Bibliografie tematiche / PDE2A

Letteratura scientifica selezionata sul tema "PDE2A"

Autore: Grafiati

Pubblicato: 6 luglio 2024

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Articoli di riviste sul tema "PDE2A":

Skryabin, Egor B., Kirstie A. De Jong, Hariharan Subramanian, Nadja I. Bork, Alexander Froese, Boris V. Skryabin e 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, n. 11 (4 giugno 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.

Ivey, F. Douglas, Lili Wang, Didem Demirbas, Christina Allain e Charles S. Hoffman. "Development of a Fission Yeast-Based High-Throughput Screen to Identify Chemical Regulators of cAMP Phosphodiesterases". Journal of Biomolecular Screening 13, n. 1 (26 novembre 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)

Manns, J. M., K. J. Brennan, S. B. Sheth e R. W. Colman. "Differential Regulation of Human Platelet Responses by cGMP Inhibited and Stimulated cAMP Phosphodiesterases". Thrombosis and Haemostasis 87, n. 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.

Carvalho, Thays Maria da Conceição Silva, Silvia Cardarelli, Mauro Giorgi, Andrea Lenzi, Andrea M. Isidori e Fabio Naro. "Phosphodiesterases Expression during Murine Cardiac Development". International Journal of Molecular Sciences 22, n. 5 (5 marzo 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.

Chen, Ling, Suying Cui, Haiyang Yu, Gaowen Li, Na Liu, Qiang Wu, Han-Ting Zhang, James M. O’Donnell, Gang Wang e Ying Xu. "Reduced phosphodiesterase-2 activity in the amygdala results in anxiolytic-like effects on behavior in mice". Journal of Psychopharmacology 33, n. 5 (5 marzo 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.

Chen, Lin, Jinchi Zhou, Zifeng Zhao, Yuhan Zhu, Jinliang Xing, Jiaze An e 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, n. 1 (23 dicembre 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.

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, n. 8 (21 aprile 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.

Matthiesen, Karina, e Jacob Nielsen. "Binding of cyclic nucleotides to phosphodiesterase 10A and 11A GAF domains does not stimulate catalytic activity". Biochemical Journal 423, n. 3 (12 ottobre 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.

Ritawidya, Ludwig, Briel, Brust e 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, n. 15 (31 luglio 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.

Rentsendorj, Otgonchimeg, Mahendra Damarla, Neil R. Aggarwal, Ji-Young Choi, Laura Johnston, Franco R. D'Alessio, Michael T. Crow e 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, n. 2 (agosto 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.

Più fonti

Tesi sul tema "PDE2A":

Lobo, Miguel Gonçalo de Oliveira Jones Ferrão. "Role of PDE2A in cAMP/PKA signaling compartmentalization". Thesis, University of Oxford, 2018. http://ora.ox.ac.uk/objects/uuid:e647c600-48e4-4222-85e7-019f91745608.

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Background and Aims : cAMP/PKA signaling is compartmentalized within the cell, with tight spatial and temporal control of signal propagation underpinning specificity of response. The cAMP-degrading enzymes, phosphodiesterases (PDEs), are key regulators of this process. They are situated in specific subcellular domains within which they control local cAMP levels. Several components of the cAMP/PKA cascade have been identified in different mitochondrial compartments, including isoform 2 of PDE2A and multiple A-kinase anchoring proteins, suggesting the presence of multiple cAMP/PKA signaling domains within the organelle. The aims of this project were to examine the role of PDE2A in cAMP/PKA signaling compartmentalization and its biological function, with a particular focus on its role at the mitochondria. Methods : Real-time PCR and fluorescence imaging were used to assess PDE2A expression and localization in different cell lines and tissues. Co-immunoprecipitation (Co-IP) was used to validate PDE2A2 interactors. Co-IP, electron microscopy and live-cell imaging were used to explore the role of PDE2A2 at the mitochondria. Fluorescence Resonance Energy Transfer (FRET) was used to investigate the involvement of PDE2A on endoplasmic reticulum (ER) Ca²⁺ handling and local cAMP/PKA dynamics. Results : PDE2A2 localizes to the outer mitochondria membrane and intermembrane space and it interacts with several mitochondria and ER proteins, including components of the MINOS (mitochondrial inner membrane organizing system) complex and Caveolins. Functionally, PDE2A2 is involved in mitochondria degradation by mitophagy while PDE2A1 seems to be involved in the regulation of Ca²⁺ release from the ER. Phosphatases are responsible for the differential PKA dynamics between cytosol and ER. Conclusions : PDE2A isoforms localize to different compartments and are involved in distinct cellular functions. The data presented in this thesis demonstrate that PDE2A2 activity at the mitochondria controls mitochondria clearance by mitophagy. This mechanism is dysregulated in multiple pathological conditions, making PDE2A2 a potential therapeutic target.

Delhaye, Sébastien. "Rôle de la phosphodiestérase 2A dans la physiopathologie du syndrome de l’X fragile". Electronic Thesis or Diss., Université Côte d'Azur, 2021. http://theses.univ-cotedazur.fr/2021COAZ6014.

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Le Syndrome de l’X Fragile (SXF) est la forme la plus fréquente de déficience intellectuelle héréditaire. Le phénotype des patients SXF est complexe. En effet, ils présentent aussi des traits autistiques, de l’hyperactivité et un déficit de l’attention. Au niveau du cerveau, le phénotype majeur est la présence d’épines dendritiques plus nombreuses, plus longues et plus fines. Ces anomalies morphologiques sont associées à des formes altérées de plasticité synaptique chez le modèle murin de SXF, la souris Fmr1-KO. Le SXF est causé par l’expansion (plus de 200 fois) du triplet nucléotidique CGG dans le 5’UTR du gène Fragile X Mental Retardation 1 (FMR1). L’hyperméthylation de cette région du gène FMR1 et, surtout de son promoteur, induit la suppression de l’expression de FMR1 et donc l’absence de la protéine FMRP codé par ce dernier. Une expansion entre 50 et 200 fois du triplet est considérée comme une prémutation et est associée à deux autres maladies : le syndrome du tremblement-ataxie lié au X Fragile (FXTAS), une maladie neurodégénérative, et l’insuffisance ovarienne liée à la prémutation de l’X Fragile (FXPOI). FMRP se lie à l’ARNm et est impliquée dans la régulation de plusieurs étapes du métabolisme de l’ARN, en particulier dans la modulation de la traduction de plusieurs protéines synaptiques. Aucune thérapie n’est aujourd’hui disponible pour traiter les patients atteints de SXF. J’ai montré que FMRP module l’expression de la Phosphodiesterase 2A (PDE2A) au niveau synaptique. PDE2A est une enzyme impliquée dans la dégradation de l’AMPc et du GMPc, deux seconds messagers qui jouent un rôle critique dans le développement et la différenciation des neurones. Quand FMRP est absente, le niveau et l’activité de PDE2A sont augmentés et, en conséquence, les niveaux d’AMPc et de GMPc sont réduits dans le cortex et l’hippocampe. J’ai montré que le traitement avec un inhibiteur spécifique de la PDE2A, le BAY 60-7550, rétablit les déficits sociaux chez les souris Fmr1-KO jeunes et adolescentes, la morphologie anormale des épines dendritiques et la Long Term Depression mGluR-dépendante exagérée. Afin de valider par une approche génétique que la réduction du niveau (et de l’activité) de la PDE2A pourrait avoir un rôle thérapeutique pour le SXF, j’ai croisé la lignée Pde2a+/- avec les souris Fmr1-KO et analysé le phénotype comportemental, la morphologie neuronale et les voies de signalisation liées à l’AMPc et au GMPc dans l’hippocampe et le cortex des souris générées par ce croisement. En effet, j’ai pu montrer que les animaux Fmr1-KOxPde2a+/- ont un phénotype sociocognitif normal comparé aux les animaux Fmr1-KO et Pde2a+/-. En effet, les souris Pde2a+/- ont un comportement très similaire à celui des animaux Fmr1-KO même si les altérations moléculaires dans le cerveau apparaissent inversées comparées à celles des souris Fmr1-KO. Dans leur ensemble, mes résultats montrent l’importance des voies AMPc et GMPc qui dépendent de PDE2A dans la pathophysiologie de FXS et dans le neurodéveloppement. En effet, j’ai identifié un nouveau modèle de maladies du développement du cerveau dû à la réduction du niveau d’activité de Pde2a+/-. Dans la première partie de mon doctorat, j’ai contribué à l’identification de la morphologie des neurones corticaux obtenus à partir d’un modèle murin de FXTAS
Fragile X Syndrome (FXS) is the most common form of inherited intellectual disability (ID). In addition to ID, patients might exhibit autistic features, hyperactivity and attention-deficit disorder, language dysfunction and seizures. Approved and effective therapies are not yet available for FXS. The main hallmark of FXS in the brain is the presence of immature and denser dendritic spines. This abnormality is associated with altered synaptic plasticity in our animal model of FXS, the Fmr1-KO mice. FXS is caused by a CGG repeat expansion with a number of repeats higher than 200 in the 5’UTR of the Fragile X Mental Retardation 1 (FMR1) gene. Methylation of this region and of its surrounding sequences, including the promoter of FMR1, results into the silencing of the gene and the loss of its encoded protein, FMRP. An expansion with a number of repeats variable between 50 and 200 is considered as a premutation and is associated with two pathological conditions other than FXS: the Fragile X-associated Tremor Ataxia Syndrome (FXTAS), and the Fragile Xassociated Primary Ovarian Insufficiency (FXPOI). FMRP is an RNA-binding protein implicated in various steps of RNA metabolism. In particular, it plays a role in the translational regulation of a subset of synaptic proteins. We showed that FMRP modulates the synaptic expression of Phosphodiesterase 2A (PDE2A), an enzyme implicated in the degradation of cAMP and cGMP. In. the absence of FMRP, the levels and the activity of PDE2A are increased, and, consequently, cAMP/cGMP levels are reduced in the cortex and hippocampus of Fmr1-KO mice. The blockade of PDE2A with a specific and powerful inhibitor of PDE2A, Bay 607550, rescues various in vitro, ex vivo and in vivo FXS phenotypes. In particular, I contributed to this study by showing that the treatment with Bay 60-7550 rescues social deficits in young and adolescent Fmr1-KO mice and abnormal dendritic spine morphology in hippocampus. In order to validate this new therapeutic target for FXS, I crossed Pde2a+/- mice with Fmr1-KO mice and analyzed their behavior, neuronal morphology and signaling pathways linked to cAMP/cGMP levels in the hippocampus and cortex. I found that double mutant animals (Fmr1-KO x Pde2a+/-) have a normal social and cognitive behavior compared to both Fmr1-KO and Pde2a+/- mice. Indeed, Pde2a+/- mice display behavioral deficits similar to those characterizing the Fmr1-KO mouse, even if the molecular alterations seem to be opposite. In conclusion, my results highlight the key role of PDE2A-dependent cAMP and cGMP levels and their correlated pathways in neurodevelopment. Furthermore, in addition to my main project, in the first part of my doctoral stage, I participated to the characterization of neuronal morphology in the mice model of FXTAS showing that this neurodevelopmental marker is dependent on the level of the Fmr1 mRNA, which displays elevated levels in these mice in the presence of the Fmr1 premutation

Law, Robert. "PDE3A signalling in blood platelets". Thesis, University of Hull, 2016. http://hydra.hull.ac.uk/resources/hull:13761.

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Cyclic 3’, 5’ adenosine monophosphate (cAMP) signalling downstream of prostacyclin (PGI₂) is a key inhibitory pathway in blood platelets. This pathway is dynamically regulated by phosphodiesterase 3A (PDE3A), which hydrolyses cAMP into metabolically inactive AMP. Although PDE3A is an established drug target in anti-platelet therapies, the molecular mechanisms that underlie its function in platelets remain unclear. Therefore, the major aim of this study was to further explore PDE3A signalling in human platelets. Using a combination of cell fractionation and immunoblotting we identified two PDE3A splice variants in platelets, PDE3A1 and PDE3A2, that were differentially localised within the cell. PDE3A1 was located in the membrane fraction, whereas PDE3A2 was primarily located in the cytosolic fraction. Treatment of platelets with PGI2 induced a transient phosphorylation of PDE3A2 at Ser³¹² in a PKA dependent manner. In contrast, no phosphorylation of PDE3A1 was detected. The phosphorylation of PDE3A2 was associated with increased PDE3A enzymatic activity, which suggested that cAMP signalling activated only the cytosolic form of the enzyme. In many cells, A-kinase anchoring proteins (AKAPs) orchestrate a coordinated response between PKA and its effector proteins. The phosphorylation and activation of PDE3A2 in response to PGI2 was blunted by a cell permeable peptide inhibitor of PKA-AKAP interactions suggesting that PKA-mediated activation of PDE3A2 was dependent on an AKAP. Using a cAMP-pull down approach to enrich cAMP binding proteins combined with immunoblotting, we confirmed the presence of two AKAP7 isoforms (δ and γ) in platelets. Additionally, we found that AKAP7δ co-precipitated with PDE3A2 and possessed associated PDE3A activity. Furthermore, AKAP7 also possessed PKA activity, which was a result of its constitutive association with PKA-II. Critically, immunoprecipitated PDE3A was found to be co-associated with both PKA-II and AKAP7δ. The findings in this thesis suggest that blood platelets express multiple differentially-regulated PDE3A splice variants, of which PDE3A2 is regulated by PKA-II within a novel cytosolic AKAP7δ facilitated signalling complex. The selective inhibition of PDE3A splice variants and/or pharmacological disruption of PDE3A signalosomes may provide safer and more specific ways of controlling pathological platelet activation.

Wilson, Moira Ann. "Characterisation and analysis of PDE4A phosphodiesterase isoforms". Thesis, University of Glasgow, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.307182.

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Johnston, Lee Ann. "The investigation of two novel PDE4A enzymes". Thesis, University of Glasgow, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.400759.

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Livie, Craig. "Determining the role of PDE2 within the mitochondria". Thesis, University of Glasgow, 2015. http://theses.gla.ac.uk/6683/.

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3’,5’-cyclic adenosine monophosphate (cAMP) is a near ubiquitous second messenger responsible for the regulation of a myriad of physiological processes. It is produced by the adenylyl cyclases (AC) and degraded by phosphodiesterases (PDEs). The primary effector of cAMP is protein kinase A (PKA). In order to overcome cross-contamination of separate cAMP-mediated processes within the same cell strict spatiotemporal control is required. Compartmentalisation sculpts cAMP gradients allowing targeted cAMP/PKA action with the cell. This is achieved by the tethering of unique isoforms of AC, PKA and PDEs to distinct subcellular locations. This subcellular targeting is often carried out by A kinase anchoring proteins (AKAPs) which act as docking sites for the components of the cAMP signalling machinery. A number of AKAPs have been identified as tethering components of the cAMP signalling cascade to organelles facilitating the cultivation of a discrete localised pool of cAMP. This allows for the highly specific PKA-mediated phosphorylation of target proteins. There are reports of two AKAPs localised at the mitochondria: optic atrophy 1 (OPA1) and sphingosine kinase anchoring protein (SKIP). However, despite the acknowledged presence of these two key components of the cAMP signalling cascade being present at the mitochondria little is known about the functional relevance of cAMP signalling within the mitochondria. In this study, I established PDE2 as located within the mitochondria of both primary cardiac cells and a cardiac cell line. Furthermore, the PDE2 isoform present was identified as PDE 2A2. It was then demonstrated that PDE 2A2 was part of a previously identified protein complex located within the mitochondria known as the mitochondrial inner membrane organising system (MINOS) complex. Furthermore, the potential for direct protein-protein interactions between PDE2 and MINOS constituents was examined. It was then demonstrated that when PDE2 activity/expression was reduced mitochondrial length would significantly increase and when PDE2 was overexpressed mitochondrial length would significantly decrease. Furthermore, manipulation of PDE2 expression/activity also led to significant changes in mitochondrial membrane potential (MMP). In summary, the data presented here indicate that PDE 2A2 is part of a multiprotein complex located within the mitochondria. Furthermore, disruption of PDE 2A2 within this complex leads to alterations in mitochondrial physiology.

Begg, Fiona A. "Cloning and biochemical characterisation of two novel PDE4A cAMP phosphodiesterases". Thesis, University of Glasgow, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.394925.

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Sekharan, Monica R. "Structural studies of the cGMP-binding GAF domain of PDE5A /". Thesis, Connect to this title online; UW restricted, 2004. http://hdl.handle.net/1773/8502.

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Ercu, Maria [Verfasser]. "Molecular mechanisms underlying PDE3A-caused hypertension with brachydactyly (HTNB) / Maria Ercu". Berlin : Freie Universität Berlin, 2020. http://d-nb.info/1222513862/34.

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Lounas, Amel. "Fonction et localisation de la PDE8A dans les cellules ovariennes porcines et son implication dans la stéroïdogenèse". Master's thesis, Université Laval, 2017. http://hdl.handle.net/20.500.11794/27731.

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Les nucléotides cycliques sont des seconds messagers intracellulaires possédant une grande importance dans la signalisation cellulaire du follicule ovarien. Les niveaux intracellulaires en nucléotides cycliques tel que l'adénosine monophosphate cyclique (AMPc) dépendent de leur synthèse, assurée par l'adenylyl-cyclase (AC) ainsi que leur dégradation par les phosphodiéstérases (PDE). Ces dernières appartiennent à la superfamille des métalophosphohydrolases, elles hydrolysent le groupement phosphate en 3' des nucléotides cycliques pour produire un nucléotide 5' phosphate. Dans les cellules ovariennes, plusieurs familles de PDE ont été identifiées, agissant comme modulateurs des taux intracellulaires de nucléotides cycliques. Dans le présent projet, nous nous attarderons à étudier la signalisation cellulaire chez les cellules ovariennes impliquant l'AMPc. La régulation de ses concentrations intracellulaires affecte plusieurs processus physiologiques. Le projet s'intéresse particulièrement à une famille d'enzyme de dégradation de l'AMPc, la phosphodiestérase8A (PDE8A). Nous voulons donc valider la présence fonctionnelle de la famille de PDE8A dans les cellules ovariennes ainsi que la mitochondrie afin de comprendre l'implication de cette enzyme dans la physiologie cellulaire en s'attardant à la stéroïdogenèse, étant donné que les mitochondries sont un organite cellulaire essentiel pour la stéroïdogenèse parce qu'elles représentent le site de synthèses de plusieurs hormones stéroïdiennes. En effet, des récents travaux ont montré la famille PDE8 comme un régulateur de la stéroïdogenèse dans les cellules de Leydig. Dans cette étude, nous avons montré que le transcrit de PDE8A ainsi que sa protéine étaient exprimés dans les cellules de la granulosa, les cellules du cumulus et l'ovocyte chez le porc. Ainsi, la protéine PDE8a a été détectée par western blot dans des mitochondries isolées à partir des cellules de granulosa et des complexe ovocyte-cumulus (COC). Une co-localisation entre le signal immunoréactive de la PDE8A et le marquage réalisé par mitotracker a été observée dans les cellules de granulosa et des mitochondries isolées. De plus, la présence fonctionnelle de la PDE8 mesurée en tant qu'activité AMPc-PDE sensible au PF-04957325 a été détectée dans des cellules de la granulosa et des mitochondries isolées supportant la présence fonctionnelle de la PDE8A dans les mitochondries isolées. De ce fait, cette observation soutient encore la localisation fonctionnelle mitochondriale de la PDE8A. Une association entre la mitochondrie et la PDE8A a aussi été démontrée par immunomicroscopie électronique qui a confirmé l'ancrage de la protéine sur la membrane mitochondriale externe. Pour évaluer l'implication de la mitochondrie dans la stéroïdogenèse, l'effet de PDE8A sur la production de progestérone a été mesuré dans les complexes ovocyte-cumulus en utilisant le PF-04957325 comme un inhibiteur spécifique de PDE8. Lorsque les COC sont cultivés sans FSH, un niveau basal de progestérone est mesuré. Par contre en présence de FSH une augmentation significative de sécrétion de progestérone est observée. En utilisant un inhibiteur spécifique de la PDE8 (PF-04957325) avec la FSH nous avons obtenu une augmentation encore plus importante de la sécrétion de progestérone. Ces résultats démontrent la présence fonctionnelle de PDE8A dans les cellules de la granulosa et les complexes ovocyte-cumulus. Puisque les mitochondries sont l'une des localisations de PDE8A, l'effet de l'inhibiteur spécifique de PDE8 sur la sécrétion de progestérone soutient la contribution mitochondriale de PDE8 dans la stéroïdogenèse.

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Libri sul tema "PDE2A":

Sewell, Granville. Solving Partial Differential Equation Applications with PDE2D. Hoboken, NJ, USA: John Wiley & Sons, Inc., 2018. http://dx.doi.org/10.1002/9781119507918.

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Sewell, Granville. Solving Partial Differential Equation Applications with PDE2D. Wiley & Sons, Limited, John, 2018.

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Sewell, Granville. Solving Partial Differential Equation Applications with PDE2D. Wiley & Sons, Incorporated, John, 2018.

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Sewell, Granville. Solving Partial Differential Equation Applications with PDE2D. Wiley, 2018.

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Sewell, Granville. Solving Partial Differential Equation Applications with PDE2D. Wiley & Sons, Incorporated, John, 2018.

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Capitoli di libri sul tema "PDE2A":

Lobo, Miguel J., e Manuela Zaccolo. "PDE2A". In Encyclopedia of Signaling Molecules, 3826–34. Cham: Springer International Publishing, 2018. http://dx.doi.org/10.1007/978-3-319-67199-4_101603.

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Lobo, Miguel J., e Manuela Zaccolo. "PDE2A". In Encyclopedia of Signaling Molecules, 1–8. New York, NY: Springer New York, 2016. http://dx.doi.org/10.1007/978-1-4614-6438-9_101603-1.

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Zahid, Sarwar, Kari Branham, Dana Schlegel, Mark E. Pennesi, Michel Michaelides, John Heckenlively e Thiran Jayasundera. "PDE6A". In Retinal Dystrophy Gene Atlas, 175–76. Cham: Springer International Publishing, 2018. http://dx.doi.org/10.1007/978-3-319-10867-4_54.

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Petersen-Jones, Simon M., Laurence M. Occelli, Martin Biel e Stylianos Michalakis. "Advancing Gene Therapy for PDE6A Retinitis Pigmentosa". In Retinal Degenerative Diseases, 103–7. Cham: Springer International Publishing, 2019. http://dx.doi.org/10.1007/978-3-030-27378-1_17.

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Pardasani, R. T., e P. Pardasani. "Effective magnetic moment of [Co(pdea)2(BF4)2]⋅4H2O". In Magnetic Properties of Paramagnetic Compounds, 3392. Berlin, Heidelberg: Springer Berlin Heidelberg, 2012. http://dx.doi.org/10.1007/978-3-642-23675-4_3057.

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Meins, M., A. Janecke, C. Marschke, M. J. Denton, G. Kumaramanickavel, S. Pittler e A. Gal. "Mutations in PDE6A, the Gene Encoding the α-Subunit of Rod Photoreceptor Cgmp-Specific Phosphodiesterase, are Rare in Autosomal Recessive Retinitis Pigmentosa". In Degenerative Retinal Diseases, 237–44. Boston, MA: Springer US, 1997. http://dx.doi.org/10.1007/978-1-4615-5933-7_26.

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Pierce, Kenneth E., Paul G. Curran, Christopher P. Zelinka, Andy J. Fischer, Simon M. Petersen-Jones e Joshua T. Bartoe. "Sildenafil Administration in Dogs Heterozygous for a Functional Null Mutation in Pde6a: Suppressed Rod-Mediated ERG Responses and Apparent Retinal Outer Nuclear Layer Thinning". In Retinal Degenerative Diseases, 371–76. Cham: Springer International Publishing, 2019. http://dx.doi.org/10.1007/978-3-030-27378-1_61.

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"Introduction to PDE2D". In Solving Partial Differential Equation Applications with PDE2D, 1–20. Hoboken, NJ, USA: John Wiley & Sons, Inc., 2018. http://dx.doi.org/10.1002/9781119507918.ch0.

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Martinez, Sergio E. "PDE2 Structure and Functions". In Cyclic Nucleotide Phosphodiesterases in Health and Disease, 55–77. CRC Press, 2006. http://dx.doi.org/10.1201/9781420020847-4.

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Martinez, Sergio. "PDE2 Structure and Functions". In Cyclic Nucleotide Phosphodiesterases in Health and Disease. CRC Press, 2006. http://dx.doi.org/10.1201/9781420020847.ch4.

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Atti di convegni sul tema "PDE2A":

Doummar, D., C. Dentel, V. Bouilleret, B. Dozieres-Puyravel, H. Nasser, E. Hirsch, C. Mignot e G. Rudolf. "Biallelic PDE2A Mutations: A New Cause of Intellectual Disability with Paroxysmal Dyskinesia and/or Epilepsy". In Abstracts of the 47th Annual Meeting of the SENP (Société Européenne De Neurologie Pédiatrique). Georg Thieme Verlag KG, 2019. http://dx.doi.org/10.1055/s-0039-1685434.

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Rentsendorj, Otgonchimeg, Franco D'Alessio, Aigul Moldobaeva, Y. Eto e David B. Pearse. "LPS Induced INOS Expression Is Negatively Regulated By Phosphodiesterase 2A (PDE2A) In Lung And Peritoneal Macrophages". In American Thoracic Society 2012 International Conference, May 18-23, 2012 • San Francisco, California. American Thoracic Society, 2012. http://dx.doi.org/10.1164/ajrccm-conference.2012.185.1_meetingabstracts.a5062.

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Rentsendorj, Otgonchimeg, Mahendra Damarla, Michael T. Crow, Ji-Young Choi, Franco D'Alessio e David B. Pearse. "Phosphodiesterase 2A (PDE2A) Upregulates Inducible Nitric Oxide Synthase (INOS) In Lung Injury From Intra-Tracheal LPS And Large Tidal Volume Ventilation In Mice". In American Thoracic Society 2011 International Conference, May 13-18, 2011 • Denver Colorado. American Thoracic Society, 2011. http://dx.doi.org/10.1164/ajrccm-conference.2011.183.1_meetingabstracts.a2107.

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Wu, Xiaoyun, Timothy Lewis, Luc de Waal, Galen Gao, Jian Zhang, Monica Schenone, Colin Garvie et al. "Abstract 2028: PDE3A modulation for cancer therapy". In Proceedings: AACR Annual Meeting 2017; April 1-5, 2017; Washington, DC. American Association for Cancer Research, 2017. http://dx.doi.org/10.1158/1538-7445.am2017-2028.

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Li, Gang, e Songqi Huang. "PDEA target weight determination methods based on GRA / AHP". In 2009 IEEE International Conference on Grey Systems and Intelligent Services (GSIS 2009). IEEE, 2009. http://dx.doi.org/10.1109/gsis.2009.5408342.

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Tergau, Katharina, Moritz Gröner, Rebecca Firneburg, Eleder Cachorro, Mario Günscht, Kevser Kocas, Carolin Richter, Ali El-Armouche e Susanne Kämmerer. "The cGMP-induced PDE2 stimulation as a novel antiarrhythmic strategy". In cGMP: Generators, Effectors and Therapeutic Implications. ScienceOpen, 2024. http://dx.doi.org/10.14293/cgmp.000015.v1.

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Wu, Xiaoyun, Malvina Papanastasiou, Gavin Schnitzler, Colin Garvie, Stephanie Hoyt, Terry Zhang, James Mullahoo et al. "Abstract 1219: Deep mutational scanning of PDE3A identifies residues required for DNMDP response". In Proceedings: AACR Annual Meeting 2021; April 10-15, 2021 and May 17-21, 2021; Philadelphia, PA. American Association for Cancer Research, 2021. http://dx.doi.org/10.1158/1538-7445.am2021-1219.

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Hou, Qingfeng, Xiaobo Zheng, Donghong Guo, Youyi Zhu, Hui Yang, Xingguang Xu, Yuanyuan Wang, Gang Chen, Guangxin Hu e Jinben Wang. "PDEA-Based Amphiphilic Polymer Enables pH-Responsive Emulsions for a Rapid Demulsification". In SPE International Conference on Oilfield Chemistry. Society of Petroleum Engineers, 2019. http://dx.doi.org/10.2118/193640-ms.

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Jiao, Ai-Ying, e Jun-Hai Ma. "An Empirical Research of Bohai Rim Container Terminal Based on PDEA Model". In 2008 4th International Conference on Wireless Communications, Networking and Mobile Computing (WiCOM). IEEE, 2008. http://dx.doi.org/10.1109/wicom.2008.1610.

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