scholarly journals Cyclic nucleotide signalling in malaria parasites

Open Biology ◽  
2017 ◽  
Vol 7 (12) ◽  
pp. 170213 ◽  
Author(s):  
David A. Baker ◽  
Laura G. Drought ◽  
Christian Flueck ◽  
Stephanie D. Nofal ◽  
Avnish Patel ◽  
...  
Keyword(s):  
Cyclic Nucleotides ◽  
Cyclic Nucleotide ◽  
Malaria Parasite ◽  
Cell Function ◽  
Animal Cell ◽  
Adenosine Monophosphate ◽  
Cell Types ◽  
Guanosine Monophosphate ◽  
Parasite Life Cycle ◽  
Malaria Parasites

The cyclic nucleotides 3′, 5′-cyclic adenosine monophosphate (cAMP) and 3′, 5′-cyclic guanosine monophosphate (cGMP) are intracellular messengers found in most animal cell types. They usually mediate an extracellular stimulus to drive a change in cell function through activation of their respective cyclic nucleotide-dependent protein kinases, PKA and PKG. The enzymatic components of the malaria parasite cyclic nucleotide signalling pathways have been identified, and the genetic and biochemical studies of these enzymes carried out to date are reviewed herein. What has become very clear is that cyclic nucleotides play vital roles in controlling every stage of the complex malaria parasite life cycle. Our understanding of the involvement of cyclic nucleotide signalling in orchestrating the complex biology of malaria parasites is still in its infancy, but the recent advances in our genetic tools and the increasing interest in signalling will deliver more rapid progress in the coming years.

scholarly journals A Cell-Based PDE4 Assay in 1536-Well Plate Format for High-Throughput Screening

2008 ◽  
Vol 13 (7) ◽  
pp. 609-618 ◽  
Author(s):  
Steven A. Titus ◽  
Xiao Li ◽  
Noel Southall ◽  
Jianming Lu ◽  
James Inglese ◽  
...  
Keyword(s):  
Cyclic Nucleotides ◽  
Cyclic Nucleotide ◽  
High Throughput Screening ◽  
Drug Targets ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Cyclic Guanosine Monophosphate ◽  
Guanosine Monophosphate ◽  
Compound Screening ◽  
A Cell

The cyclic nucleotide phosphodiesterases (PDEs) are intracellular enzymes that catalyze the hydrolysis of 3,′5′-cyclic nucleotides, such as cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), to their corresponding 5′nucleotide monophosphates. These enzymes play an important role in controlling cellular concentrations of cyclic nucleotides and thus regulate a variety of cellular signaling events. PDEs are emerging as drug targets for several diseases, including asthma, cardiovascular disease, attention-deficit hyperactivity disorder, Parkinson's disease, and Alzheimer's disease. Although biochemical assays with purified recombinant PDE enzymes and cAMP or cGMP substrate are commonly used for compound screening, cell-based assays would provide a better assessment of compound activity in a more physiological context. The authors report the development and validation of a new cell-based PDE4 assay using a constitutively active G-protein—coupled receptor as a driving force for cAMP production and a cyclic nucleotide—gated cation channel as a biosensor in 1536-well plates. ( Journal of Biomolecular Screening 2008:609-618)

Cyclic Nucleotide-Activated Currents in Cultured Olfactory Receptor Neurons of the Hawkmoth Manduca sexta

2008 ◽  
Vol 100 (5) ◽  
pp. 2866-2877 ◽  
Author(s):  
Steffi Krannich ◽  
Monika Stengl
Keyword(s):  
Manduca Sexta ◽  
Cyclic Nucleotide ◽  
Olfactory Receptor ◽  
Low Voltage ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Guanosine Monophosphate ◽  
Olfactory Receptor Neurons ◽  
Cation Channels ◽  
Receptor Neurons

Moth pheromones cause rises in intracellular Ca2+ concentrations that activate Ca2+-dependent cation channels in antennal olfactory receptor neurons. In addition, mechanisms of adaptation and sensitization depend on changes in cyclic nucleotide concentrations. Here, cyclic nucleotide-activated currents in cultured olfactory receptor neurons of the moth Manduca sexta are described, which share properties with currents through vertebrate cyclic nucleotide-gated channels. The cyclic nucleotide-activated currents of M. sexta carried Ca2+ and monovalent cations. They were directly activated by cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), modulated by Ca2+/calmodulin, and inhibited by lanthanum. M. sexta cyclic nucleotide-activated currents developed in an all-or-none manner, which suggests that the underlying channels are coupled and act coordinately. At least one cAMP- and two cGMP-activated nonselective cation currents could be distinguished. Compared with the cAMP-activated current, both cGMP-activated currents appeared to conduct more Ca2+ and showed a stronger down-regulation by Ca2+/calmodulin-dependent negative feedback. Furthermore, both cGMP-activated currents differed in their Ca2+-dependent inhibition. Thus M. sexta olfactory receptor neurons, like vertebrate sensory neurons, appear to express nonselective cyclic nucleotide-activated cation channels with different subunit compositions. Besides the nonselective cyclic nucleotide-activated cation currents, olfactory receptor neurons express a cAMP-dependent current. This current resembled a protein kinase-modulated low-voltage–activated Ca2+ current.

Cyclic nucleotide antagonists of cholecystokinin: structural requirements for interaction with the cholecystokinin receptor

1982 ◽  
Vol 242 (2) ◽  
pp. G161-G167 ◽  
Author(s):  
N. Barlas ◽  
R. T. Jensen ◽  
M. C. Beinfeld ◽  
J. D. Gardner
Keyword(s):  
Cyclic Nucleotides ◽  
Cyclic Nucleotide ◽  
Cell Function ◽  
Pancreatic Enzyme ◽  
Structural Similarity ◽  
Membrane Receptors ◽  
Biologically Active ◽  
Enzyme Secretion ◽  
Pancreatic Acini ◽  
Derivatives Of

Previously, we have found that, in pancreatic acini, butyryl derivatives of cGMP antagonize the action of cholecystokinin by inhibiting binding of the peptide to its membrane receptors. In the present study, we found that derivatives of cAMP and cIMP can also inhibit binding of cholecystokinin as well as its actions on acinar cell function. Moreover, the inhibition caused by cyclic nucleotide derivatives did not require the presence of a butyryl moiety, because certain 8-bromo-cyclic nucleotides also inhibited the interaction of cholecystokinin with its receptors. Cyclic nucleotide derivatives can also increase pancreatic enzyme secretion; however, for the various cyclic nucleotides tested, there was no apparent correlation between their abilities to stimulate enzyme secretion and their abilities to antagonize the actions of cholecystokinin. Finally, cyclic nucleotide derivatives also inhibited binding of 125I-cholecystokinin to antibodies that were specific for the biologically active, C-terminal region of cholecystokinin. Thus, certain cyclic nucleotide derivatives possess a conformational structural which resembles that of the biologically active portion of cholecystokinin, and this structural similarity accounts for the abilities of these nucleotide derivatives to interact with cholecystokinin receptors and, by so doing, to inhibit the action of cholecystokinin on its target tissues.

scholarly journals Activation of Gingival Fibroblasts by Bacterial Cyclic Dinucleotides and Lipopolysaccharide

Pathogens ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 792 ◽  
Author(s):  
Samira Elmanfi ◽  
Herman O. Sintim ◽  
Jie Zhou ◽  
Mervi Gürsoy ◽  
Eija Könönen ◽  
...  
Keyword(s):  
Cellular Response ◽  
Adenosine Monophosphate ◽  
Cell Types ◽  
Early Response ◽  
Guanosine Monophosphate ◽  
Gingival Fibroblasts ◽  
Concurrent Treatment ◽  
Cyclic Dinucleotides ◽  
Inflammatory Proteins ◽  
Molecular Patterns

Human gingival fibroblasts (HGFs) recognize microbe-associated molecular patterns (MAMPs) and respond with inflammatory proteins. Simultaneous impacts of bacterial cyclic di-guanosine monophosphate (c-di-GMP), cyclic di-adenosine monophosphate (c-di-AMP), and lipopolysaccharide (LPS) on gingival keratinocytes have been previously demonstrated, but the effects of these MAMPs on other periodontal cell types, such as gingival fibroblasts, remain to be clarified. The present aim was to examine the independent and combined effects of these cyclic dinucleotides and LPS on interleukin (IL) and matrix metalloproteinase (MMP) response of HGFs. The cells were incubated with c-di-GMP and c-di-AMP, either in the presence or absence of Porphyromonas gingivalis LPS, for 2 h and 24 h. The levels of IL-8, -10, and -34, and MMP-1, -2, and -3 secreted were measured by the Luminex technique. LPS alone or together with cyclic dinucleotides elevated IL-8 levels. IL-10 levels were significantly increased in the presence of c-di-GMP and LPS after 2 h but disappeared after 24 h of incubation. Concurrent treatment of c-di-AMP and LPS elevated MMP-1 levels, whereas c-di-GMP with LPS suppressed MMP-2 levels but increased MMP-3 levels. To conclude, we produce evidence that cyclic dinucleotides interact with LPS-mediated early response of gingival fibroblasts, while late cellular response is mainly regulated by LPS.

scholarly journals Druggable Targets in Cyclic Nucleotide Signaling Pathways in Apicomplexan Parasites and Kinetoplastids against Disabling Protozoan Diseases in Humans

2019 ◽  
Vol 20 (1) ◽  
pp. 138 ◽  
Author(s):  
Annette Kaiser
Keyword(s):  
Signaling Pathways ◽  
G Proteins ◽  
Cyclic Nucleotides ◽  
Cyclic Nucleotide ◽  
Environmental Changes ◽  
Small Gtpases ◽  
Effector Proteins ◽  
Guanosine Monophosphate ◽  
Apicomplexan Parasites ◽  
Nucleotide Signaling

Cell signaling in eukaryotes is an evolutionarily conserved mechanism to respond and adapt to various environmental changes. In general, signal sensation is mediated by a receptor which transfers the signal to a cascade of effector proteins. The cyclic nucleotides 3′,5′-cyclic adenosine monophosphate (cAMP) and 3′,5′-cyclic guanosine monophosphate (cGMP) are intracellular messengers mediating an extracellular stimulus to cyclic nucleotide-dependent kinases driving a change in cell function. In apicomplexan parasites and kinetoplastids, which are responsible for a variety of neglected, tropical diseases, unique mechanisms of cyclic nucleotide signaling are currently identified. Collectively, cyclic nucleotides seem to be essential for parasitic proliferation and differentiation. However, there is no a genomic evidence for canonical G-proteins in these parasites while small GTPases and secondary effector proteins with structural differences to host orthologues occur. Database entries encoding G-protein-coupled receptors (GPCRs) are still without functional proof. Instead, signals from the parasite trigger GPCR-mediated signaling in the host during parasite invasion and egress. The role of cyclic nucleotide signaling in the absence of G-proteins and GPCRs, with a particular focus on small GTPases in pathogenesis, is reviewed here. Due to the absence of G-proteins, apicomplexan parasites and kinetoplastids may use small GTPases or their secondary effector proteins and host canonical G-proteins during infection. Thus, the feasibility of targeting cyclic nucleotide signaling pathways in these parasites, will be an enormous challenge for the identification of selective, pharmacological inhibitors since canonical host proteins also contribute to pathogenesis.

Phosphodiesterase 2A Localized in the Spinal Cord Contributes to Inflammatory Pain Processing

2014 ◽  
Vol 121 (2) ◽  
pp. 372-382 ◽  
Author(s):  
Wiebke Kallenborn-Gerhardt ◽  
Ruirui Lu ◽  
Aaron Bothe ◽  
Dominique Thomas ◽  
Jessica Schlaudraff ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Animal Models ◽  
Dorsal Horn ◽  
Cyclic Nucleotides ◽  
Inflammatory Pain ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Cyclic Guanosine Monophosphate ◽  
Guanosine Monophosphate ◽  
Pain Processing

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.

scholarly journals Endothelium-Dependent Dilation of Feline Cerebral Arteries: Role of Membrane Potential and Cyclic Nucleotides

1989 ◽  
Vol 9 (3) ◽  
pp. 256-263 ◽  
Author(s):  
Joseph E. Brayden ◽  
George C. Wellman
Keyword(s):  
Membrane Potential ◽  
Cyclic Nucleotides ◽  
Cerebral Arteries ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Cyclic Guanosine Monophosphate ◽  
Guanosine Monophosphate ◽  
Membrane Potential Change ◽  
Middle Cerebral Arteries

The objective of this study was to characterize the role of membrane potential and cyclic nucleotides in endothelium-dependent dilation of cerebral arteries. Middle cerebral arteries isolated from cats were depolarized and constricted in response to serotonin or when subjected to transmural pressures >50 mm Hg. Acetylcholine (ACh) and ADP caused vasodilation and a sustained, dose-dependent hyperpolarization of up to 20 mV in this artery. The membrane potential change preceded the vasodilation by ∼6 s. Hyperpolarizations and dilations to ACh and ADP did not occur in preparations without endothelium. The hyperpolarizations were abolished by ouabain (10−5 M), which also blocked the dilator response to ACh. However, dilations to ADP were unaffected by ouabain. Methylene blue (5 × 10−5 M), a guanylate cyclase inhibitor, had no effect on the responses to ACh or ADP in the presence or absence of ouabain. Cyclic guanosine monophosphate (cGMP) levels were not altered in cerebral arteries exposed to ACh or ADP. However, ADP did increase cyclic adenosine monophosphate levels in these blood vessels. We conclude that although membrane hyperpolarizations may be adequate to cause vasodilation, at least one other pathway of endothelium-dependent vasodilation also is present in feline cerebral arteries. Cyclic GMP does not appear to be involved in this alternate pathway of dilation.

scholarly journals Challenges on Cyclic Nucleotide Phosphodiesterases Imaging with Positron Emission Tomography: Novel Radioligands and (Pre-)Clinical Insights since 2016

2021 ◽  
Vol 22 (8) ◽  
pp. 3832
Author(s):  
Susann Schröder ◽  
Matthias Scheunemann ◽  
Barbara Wenzel ◽  
Peter Brust
Keyword(s):  
Positron Emission Tomography ◽  
Cyclic Nucleotide ◽  
Intracellular Signaling ◽  
Adenosine Monophosphate ◽  
Guanosine Monophosphate ◽  
Emission Tomography ◽  
Cyclic Nucleotide Phosphodiesterases ◽  
Positron Emission ◽  
Nucleotide Phosphodiesterases

Cyclic nucleotide phosphodiesterases (PDEs) represent one of the key targets in the research field of intracellular signaling related to the second messenger molecules cyclic adenosine monophosphate (cAMP) and/or cyclic guanosine monophosphate (cGMP). Hence, non-invasive imaging of this enzyme class by positron emission tomography (PET) using appropriate isoform-selective PDE radioligands is gaining importance. This methodology enables the in vivo diagnosis and staging of numerous diseases associated with altered PDE density or activity in the periphery and the central nervous system as well as the translational evaluation of novel PDE inhibitors as therapeutics. In this follow-up review, we summarize the efforts in the development of novel PDE radioligands and highlight (pre-)clinical insights from PET studies using already known PDE radioligands since 2016.

Freeze-substitution of rye grass and ragweed pollen grains

1990 ◽  
Vol 48 (3) ◽  
pp. 686-687
Author(s):  
Liza B. Martinez ◽  
Susan M. Wick
Keyword(s):  
Cell Function ◽  
Pollen Grains ◽  
Freeze Substitution ◽  
Cell Types ◽  
Rapid Freezing ◽  
Rye Grass ◽  
Acrylic Resins ◽  
Allergenic Proteins ◽  
Cold Embedding ◽  
Structural Preservation

Rapid freezing and freeze-substitution have been employed as alternatives to chemical fixation because of the improved structural preservation obtained in various cell types. This has been attributed to biomolecular immobilization derived from the extremely rapid arrest of cell function. These methods allow the elimination of conventionally used fixatives, which may have denaturing or “masking” effects on proteins. Thus, this makes them ideal techniques for immunocytochemistry, in which preservation of both ultrastructure and antigenicity are important. These procedures are also compatible with cold embedding acrylic resins which are known to increase sensitivity in immunolabelling.This study reveals how rapid freezing and freeze-substitution may prove to be useful in the study of the mobile allergenic proteins of rye grass and ragweed. Most studies have relied on the use of osmium tetroxide to achieve the necessary ultrastructural detail in pollen whereas those that omitted it have had to contend with poor overall preservation.

Polydatin Attenuates Carbachol-induced Contraction of Guinea Pig Gallbladder

2019 ◽  
Vol 18 (1) ◽  
pp. 34-38
Author(s):  
Chen Lei ◽  
Pan Xiang ◽  
Shen Yonggang ◽  
Song Kai ◽  
Zhong Xingguo ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Guinea Pig ◽  
Smooth Muscles ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Cyclic Guanosine Monophosphate ◽  
Guanosine Monophosphate ◽  
Dependent Manner ◽  
Underlying Mechanisms ◽  
Dose Dependent

The aim of this study was to determine whether polydatin, a glucoside of resveratrol isolated from the root of Polygonum cuspidatum, warranted development as a potential therapeutic for ameliorating the pain originating from gallbladder spasm disorders and the underlying mechanisms. Guinea pig gallbladder smooth muscles were treated with polydatin and specific inhibitors to explore the mechanisms underpinning polydatin-induced relaxation of carbachol-precontracted guinea pig gallbladder. Our results shown that polydatin relaxed carbachol-induced contraction in a dose-dependent manner through the nitric oxide/cyclic guanosine monophosphate/protein kinase G and the cyclic adenosine monophosphate/protein kinase A signaling pathways as well as the myosin light chain kinase and potassium channels. Our findings suggested that there was value in further exploring the potential therapeutic use of polydatin in gallbladder spasm disorders.

Sign in / Sign up

Export Citation Format

Share Document