scholarly journals Clinical and Molecular Genetics of the Phosphodiesterases (PDEs)

2013 ◽  
Vol 35 (2) ◽  
pp. 195-233 ◽  
Author(s):  
Monalisa F. Azevedo ◽  
Fabio R. Faucz ◽  
Eirini Bimpaki ◽  
Anelia Horvath ◽  
Isaac Levy ◽  
...  
Keyword(s):  
Cyclic Nucleotide ◽  
Heart Function ◽  
Biological Effects ◽  
Genetic Diseases ◽  
Functional Variants ◽  
Cgmp Signaling ◽  
Health And Disease ◽  
Nucleotide Signaling ◽  
Hydrolysis Of ◽  
Camp And Cgmp

Abstract Cyclic nucleotide phosphodiesterases (PDEs) are enzymes that have the unique function of terminating cyclic nucleotide signaling by catalyzing the hydrolysis of cAMP and GMP. They are critical regulators of the intracellular concentrations of cAMP and cGMP as well as of their signaling pathways and downstream biological effects. PDEs have been exploited pharmacologically for more than half a century, and some of the most successful drugs worldwide today affect PDE function. Recently, mutations in PDE genes have been identified as causative of certain human genetic diseases; even more recently, functional variants of PDE genes have been suggested to play a potential role in predisposition to tumors and/or cancer, especially in cAMP-sensitive tissues. Mouse models have been developed that point to wide developmental effects of PDEs from heart function to reproduction, to tumors, and beyond. This review brings together knowledge from a variety of disciplines (biochemistry and pharmacology, oncology, endocrinology, and reproductive sciences) with emphasis on recent research on PDEs, how PDEs affect cAMP and cGMP signaling in health and disease, and what pharmacological exploitations of PDEs may be useful in modulating cyclic nucleotide signaling in a way that prevents or treats certain human diseases.

Cyclic Nucleotides Signaling and Phosphodiesterase Inhibition: Defying Alzheimer’s Disease

2020 ◽  
Vol 21 (13) ◽  
pp. 1371-1384 ◽  
Author(s):  
Vivek K. Sharma ◽  
Thakur G. Singh ◽  
Shareen Singh
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cyclic Nucleotides ◽  
Cyclic Nucleotide ◽  
Phosphodiesterase Inhibitors ◽  
Physiological Status ◽  
Altered Expression ◽  
Brain Functions ◽  
Nucleotide Signaling ◽  
Camp And Cgmp

Defects in brain functions associated with aging and neurodegenerative diseases benefit insignificantly from existing options, suggesting that there is a lack of understanding of pathological mechanisms. Alzheimer’s disease (AD) is such a nearly untreatable, allied to age neurological deterioration for which only the symptomatic cure is available and the agents able to mould progression of the disease, is still far away. The altered expression of phosphodiesterases (PDE) and deregulated cyclic nucleotide signaling in AD has provoked a new thought of targeting cyclic nucleotide signaling in AD. Targeting cyclic nucleotides as an intracellular messenger seems to be a viable approach for certain biological processes in the brain and controlling substantial. Whereas, the synthesis, execution, and/or degradation of cyclic nucleotides has been closely linked to cognitive deficits. In relation to cognition, the cyclic nucleotides (cAMP and cGMP) have an imperative execution in different phases of memory, including gene transcription, neurogenesis, neuronal circuitry, synaptic plasticity and neuronal survival, etc. AD is witnessed by impairments of these basic processes underlying cognition, suggesting a crucial role of cAMP/cGMP signaling in AD populations. Phosphodiesterase inhibitors are the exclusive set of enzymes to facilitate hydrolysis and degradation of cAMP and cGMP thereby, maintains their optimum levels initiating it as an interesting target to explore. The present work reviews a neuroprotective and substantial influence of PDE inhibition on physiological status, pathological progression and neurobiological markers of AD in consonance with the intensities of cAMP and cGMP.

scholarly journals cGMP signaling: probing antagonistic cyclic nucleotide platelet signals by modeling and experiment

2021 ◽  
Author(s):  
Tim Breitenbach ◽  
Nils Englert ◽  
Özge Osmanoglu ◽  
Natalia Rukoyatkina ◽  
Gaby Wangorsch ◽  
...  
Keyword(s):  
Cyclic Nucleotide ◽  
Optimization Methods ◽  
Data Driven ◽  
Pharmacological Interventions ◽  
Modular Model ◽  
Vasp Phosphorylation ◽  
Cgmp Signaling ◽  
Data Driven Modeling ◽  
External Stimuli ◽  
Camp And Cgmp

AbstractBackgroundThe cyclic nucleotides cAMP and cGMP inhibit platelet activation.ResultsWe extended an older model and systematically integrated drugs as external stimuli. Data driven modeling allowed us to design models that provide a quantitative output for quantitative input information. This relies on condensed information about involved regulation and modeling of pharmacological interventions by systematic optimization methods. By multi-experiment fitting, we validated our model optimizing the parameters of the model. In addition, we show how the output of the developed cGMP model can be used as input for a modular model of VASP phosphorylation and for the activity of cAMP and cGMP pathways in platelets.ConclusionsWe present a model for cGMP signaling and VASP phosphorylation, that allows to estimate drug action on any of the inhibitory cyclic nucleotide pathways (cGMP, cAMP) and has been validated by experimental data.

scholarly journals Alterations of cAMP/cGMP Signaling Pathways in Lupus Nephritis

2021 ◽  
Vol 3 (2) ◽  
pp. 8-12
Author(s):  
Issaka Yougbare
Keyword(s):  
Lupus Nephritis ◽  
Signaling Pathways ◽  
Disease Progression ◽  
Lupus Erythematosus ◽  
Cyclic Nucleotide ◽  
Clinical Manifestations ◽  
Pde4 Inhibitor ◽  
Promising Therapeutic Approach ◽  
Cgmp Signaling ◽  
Nucleotide Signaling

Systemic lupus erythematosus (SLE) is an autoimmune disease with a broad spectrum of clinical manifestations, but its pathogenesis remains fairly understood. Cyclic nucleotide signaling pathways in immune cells and kidney are emerging as cellular mechanisms governing SLE disease progression. Upregulations of cGMP/cAMP metabolism lead to lupus nephritis and abnormal kidney remodeling/hypertrophy. PDE4 family remains the major cAMP hydrolyzing enzyme as PDE1 is responsible for cGMP breakdown in kidney. SLE disease progression to lupus nephritis is correlated with increase PDE1 and PDE4 activities resulting in lower cyclic nucleotide levels in kidney. Administration of Nimodipine, a PDE1 inhibitor prevents the lymphoproliferative phenotype and exert anti-proliferative effects on mesangial cells while PDE4 inhibitor NCS 613 prevents inflammatory cytokines release, immune complex deposition, and nephritis in MRL/lpr lupus prone mice. In this review, we highlight recent findings of alterations of cyclic nucleotide signaling pathways in lupus nephritis. Given the role of cAMP/cGMP signaling in kidney function, dual inhibition of PDE1 and PDE4 may represent a promising therapeutic approach to tackle lupus nephritis.

Pharmaceutical and Biotechnological Applications of Transgenic Technology

2018 ◽  
Vol 11 (4) ◽  
pp. 4145-4153
Author(s):  
D Samba Reddy ◽  
Tina Reddy
Keyword(s):  
Mammalian Species ◽  
Genetic Diseases ◽  
Transgenic Animals ◽  
Transgenic Animal ◽  
Pharmaceutical Products ◽  
Conditional Knockout ◽  
Knock Out ◽  
Transgenic Lines ◽  
Health And Disease ◽  
Or Genes

A transgenic animal is a genetically modified species in which researchers have modified an existing gene or genes by genetic engineering techniques. Genetic modification involves the mutation, insertion, or deletion of genes. Mouse is the most widely used mammalian species for creating transgenic lines. There are two types of transgenic animals: (i) gene deleted (“knock-out”) and (ii) gene overexpressed (“knock-in”). The loss or gain of gene activity often causes changes in a mouse's phenotype, which includes appearance, behavior and other observable characteristics. Knockout mice are key animal models for studying the role of genes which have been sequenced but whose functions have not been determined.  They include constitutive knockouts (gene deleted since birth) and conditional knockout (gene turned off later after birth).  The first knockout mouse was created in 1989 by Mario Capecchi, Martin Evans, and Oliver Smithies, for which they were awarded the 2007 Nobel Prize in Physiology or Medicine.  Transgenic mouse models have revolutionized the biomedical research and provided a power tool for understanding health and disease. Transgenic animals have been created for bulk production of biotechnology and pharmaceutical products.  In 2009, the FDA approved the first human biological drug ATryn, an anticoagulant extracted from the transgenic goat's milk. The recently discovered CRISPER gene editing technology is providing new frontiers in correcting abnormal genes and hopefully provide cures for genetic diseases in the future.    

A Fluorescence Polarization Assay for Cyclic Nucleotide Phosphodiesterases

2002 ◽  
Vol 7 (3) ◽  
pp. 215-222 ◽  
Author(s):  
Wei Huang ◽  
Yan Zhang ◽  
J. Richard Sportsman
Keyword(s):  
Cyclic Nucleotide ◽  
Fluorescence Polarization ◽  
Drug Targets ◽  
Second Messengers ◽  
Reaction Products ◽  
Cyclic Nucleotide Phosphodiesterases ◽  
Extracellular Signals ◽  
Fluorescence Polarization Assay ◽  
Hydrolysis Of ◽  
Nucleotide Phosphodiesterases

Cyclic nucleotide phosphodiesterases (PDEs) catalyze the hydrolysis of the 3′-ester bond of cyclic AMP (cAMP) and cyclic GMP (cGMP), important second messengers in the transduction of a variety of extracellular signals. There is growing interest in the study of PDEs as drug targets for novel therapeutics. We describe the development of a homogeneous fluorescence polarization assay for PDEs based on the strong binding of PDE reaction products (i.e., AMP or GMP) onto modified nanoparticles through interactions with immobilized trivalent metal cations. This assay technology (IMAP) is applicable to both cAMP- and cGMP-specific PDEs. Results of the assay in 384- and 1536-well microplates are presented.

Hydrolysis of the non-canonical cyclic nucleotide cUMP by PDE9A: kinetics and binding mode

2018 ◽  
Vol 392 (2) ◽  
pp. 199-208
Author(s):  
Jessica Scharrenbroich ◽  
Volkhard Kaever ◽  
Stefan Dove ◽  
Roland Seifert ◽  
Erich H. Schneider
Keyword(s):  
Cyclic Nucleotide ◽  
Binding Mode ◽  
Hydrolysis Of

scholarly journals Advances and Perspectives of Light-gated Phosphodiesterases for Optogenetic Applications

2020 ◽  
Author(s):  
Yuehui Tian ◽  
Shang Yang ◽  
Shiqiang Gao
Keyword(s):  
Intracellular Signaling ◽  
Second Messengers ◽  
Cell Physiology ◽  
Intracellular Camp ◽  
Animal Cells ◽  
Signaling Mechanism ◽  
Surface Receptors ◽  
Cgmp Signaling ◽  
Pros And Cons ◽  
Camp And Cgmp

Second messengers, cyclic adenosine 3'-5'-monophosphate (cAMP) and cyclic guanosine 3'-5'-monophosphate (cGMP) are playing important roles in many animal cells by regulating intracellular signaling pathways and modulating cell physiology. Environmental cues like temperature, light and chemical compounds can stimulate cell surface receptors and trigger the generation of second messengers and the following regulations. Spread of cAMP and cGMP is further shaped by cyclic nucleotide phosphodiesterases (PDEs) for orchestration of intracellular microdomain signaling. However, localized intracellular cAMP and cGMP signaling requires further investigation. Optogenetic manipulation of cAMP and cGMP offers new opportunities of spatio-temporally precise study of their signaling mechanism. Light-gated nucleotide cyclases are well developed and applied for cAMP/cGMP manipulation. Recently discovered rhodopsin phosphodiesterase gene from protists established new and direct biological connection between light and PDEs. Light-regulated PDEs are under development and of demand to complete the toolkit of cAMP/cGMP manipulation. In this review, we summarize the state of the art, pros and cons of artificial and natural light-regulated PDEs and discuss potential new strategies of developing light-gated PDEs for optogenetic manipulation.

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