 (July 2015): 11–20. http://dx.doi.org/10.1530/rep-14-0436.

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Phosphodiesterases (PDEs) are important regulators of the intracellular cAMP concentration, which is a central second messenger that affects a multitude of intracellular functions. In the ovaries, cAMP exerts diverse functions, including regulation of ovulation and it has been suggested that augmented cAMP levels stimulate primordial follicle growth. The present study examined the gene expression, enzyme activity and immunolocalization of the different cAMP hydrolysing PDEs families in the rat ovary. Further, the effect of PDE4 inhibition on primordial follicle activation in cultured neonatal rat ovaries was also evaluated. We found varied expression of all eight families in the ovary with Pde7b and Pde8a having the highest expression each accounting for more than 20% of the total PDE mRNA. PDE4 accounted for 15–26% of the total PDE activity. Immunoreactive PDE11A was found in the oocytes and PDE2A in the corpora lutea. Incubating neonatal rat ovaries with PDE4 inhibitors did not increase primordial follicle activation or change the expression of the developing follicle markers Gdf9, Amh, Inha, the proliferation marker Mki67 or the primordial follicle marker Tmeff2. In addition, the cAMP analogue 8-bromo-cAMP did not increase AKT1 or FOXO3A phosphorylation associated with follicle activation or increase the expression of Kitlg known to be associated with follicle differentiation but did increase the Tmeff2, Mki67 and Inha expression in a dose-dependent manner. In conclusion, this study shows that both Pde7b and Pde8a are highly expressed in the rodent ovary and that PDE4 inhibition does not cause an increase in primordial follicle activation.

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Ma, Y. S., Y. H. Xie, D. Ma, J. J. Zhang, and H. J. Liu. "Shear stress-induced MMP1 and PDE2A expressions in coronary atherosclerosis." Bratislava Medical Journal 122, no. 04 (2021): 287–92. http://dx.doi.org/10.4149/bll_2021_048.

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Doummar, Diane, Christel Dentel, Romane Lyautey, Julia Metreau, Boris Keren, Nathalie Drouot, Ludivine Malherbe, et al. "Biallelic PDE2A variants: a new cause of syndromic paroxysmal dyskinesia." European Journal of Human Genetics 28, no. 10 (May 28, 2020): 1403–13. http://dx.doi.org/10.1038/s41431-020-0641-9.

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Adderley, Shaquria P., Eileen A. Dufaux, Meera Sridharan, Elizabeth A. Bowles, Madelyn S. Hanson, Alan H. Stephenson, Mary L. Ellsworth, and Randy S. Sprague. "Iloprost- and isoproterenol-induced increases in cAMP are regulated by different phosphodiesterases in erythrocytes of both rabbits and humans." American Journal of Physiology-Heart and Circulatory Physiology 296, no. 5 (May 2009): H1617—H1624. http://dx.doi.org/10.1152/ajpheart.01226.2008.

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Activation of the G protein Gs results in increases in cAMP, a necessary step in the pathway for ATP release from rabbit and human erythrocytes. In all cells, the level of cAMP is the product of its synthesis by adenylyl cyclase and its hydrolysis by phosphodiesterases (PDEs). Both iloprost (Ilo), a PGI2 analog, and isoproterenol (Iso), a β-agonist, stimulate receptor-mediated increases in cAMP in rabbit and human erythrocytes. However, the specific PDEs associated with each of these signaling pathways in the erythrocyte have not been fully characterized. Previously, we reported that PDE3B is present in rabbit and human erythrocyte membranes and that PDE3 inhibitors potentiate Ilo-induced increases in cAMP. Here we report that inhibitors of either PDE2 or PDE4, erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA) and rolipram, respectively, potentiate Iso-induced increases in cAMP in rabbit and human erythrocytes. Importantly, these inhibitors had no effect on cAMP increases associated with the incubation of erythrocytes with Ilo. In addition, we establish, for the first time, the presence of PDE2A protein in rabbit and human erythrocyte membranes. Finally, we determined that preincubation of human erythrocytes with EHNA and rolipram together potentiate Iso-induced ATP release, whereas preincubation with cilostazol enhances Ilo-induced release of ATP. These results are consistent with the hypothesis that, in rabbit and human erythrocytes, Ilo-induced increases in cAMP and ATP release are regulated by PDE3, whereas those associated with Iso are regulated by the activities of both PDE2 and PDE4. These studies demonstrate that PDE activity in these cells is localized to specific signaling pathways.

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Trabanco, Andrés A., Peter Buijnsters, and Frederik J. R. Rombouts. "Towards selective phosphodiesterase 2A (PDE2A) inhibitors: a patent review (2010 - present)." Expert Opinion on Therapeutic Patents 26, no. 8 (June 30, 2016): 933–46. http://dx.doi.org/10.1080/13543776.2016.1203902.

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Farmer, Reagan, Steven D. Burbano, Neema S. Patel, Angelo Sarmiento, Abigail J. Smith, and Michy P. Kelly. "Phosphodiesterases PDE2A and PDE10A both change mRNA expression in the human brain with age, but only PDE2A changes in a region-specific manner with psychiatric disease." Cellular Signalling 70 (June 2020): 109592. http://dx.doi.org/10.1016/j.cellsig.2020.109592.

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Fernández-Fernández, Diego, Holger Rosenbrock, and Katja S. Kroker. "Inhibition of PDE2A, but not PDE9A, modulates presynaptic short-term plasticity measured by paired-pulse facilitation in the CA1 region of the hippocampus." Synapse 69, no. 10 (July 29, 2015): 484–96. http://dx.doi.org/10.1002/syn.21840.

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Zlobin, Alexander S., Natalia A. Volkova, Natalia A. Zinovieva, Baylar S. Iolchiev, Vugar A. Bagirov, Pavel M. Borodin, Tatiana I. Axenovich, and Yakov A. Tsepilov. "Loci Associated with Negative Heterosis for Viability and Meat Productivity in Interspecific Sheep Hybrids." Animals 13, no. 1 (January 3, 2023): 184. http://dx.doi.org/10.3390/ani13010184.

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Negative heterosis can occur on different economically important traits, but the exact biological mechanisms of this phenomenon are still unknown. The present study focuses on determining the genetic factors associated with negative heterosis in interspecific hybrids between domestic sheep (Ovis aries) and argali (Ovis ammon). One locus (rs417431015) associated with viability and two loci (rs413302370, rs402808951) associated with meat productivity were identified. One gene (ARAP2) was prioritized for viability and three for meat productivity (PDE2A, ARAP1, and PCDH15). The loci associated with meat productivity were demonstrated to fit the overdominant inheritance model and could potentially be involved int negative heterosis mechanisms.

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Naganawa, M., R. N. Waterhouse, N. Nabulsi, S. F. Lin, D. Labaree, J. Ropchan, S. Tarabar, et al. "First-in-Human Assessment of the Novel PDE2A PET Radiotracer 18F-PF-05270430." Journal of Nuclear Medicine 57, no. 9 (April 21, 2016): 1388–95. http://dx.doi.org/10.2967/jnumed.115.166850.

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Haidar, Zahraa, Nadine Jalkh, Sandra Corbani, Joelle Abou‐Ghoch, Ali Fawaz, Cybel Mehawej, and Eliane Chouery. "A Homozygous Splicing Mutation in PDE2A in a Family With Atypical Rett Syndrome." Movement Disorders 35, no. 5 (March 20, 2020): 896–99. http://dx.doi.org/10.1002/mds.28023.

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Wunder, Frank, Mark Jean Gnoth, Andreas Geerts, and Daniel Barufe. "A Novel PDE2A Reporter Cell Line: Characterization of the Cellular Activity of PDE Inhibitors." Molecular Pharmaceutics 6, no. 1 (December 2, 2008): 326–36. http://dx.doi.org/10.1021/mp800127n.

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Salpietro, Vincenzo, Belen Perez-Dueñas, Kosuke Nakashima, Victoria San Antonio-Arce, Andreea Manole, Stephanie Efthymiou, Jana Vandrovcova, et al. "A homozygous loss-of-function mutation in PDE2A associated to early-onset hereditary chorea." Movement Disorders 33, no. 3 (February 2, 2018): 482–88. http://dx.doi.org/10.1002/mds.27286.

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Claire, Nicolas, Shittl Julia, Pertuiset Claire, Mehel Hind, Courilleau Delphine, Jullian Jean-Christophe, Cresteil Thierry, et al. "0310 Assay development and high-throughput screening to identify PDE2A activators to treat heart failure." Archives of Cardiovascular Diseases Supplements 6 (April 2014): 43. http://dx.doi.org/10.1016/s1878-6480(14)71379-5.

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Zhang, Zhao-Xiong, Qiang Han, and Shu-Ye Liu. "Clinical significance of PDE2A in prognosis and immune infiltration in gastrointestinal cancer based on bioinformatics analysis." World Chinese Journal of Digestology 29, no. 18 (September 28, 2021): 1055–63. http://dx.doi.org/10.11569/wcjd.v29.i18.1055.

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Li, San-Zhong, Kai-Xi Ren, Jing Zhao, Shuang Wu, Juan Li, Jian Zang, Zhou Fei, and Jun-Long Zhao. "miR-139/PDE2A-Notch1 feedback circuit represses stemness of gliomas by inhibiting Wnt/β-catenin signaling." International Journal of Biological Sciences 17, no. 13 (2021): 3508–21. http://dx.doi.org/10.7150/ijbs.62858.

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Sadhu, Krishna, Kelly Hensley, Vince A. Florio, and Sharon L. Wolda. "Differential Expression of the Cyclic GMP-stimulated Phosphodiesterase PDE2A in Human Venous and Capillary Endothelial Cells." Journal of Histochemistry & Cytochemistry 47, no. 7 (July 1999): 895–905. http://dx.doi.org/10.1177/002215549904700707.

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Cann, M. J. "Sodium regulation of GAF domain function." Biochemical Society Transactions 35, no. 5 (October 25, 2007): 1032–34. http://dx.doi.org/10.1042/bst0351032.

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Abstract:

Cyclic nucleotide PDEs (phosphodiesterases) regulate cellular levels of cAMP and cGMP by controlling the rate of degradation. Several mammalian PDE isoforms possess N-terminal GAF (found in cGMP PDEs, Anabaena adenylate cyclases and Escherichia coli FhlA; where FhlA is formate hydrogen lyase transcriptional activator) domains that bind cyclic nucleotides. Similarly, the CyaB1 and CyaB2 ACs (adenylate cyclases) of the cyanobacterium Anabaena PCC 7120 bind cAMP through one (CyaB1) or two (CyaB2) N-terminal GAF domains and mediate autoregulation of the AC domain. Sodium inhibits the activity of CyaB1, CyaB2 and mammalian PDE2A in vitro through modulation of GAF domain function. Furthermore, genetic ablation of cyaB1 and cyaB2 gives rise to Anabaena strains defective in homoeostasis at limiting sodium. Sodium regulation of GAF domain function has therefore been conserved since the eukaryotic/prokaryotic divergence. The GAF domain is the first identified protein domain to directly sense and signal changes in environmental sodium.

Journal articles on the topic 'PDE2A'

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