Sex, sensitivity, and second messengers: differential effect of cyclic nucleotide mediated inhibition in the chemosensory system of fiddler crabs

2001 ◽  
Vol 187 (6) ◽  
pp. 489-498 ◽  
Author(s):  
Marc Weissburg
Keyword(s):  
Cyclic Nucleotide ◽  
Differential Effect ◽  
Second Messengers ◽  
Fiddler Crabs ◽  
Chemosensory System

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.

scholarly journals Cyclic Nucleotide (cNMP) Analogues: Past, Present and Future

2021 ◽  
Vol 22 (23) ◽  
pp. 12879
Author(s):  
Erik Maronde
Keyword(s):  
Cyclic Nucleotide ◽  
Second Messengers ◽  
Nucleotide Analogues ◽  
Drug Candidates ◽  
Physiological Signal ◽  
Cellular Events ◽  
Current State ◽  
Dependent Protein ◽  
Target Molecules ◽  
Basic And Applied Research

Cyclic nucleotides are important second messengers involved in cellular events, and analogues of this type of molecules are promising drug candidates. Some cyclic nucleotide analogues have become standard tools for the investigation of biochemical and physiological signal transduction pathways, such as the Rp-diastereomers of adenosine and guanosine 3′,5′-cyclic monophosphorothioate, which are competitive inhibitors of cAMP- and cGMP-dependent protein kinases. Next generation analogues exhibit a higher membrane permeability, increased resistance against degradation, and improved target specificity, or are caged or photoactivatable for fast and/or targeted cellular imaging. Novel specific nucleotide analogues activating or inhibiting cyclic nucleotide-dependent ion channels, EPAC/GEF proteins, and bacterial target molecules have been developed, opening new avenues for basic and applied research. This review provides an overview of the current state of the field, what can be expected in the future and some practical considerations for the use of cyclic nucleotide analogues in biological systems.

scholarly journals Cellular Effects of 2´,3´-Cyclic Nucleotide Monophosphates in Gram-Negative Bacteria

2021 ◽  
Author(s):  
Yashasvika Duggal ◽  
Jennifer E. Kurasz ◽  
Benjamin M. Fontaine ◽  
Nick J. Marotta ◽  
Shikha S. Chauhan ◽  
...  
Keyword(s):  
Cyclic Nucleotide ◽  
Intracellular Signaling ◽  
Biofilm Formation ◽  
Second Messengers ◽  
Rna Degradation ◽  
Signaling Molecules ◽  
Nucleotide Metabolism ◽  
E Coli ◽  
Cellular Processes ◽  
Intracellular Signaling Molecules

Organismal adaptations to environmental stimuli are governed by intracellular signaling molecules such as nucleotide second messengers. Recent studies have identified functional roles for the non-canonical 2´,3´-cyclic nucleotide monophosphates (2´,3´-cNMPs) in both eukaryotes and prokaryotes. In Escherichia coli , 2´,3´-cNMPs are produced by RNase I-catalyzed RNA degradation, and these cyclic nucleotides modulate biofilm formation through unknown mechanisms. The present work dissects cellular processes in E. coli and Salmonella Typhimurium that are modulated by 2´,3´-cNMPs through the development of cell-permeable 2´,3´-cNMP analogs and a 2´,3´-cyclic nucleotide phosphodiesterase. Utilization of these chemical and enzymatic tools, in conjunction with phenotypic and transcriptomic investigations, identified pathways regulated by 2´,3´-cNMPs, including flagellar motility and biofilm formation, and by oligoribonucleotides with 3’-terminal 2´,3´-cyclic phosphates, including responses to cellular stress. Furthermore, interrogation of metabolomic and organismal databases has identified 2´,3´-cNMPs in numerous organisms and homologs of the E. coli metabolic proteins that are involved in key eukaryotic pathways. Thus, the present work provides key insights into the roles of these understudied facets of nucleotide metabolism and signaling in prokaryotic physiology and suggest broad roles for 2´,3´-cNMPs among bacteria and eukaryotes. IMPORTANCE Bacteria adapt to environmental challenges by producing intracellular signaling molecules which control downstream pathways and alter cellular processes for survival. Nucleotide second messengers serve to transduce extracellular signals and regulate a wide array of intracellular pathways. Recently, 2´,3´-cyclic nucleotide monophosphates (2´,3´-cNMPs) were identified for contributing to the regulation of cellular pathways in eukaryotes and prokaryotes. In this study we define previously unknown cell processes that are affected by fluctuating 2´,3´-cNMP levels or RNA oligomers with 2´,3´-cyclic phosphate termini in E. coli and Salmonella Typhimurium, providing a framework for studying novel signaling networks in prokaryotes. Furthermore, we utilize metabolomics databases to identify additional prokaryotic and eukaryotic species that generate 2´,3´-cNMPs as a resource for future studies.

Lower esophageal sphincter relaxation is associated with increased cyclic nucleotide content

1986 ◽  
Vol 251 (6) ◽  
pp. G786-G793 ◽  
Author(s):  
T. J. Torphy ◽  
C. F. Fine ◽  
M. Burman ◽  
M. S. Barnette ◽  
H. S. Ormsbee
Keyword(s):  
Lower Esophageal Sphincter ◽  
Cyclic Nucleotide ◽  
Second Messengers ◽  
Electrical Field Stimulation ◽  
Dependent Manner ◽  
Frequency Dependent ◽  
Camp Content ◽  
Cyclic Monophosphate ◽  
Nucleotide Content ◽  
Esophageal Sphincter

Experiments were conducted to determine whether relaxation of the opossum isolated lower esophageal sphincter (LES), induced by electrical field stimulation (EFS) or various pharmacological agents, is associated with changes in cyclic nucleotide content. EFS relaxed the LES in a frequency-dependent manner with 0.7 Hz producing half-maximal relaxation. Control tissues and tissues stimulated at various frequencies were clamp-frozen and assayed for cyclic nucleotide content. EFS had no effect on adenosine 3',5'-cyclic monophosphate (cAMP) content but increased guanosine 3',5'-cyclic monophosphate (cGMP) content in a frequency-dependent manner. Tetrodotoxin eliminated both the relaxation and cGMP accumulation in response to EFS. Vasoactive intestinal polypeptide (VIP) relaxed the LES with an EC50 of 0.1 microM. In contrast to the results with EFS, VIP enhanced cAMP content but had no effect on cGMP content. Relaxation of the LES produced by sodium nitroprusside or atriopeptin II was accompanied by an increase in cGMP accumulation, whereas isoproterenol- and dopamine-induced relaxation was accompanied by an increase in cAMP content. The data indicate that, depending on the stimulus, increases in either cAMP or cGMP content can accompany LES relaxation. These results are consistent with the proposed role of cyclic nucleotides as second messengers mediating LES relaxation.

scholarly journals Gap Junction Channels Exhibit Connexin-specific Permeability to Cyclic Nucleotides

2008 ◽  
Vol 131 (4) ◽  
pp. 293-305 ◽  
Author(s):  
Giedrius Kanaporis ◽  
Gulistan Mese ◽  
Laima Valiuniene ◽  
Thomas W. White ◽  
Peter R. Brink ◽  
...  
Keyword(s):  
Gap Junction ◽  
Cyclic Nucleotide ◽  
Recipient Cell ◽  
Second Messengers ◽  
Functional Changes ◽  
Gap Junction Channels ◽  
Wide Range ◽  
Junctional Conductance ◽  
Specific Permeability

Gap junction channels exhibit connexin dependent biophysical properties, including selective intercellular passage of larger solutes, such as second messengers and siRNA. Here, we report the determination of cyclic nucleotide (cAMP) permeability through gap junction channels composed of Cx43, Cx40, or Cx26 using simultaneous measurements of junctional conductance and intercellular transfer of cAMP. For cAMP detection the recipient cells were transfected with a reporter gene, the cyclic nucleotide-modulated channel from sea urchin sperm (SpIH). cAMP was introduced via patch pipette into the cell of the pair that did not express SpIH. SpIH-derived currents (Ih) were recorded from the other cell of a pair that expressed SpIH. cAMP diffusion through gap junction channels to the neighboring SpIH-transfected cell resulted in a five to sixfold increase in Ih current over time. Cyclic AMP transfer was observed for homotypic Cx43 channels over a wide range of conductances. However, homotypic Cx40 and homotypic Cx26 exhibited reduced cAMP permeability in comparison to Cx43. The cAMP/K+ permeability ratios were 0.18, 0.027, and 0.018 for Cx43, Cx26, and Cx40, respectively. Cx43 channels were ∼10 to 7 times more permeable to cAMP than Cx40 or Cx26 (Cx43 > Cx26 ≥ Cx40), suggesting that these channels have distinctly different selectivity for negatively charged larger solutes involved in metabolic/biochemical coupling. These data suggest that Cx43 permeability to cAMP results in a rapid delivery of cAMP from cell to cell in sufficient quantity before degradation by phosphodiesterase to trigger relevant intracellular responses. The data also suggest that the reduced permeability of Cx26 and Cx40 might compromise their ability to deliver cAMP rapidly enough to cause functional changes in a recipient cell.

scholarly journals The dynamic interplay of host and viral enzymes in type III CRISPR-mediated cyclic nucleotide signalling

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Januka S Athukoralage ◽  
Shirley Graham ◽  
Christophe Rouillon ◽  
Sabine Grüschow ◽  
Clarissa M Czekster ◽  
...  
Keyword(s):  
Cyclic Nucleotide ◽  
Second Messengers ◽  
Sulfolobus Solfataricus ◽  
Comprehensive Analysis ◽  
Cyclase Activity ◽  
Rna Cleavage ◽  
Abortive Infection ◽  
Type Iii ◽  
Dynamic Interplay

Cyclic nucleotide second messengers are increasingly implicated in prokaryotic anti-viral defence systems. Type III CRISPR systems synthesise cyclic oligoadenylate (cOA) upon detecting foreign RNA, activating ancillary nucleases that can be toxic to cells, necessitating mechanisms to remove cOA in systems that operate via immunity rather than abortive infection. Previously, we demonstrated that the Sulfolobus solfataricus type III-D CRISPR complex generates cyclic tetra-adenylate (cA4), activating the ribonuclease Csx1, and showed that subsequent RNA cleavage and dissociation acts as an ‘off-switch’ for the cyclase activity. Subsequently, we identified the cellular ring nuclease Crn1, which slowly degrades cA4 to reset the system (Rouillon et al., 2018), and demonstrated that viruses can subvert type III CRISPR immunity by means of a potent anti-CRISPR ring nuclease variant AcrIII-1. Here, we present a comprehensive analysis of the dynamic interplay between these enzymes, governing cyclic nucleotide levels and infection outcomes in virus-host conflict.

Cyclic Nucleotide Phosphodiesterases (PDEs): Diverse Regulators of Cyclic Nucleotide Signals and Inviting Molecular Targets for Novel Therapeutic Agents

1999 ◽  
Vol 82 (08) ◽  
pp. 407-411 ◽  
Author(s):  
E. Degerman ◽  
V. C. Manganiello
Keyword(s):  
Cyclic Nucleotide ◽  
Transcription Initiation ◽  
Inflammatory Responses ◽  
Second Messengers ◽  
Gene Families ◽  
Therapeutic Agents ◽  
Cyclic Nucleotide Phosphodiesterases ◽  
Alternative Mrna Splicing ◽  
Hydrolysis Of ◽  
Nucleotide Phosphodiesterases

IntroductionCyclic adenosine 3’5’-monophosphate (cAMP) and cyclic guanosine 3’5’-monophoshpate (cGMP) are critical intracellular second-messengers involved in the transduction of a wide variety of extracellular stimuli, including peptide hormones, growth factors, cytokines, neurotransmitters and light. These messengers modulate many fundamental biological processes, including growth, differentiation, apoptosis, glycogenolysis, lipolysis, immune/inflammatory responses, etc.By catalyzing hydrolysis of cAMP and cGMP, cyclic nucleotide phosphodiesterases (PDEs) are important determinants in regulating the intracellular concentrations and, consequently, the biological actions of these second-messengers (Fig. 1). The advent of molecular genetics has revealed the extraordinary complexity and diversity of the mammalian PDE superfamily, which contains at least 10 highly regulated and structurally-related gene families (PDEs 1-10).1-8 As depicted in Figure 1, some PDEs are highly specific for hydrolysis of cAMP (PDEs 4,7,8), some are cGMP-specific (PDEs 5,6,9), and some exhibit mixed specificity (PDEs 1,2,3,10). Most gene families are comprised of more than one isogene (indicated by A-D in Table 1). At least 19 genes encoding more than 30 isoforms have been identified. PDE families differ with respect to their primary structures, sensitivity to specific inhibitors, tissue distribution, subcellular localization, and mechanisms of regulation (Table 1).2-6 Within individual families, different mRNAs are generated from the same gene by use of different transcription initiation sites or by alternative mRNA splicing. These variant PDE isoforms are often tissue-specific and selectively expressed in various tissues and cell types.2-6 The importance of cyclic nucleotide signaling in cell regulation and the molecular diversity of PDEs has presented targets for selective interventions and development of family-specific PDE inhibitors as therapeutic agents. This brief review will discuss some general characteristics of PDEs and then focus on the cellular biology and diverse functions of different PDE isoforms and their potential as therapeutic targets.

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