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      Special Issue on “New Advances in Cyclic AMP Signalling”—An Editorial Overview

      editorial
      Cells
      MDPI
      cyclic AMP, EPAC, PKA, POPDC, AKAP, adenylate cyclase, cyclic AMP phosphodiesterases, GPCRs

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          Abstract

          The cyclic nucleotides 3′,5′-adenosine monophosphate (cyclic AMP) signalling system underlies the control of many biological events and disease processes in man. Cyclic AMP is synthesised by adenylate cyclase (AC) enzymes in order to activate effector proteins and it is then degraded by phosphodiesterase (PDE) enzymes. Research in recent years has identified a range of cell-type-specific cyclic AMP effector proteins, including protein kinase A (PKA), exchange factor directly activated by cyclic AMP (EPAC), cyclic AMP responsive ion channels (CICs), and the Popeye domain containing (POPDC) proteins, which participate in different signalling mechanisms. In addition, recent advances have revealed new mechanisms of action for cyclic AMP signalling, including new effectors and new levels of compartmentalization into nanodomains, involving AKAP proteins and targeted adenylate cyclase and phosphodiesterase enzymes. This Special Issue contains 21 papers that highlight advances in our current understanding of the biology of compartmentlised cyclic AMP signalling. This ranges from issues of pathogenesis and associated molecular pathways, functional assessment of novel nanodomains, to the development of novel tool molecules and new techniques for imaging cyclic AMP compartmentilisation. This editorial aims to summarise these papers within the wider context of cyclic AMP signalling.

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          Most cited references68

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          Air Pollution and Cardiovascular Disease

          Fine particulate matter <2.5 μm (PM2.5) air pollution is the most important environmental risk factor contributing to global cardiovascular (CV) mortality and disability. Short-term elevations in PM2.5 increase the relative risk of acute CV events by 1% to 3% within a few days. Longer-term exposures over several years increase this risk by a larger magnitude (∼10%), which is partially attributable to the development of cardiometabolic conditions (e.g., hypertension and diabetes mellitus). As such, ambient PM2.5 poses a major threat to global public health. In this review, the authors provide an overview of air pollution and health, including assessment of exposure, impact on CV outcomes, mechanistic underpinnings, and impact of air pollution reduction strategies to mitigate CV risk. The review concludes with future challenges, including the inextricable link between air pollution and climate change, and calls for large-scale trials to allow the promulgation of formal evidence-based recommendations to lower air pollution-induced health risks.
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            Beta2-adrenergic receptor redistribution in heart failure changes cAMP compartmentation.

            The beta1- and beta2-adrenergic receptors (betaARs) on the surface of cardiomyocytes mediate distinct effects on cardiac function and the development of heart failure by regulating production of the second messenger cyclic adenosine monophosphate (cAMP). The spatial localization in cardiomyocytes of these betaARs, which are coupled to heterotrimeric guanine nucleotide-binding proteins (G proteins), and the functional implications of their localization have been unclear. We combined nanoscale live-cell scanning ion conductance and fluorescence resonance energy transfer microscopy techniques and found that, in cardiomyocytes from healthy adult rats and mice, spatially confined beta2AR-induced cAMP signals are localized exclusively to the deep transverse tubules, whereas functional beta1ARs are distributed across the entire cell surface. In cardiomyocytes derived from a rat model of chronic heart failure, beta2ARs were redistributed from the transverse tubules to the cell crest, which led to diffuse receptor-mediated cAMP signaling. Thus, the redistribution of beta(2)ARs in heart failure changes compartmentation of cAMP and might contribute to the failing myocardial phenotype.
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              Epac is a Rap1 guanine-nucleotide-exchange factor directly activated by cyclic AMP.

              Rap1 is a small, Ras-like GTPase that was first identified as a protein that could suppress the oncogenic transformation of cells by Ras. Rap1 is activated by several extracellular stimuli and may be involved in cellular processes such as cell proliferation, cell differentiation, T-cell anergy and platelet activation. At least three different second messengers, namely diacylglycerol, calcium and cyclic AMP, are able to activate Rap1 by promoting its release of the guanine nucleotide GDP and its binding to GTP. Here we report that activation of Rap1 by forskolin and cAMP occurs independently of protein kinase A (also known as cAMP-activated protein kinase). We have cloned the gene encoding a guanine-nucleotide-exchange factor (GEF) which we have named Epac (exchange protein directly activated by cAMP). This protein contains a cAMP-binding site and a domain that is homologous to domains of known GEFs for Ras and Rap1. Epac binds cAMP in vitro and exhibits in vivo and in vitro GEF activity towards Rap1. cAMP strongly induces the GEF activity of Epac towards Rap1 both in vivo and in vitro. We conclude that Epac is a GEF for Rap1 that is regulated directly by cAMP and that Epac is a new target protein for cAMP.
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                Author and article information

                Journal
                Cells
                Cells
                cells
                Cells
                MDPI
                2073-4409
                12 October 2020
                October 2020
                : 9
                : 10
                : 2274
                Affiliations
                Institute of Biological Chemistry, Biophysics and Bioengineering, School of Engineering and Physical Sciences, Edinburgh Campus, Heriot-Watt University, Edinburgh EH14 4AS, UK; s.yarwood@ 123456hw.ac.uk
                Author information
                https://orcid.org/0000-0001-9489-9253
                Article
                cells-09-02274
                10.3390/cells9102274
                7599692
                33053803
                a16c59eb-6747-450f-a2f8-44ac9c179ab4
                © 2020 by the author.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 09 October 2020
                : 10 October 2020
                Categories
                Editorial

                cyclic amp,epac,pka,popdc,akap,adenylate cyclase,cyclic amp phosphodiesterases,gpcrs

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