Cyclic Nucleotide Research Research Articles

Earl Sutherland (1915-1975) and the Discovery of Cyclic AMP

In 1945, Earl Sutherland (1915-1974) [corrected] and associates began studies of the mechanism of hormone-induced glycogen breakdown in the liver. In 1956, their efforts culminated in the identification of cyclic AMP, an ancient molecule generated in many cell types in response to hormonal and other extracellular signals. Cyclic AMP, the original "second messenger," transmits such signals through pathways that regulate a diversity of cellular functions and capabilities: metabolic processes such as lipolysis and glycogenolysis; hormone secretion; the permeability of ion channels; gene expression; cell proliferation and survival. Indeed, it can be argued that the discovery of cyclic AMP initiated the study of intracellular signaling pathways, a major focus of contemporary biomedical inquiry. This review presents relevant details of Sutherland's career; summarizes key contributions of his mentors, Carl and Gerti Cori, to the knowledge of glycogen metabolism (contributions that were the foundation for his own research); describes the experiments that led to his identification, isolation, and characterization of cyclic AMP; assesses the significance of his work; and considers some aspects of the impact of cyclic nucleotide research on clinical medicine.

How uniform is cAMP signaling? Focus on “Systems analysis of GLP-1 receptor signaling in pancreatic β-cells”

the goal of many cell physiologists is to ascribe cellular behavior to specific molecular signaling mechanisms. However, the reductionist experimental approach commonly used to understand molecular function often makes this task harder rather than easier to accomplish because of the complexity of

Cyclic Nucleotide Binding GAF Domains from Phosphodiesterases: Structural and Mechanistic Insights

GAF domains regulate the catalytic activity of certain vertebrate cyclic nucleotide phosphodiesterases (PDEs) by allosteric, noncatalytic binding of cyclic nucleotides. GAF domains arranged in tandem are found in PDE2, -5, -6, -10, and -11, all of which regulate the cellular concentrations of the second messengers cAMP and/or cGMP. Nucleotide binding to GAF domains affects the overall conformation and the catalytic activity of full-length PDEs. The cyclic nucleotide-bound GAF domains from PDE2, -5, -6, and -10 all adopt a conserved fold but show subtle differences within the binding pocket architecture that account for a large range of nucleotide affinities and selectivity. NMR data and details from the structure of full-length nucleotide-free PDE2A reveal the dynamic nature and magnitude of the conformational change that accompanies nucleotide binding. The discussed GAF domain structures further reveal differences in dimerization properties and highlight the structural diversity within GAF domain-containing PDEs.

CGMP signalling: from bench to bedside

The 2nd International Conference on cGMP Generators, Effectors and Therapeutic Implications took place in Potsdam, Germany, during 10–12 June 2005, and was organized by L. Ignarro, F. Hofmann, H. Schmidt and J.P. Stasch (www.cyclicgmp.net). The next cGMP meeting will be held in Dresden, Germany, in June 2007. ![][1] Cyclic nucleotide research originated in the 1960s, when cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) were first identified as natural products (reviewed in Beavo & Brunton, 2002). The discovery of cAMP led to the formulation of the second‐messenger concept in hormone signalling by Earl W. Sutherland, who was duly rewarded with the Nobel Prize in 1971. Consequently, cAMP research surged ahead, whereas cGMP attracted little attention. Indeed, the biological role of cGMP was unknown until the 1980s when two key discoveries were made. First, it was found that a peptide synthesized in the heart, atrial natriuretic peptide (ANP), could stimulate cGMP synthesis by binding to a transmembrane receptor, the particulate guanylyl cyclase (pGC). Second, the elusive endothelium‐derived relaxing factor was identified as nitric oxide (NO), which stimulates soluble guanylyl cyclase (sGC) in smooth muscle cells to synthesize cGMP, thereby causing vasorelaxation. Subsequently, other components of cGMP metabolism and signal transduction were also identified (Fig 1). It is now known that cGMP‐hydrolysing phosphodiesterases (PDEs) are responsible for cGMP breakdown, and at least three types of cGMP‐binding protein transduce the cGMP signal to alter cellular function. These three types are cGMP‐modulated cation channels, cGMP‐dependent protein kinases (cGKs) and cGMP‐regulated PDEs that degrade cAMP and/or cGMP. Figure 1. Current concepts of cGMP signalling. cGMP generators (green) and effectors (red), as well as some downstream pathways and cellular functions (grey boxes) that are involved in the effects of endogenous cGMP and/or cGMP‐elevating drugs (blue), are shown. The lower part shows some current (blue) as well as potential … [1]: /embed/graphic-1.gif

Cyclic nucleotides

The natural occurrence of cyclic nucleotides in higher plants, formerly a topic of fierce debate, is now established, as is the presence of nucleotidyl cyclases and cyclic nucleotide phosphodiesterases capable of their synthesis and breakdown. Here we describe the significant properties of cyclic nucleotides, also outlining their second messenger functions and the history of plant cyclic nucleotide research over its first three decades. Findings of the last five years are detailed within the context of the functional role of cyclic nucleotides in higher plants, with particular emphasis upon nucleotidyl cyclases and cyclic nucleotide-responsive protein kinases, -binding proteins and –gated ion channels, with future objectives and strategies discussed.

Cyclic nucleotide research -- still expanding after half a century.

Since the discovery in 1957 that cyclic AMP acts as a second messenger for the hormone adrenaline, interest in this molecule and its companion, cyclic GMP, has grown. Over a period of nearly 50 years, research into second messengers has provided a framework for understanding transmembrane signal transduction, receptor-effector coupling, protein-kinase cascades and downregulation of drug responsiveness. The breadth and impact of this work is reflected by five different Nobel prizes.

Qualitative and quantitative mass spectrometric analysis of cyclic nucleotides and related enzymes

The application of fast atom bombardment mass spectrometry (MS) and collisionally induced dissociation with mass-analysed kinetic energy spectrum scanning to biochemical studies of cyclic nucleotides is reviewed. MS analysis of partially purified tissue extracts has enabled the demonstration of the natural occurrence in mammals and higher plants of five cyclic nucleotides in addition to the previously established adenosine 3′,5′-cyclic monophosphate; analysis of the products of a putative cytidylate cyclase enzyme-catalyzed reaction has demonstrated the biosynthesis of cytidine 3′,5′-cyclic monophosphate and four novel analogues as side products, thereby enabling the development of specific assays. Quantitative applications have included kinetic analysis of phosphodiesterase and cyclic nucleotide-responsive protein kinase activity, while further quantitative applications have included the structural elucidation of synthetic cyclic nucleotide derivatives used in pharmacological studies. The impact of MS upon cyclic nucleotide research and its future potential are discussed.

Advances in Cyclic Nucleotide and Protein Phosphorylation Research (Formerly Advances in Cyclic Nucleotide Research). Volume 18.Paul Greengard , G. Alan Robison

Previous articleNext article No AccessNew Biological BooksAdvances in Cyclic Nucleotide and Protein Phosphorylation Research (Formerly Advances in Cyclic Nucleotide Research). Volume 18. Paul Greengard , G. Alan Robison Michael BaranyMichael Barany Search for more articles by this author PDFPDF PLUS Add to favoritesDownload CitationTrack CitationsPermissionsReprints Share onFacebookTwitterLinkedInRedditEmail SectionsMoreDetailsFiguresReferencesCited by The Quarterly Review of Biology Volume 60, Number 3Sep., 1985 Published in association with Stony Brook University Article DOIhttps://doi.org/10.1086/414439 Views: 1Total views on this site Copyright 1985 Stony Brook Foundation, Inc.PDF download Crossref reports no articles citing this article.

Advances in Cyclic Nucleotide Research

Advances in Cyclic Nucleotide Research

HORMONES, RECEPTORS AND CYCLIC NUCLEOTIDES: PAPERS PRESENTED AT THE 6th SCANDINAVIAN MEETING ON CYCLIC NUCLEOTIDE RESEARCH, UTÖ MAY 24‐26, 1981

HORMONES, RECEPTORS AND CYCLIC NUCLEOTIDES: PAPERS PRESENTED AT THE 6^th SCANDINAVIAN MEETING ON CYCLIC NUCLEOTIDE RESEARCH, UTÖ MAY 24‐26, 1981

Advances in Cyclic Nucleotide Research.

Advances in Cyclic Nucleotide Research.

Alpha‐adrenoceptor mediated inhibition of human fat cell adenylate cyclase.

British Journal of Clinical PharmacologyVolume 8, Issue 6 p. 594-595 Free Access alpha-adrenoceptor mediated inhibition of human fat cell adenylate cyclase. H Kather, H KatherSearch for more papers by this authorJ Pries, J PriesSearch for more papers by this authorV Schrader, V SchraderSearch for more papers by this authorB Simon, B SimonSearch for more papers by this author H Kather, H KatherSearch for more papers by this authorJ Pries, J PriesSearch for more papers by this authorV Schrader, V SchraderSearch for more papers by this authorB Simon, B SimonSearch for more papers by this author First published: December 1979 https://doi.org/10.1111/j.1365-2125.1979.tb01051.xCitations: 3AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. References ARNER, P., ENGFELDT, P. & ÖSTMAN, J. (1979). Relationship between lipolysis, cyclic AMP, and fat cell size in human adipose tissue during fasting and in diabetes mellitus. Metabolism, 28, 198– 209. BURNS, T.W., LANGLEY, P.E. & ROBISON, G.A. (1972). Studies on the role of cyclic AMP in human lipolysis. Adv. Cyclic Nucleotide Res., 1, 321– 328. KATHER, H. & GEIGER, M. (1977). Adrenaline-sensitive adenylate cyclase of human fat cell ghosts; properties and hormone-sensitivity. Eur. J. clin. Invest., 7, 363– 371. KATHER, H. & SIMON, B. (1977). Catecholamine-sensitive adenylate cyclase of human fat cell ghosts; a comparative study using different β-adrenergic agonists Metabolism, 26, 1179– 1184. KUNOS, G. (1978). Adrenoceptors. Ann. Rev. Pharmac. Tox., 18, 291– 311. RODBELL, M. (1972). Methods in Cyclic Nucleotide Research, ed. M. Chasin, pp. 101– 124. ROSENQUIST, U. (1972). Inhibition of noradrenaline-induced lipolysis in hypothyroid subjects by increased α-adrenergic responsiveness. Acta med. scand., 192, 353– 359. SOLOMON, Y., LONDOS, C. & RODBELL, M. (1974). A highly sensitive adenylate cyclase assay. Analyt. Biochem., 58, 541– 548. Citing Literature Volume8, Issue6December 1979Pages 594-595 ReferencesRelatedInformation

Advances in cyclic nucleotide research, 10, current methodology

Advances in cyclic nucleotide research, 10, current methodology

Cyclic Nucleotide Research

Cyclic Nucleotide Research

Rational basis for the application of cimetidine in the therapy of human gastric hypersecretion.

British Journal of Clinical PharmacologyVolume 4, Issue 4 p. 487-488 Free Access Rational basis for the application of cimetidine in the therapy of human gastric hypersecretion. B Simon, B SimonSearch for more papers by this authorH Kather, H KatherSearch for more papers by this author B Simon, B SimonSearch for more papers by this authorH Kather, H KatherSearch for more papers by this author First published: August 1977 https://doi.org/10.1111/j.1365-2125.1977.tb00769.xAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. References HAGGIE, S.J., FERMONT, D.C. & WYLLIE, J.H. (1976). Treatment of duodenal ulcer with cimetidine. Lancet, i, 983– 986. LOWRY, O.H., ROSEBROUGH, N.J., FARR, A.L. & RANDALL, R.I. (1954). Protein measurement with the Folin phenol reagent. J. biol. Chem., 193, 265– 275. OHKURA, H. & HATTORI, N. (1975). Gastrin- and histamine-activated adenyl cyclase in isolated rat perietal cells. In Advances in Cyclic Nucleotide Research, 5, pp 819– 830, eds. G.I. Drummond, P. Greengard & G.A. Robison New York: Raven Press. POUNDER, R.E., HUNT, R.H., STEKELMAN, M., MILTONTHOMPSON, G.J. & MISIEWICZ, J.J. (1976). Healing of gastric ulcer treatment with cimetidine. Lancet, i, 337– 339. RAY, T.K. & FORTE, J.G. (1974). Adenyl cyclase of oxyntic cells. Its association with different cellular membranes. Biochem. Biophys. Acta, 320, 320– 339. SALOMON, Y., LONDOS, C. & RODBELL, M. (1974). A highly sensitive adenylate cyclase assay. Analyt. Biochem., 58, 541– 548. SIMON, B. & KATHER, H. (1977). Adenylate cyclase of human gastric mucosa. Stimulation of enzyme activity by histamine and catecholamines. Digestion, (in press). Volume4, Issue4August 1977Pages 487-488 ReferencesRelatedInformation

Book Reviews

Book reviewed in this article:Cancer Chemotherapy. M. J. Cline and C. M. Haskell.Organic Nitrates (Handbook of Experimental Pharmacology, Volume 40). Philip NeedlemanDrugs and Transport Process. B. A. CallinghamMicrobiology—1974. David SchlessingerPharmacokinetics, Drag Metabolism and Drag Interactions (Principles and Techniques of Human Research and Therapeutics, Volume III). F. Gilbert McMahonAdvances in Cyclic Nucleotide Research, Volume 6. P. Greengard and G. A. RobisonCytochromes P‐450 and b5: Structure, Function and Interation (Advances in Experimental Medicine and Biology, Volume 58). D. Y. Cooper, O. Rosenthal, R. Snyder, and C. Witmer

Book Reviews

Book reviewed in this article:The Human Heart and Circulation. Visvan Navaratnam.Basic and Therapeutic Aspects of Perinatal Pharmacology. P. L. Morselli, S. Garattini, and F. SereniThe Clinical Uses of Levodopa. Gerald SternMechanisms of Action of Benzodiazepines (Advances in Biochemical Psychopharmacology, Vol. 14). E. Costa and P. GreengardPharmacy and the Law. Carl T. DeMarco.Progress in Chemical Toxicology, Volume 5. A. StolmanFundamentals of Clinical Pharmacokinetics. John G. Wagner. HamiltonAdvances in Cyclic Nucleotide Research, Volume 5. G. I. Drummond, P. Greengard, and G. A. Robison

Advances in Cyclic Nucleotide Research, Volume 6

Advances in Cyclic Nucleotide Research, Volume 6

Advances in Cyclic Nucleotide Research. Paul Greengard , G. Alan Robison

Previous articleNext article No AccessNew Biological BooksAdvances in Cyclic Nucleotide Research. Paul Greengard , G. Alan Robison R. Maynard CaseR. Maynard Case Search for more articles by this author PDFPDF PLUS Add to favoritesDownload CitationTrack CitationsPermissionsReprints Share onFacebookTwitterLinkedInRedditEmail SectionsMoreDetailsFiguresReferencesCited by The Quarterly Review of Biology Volume 51, Number 2Jun., 1976 Published in association with Stony Brook University Article DOIhttps://doi.org/10.1086/409335 Copyright 1976 Stony Brook Foundation, Inc.PDF download Crossref reports no articles citing this article.

Book Reviews

Book reviewed in this article:Regulating New Drugs. Richard L. Landau, editor.Factors in Depression. Nathan S. Klein, editor.The Phagocytic Cell in Host Defense. J. A. Bellanti and D. H. Dayton, editors.The Antigens, Volume 1. Michael Sela, editor.The Antigens, Volume II. Michael Sela, editor.Advances in Cyclic Nucleotide Research, Volume 4. P. Greengard and G. A. Robison, editors.