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      Mammalian γ2 AMPK regulates intrinsic heart rate

      research-article
      1 , 2 , 3 , , 2 , 3 , 4 , 5 , 6 , 2 , 3 , 7 , 8 , 9 , 6 , 10 , 11 , 2 , 3 , 2 , 3 , 2 , 3 , 2 , 3 , 2 , 3 , 10 , 8 , 9 , 6 , 6 , 6 , 6 , 6 , 6 , 6 , 4 , 5 , 6 , 6 , 6 , 6 , 6 , 3 , 3 , 3 , 2 , 3 , 2 , 3 , 3 , 12 , 13 , 2 , 3 , 2 , 3 , 2 , 3 , 2 , 3 , 14 , 15 , 15 , 2 , 3 , 2 , 2 , 3 , 16 , 2 , 3 , 13 , 17 , 11 , 18 , 2 , 3 , 3 , 12 , 14 , 7 , 2 , 15 , 10 , 8 , 9 , 4 , 5 , 4 , 5 , 6 , 2 , 3 , 1 , 2 , 3 ,
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          Abstract

          AMPK is a conserved serine/threonine kinase whose activity maintains cellular energy homeostasis. Eukaryotic AMPK exists as αβγ complexes, whose regulatory γ subunit confers energy sensor function by binding adenine nucleotides. Humans bearing activating mutations in the γ2 subunit exhibit a phenotype including unexplained slowing of heart rate (bradycardia). Here, we show that γ2 AMPK activation downregulates fundamental sinoatrial cell pacemaker mechanisms to lower heart rate, including sarcolemmal hyperpolarization-activated current ( I f) and ryanodine receptor-derived diastolic local subsarcolemmal Ca 2+ release. In contrast, loss of γ2 AMPK induces a reciprocal phenotype of increased heart rate, and prevents the adaptive intrinsic bradycardia of endurance training. Our results reveal that in mammals, for which heart rate is a key determinant of cardiac energy demand, AMPK functions in an organ-specific manner to maintain cardiac energy homeostasis and determines cardiac physiological adaptation to exercise by modulating intrinsic sinoatrial cell behavior.

          Abstract

          AMPK regulates cellular energy balance using its γ subunit as an energy sensor of cellular AMP and ADP to ATP ratios. Here, the authors show that γ2 AMPK activation lowers heart rate by reducing the activity of pacemaker cells, whereas loss of γ2 AMPK increases heart rate and prevents the adaptive bradycardia of endurance training in mice.

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          Manipulation of FASTQ data with Galaxy

          Summary: Here, we describe a tool suite that functions on all of the commonly known FASTQ format variants and provides a pipeline for manipulating next generation sequencing data taken from a sequencing machine all the way through the quality filtering steps. Availability and Implementation: This open-source toolset was implemented in Python and has been integrated into the online data analysis platform Galaxy (public web access: http://usegalaxy.org; download: http://getgalaxy.org). Two short movies that highlight the functionality of tools described in this manuscript as well as results from testing components of this tool suite against a set of previously published files are available at http://usegalaxy.org/u/dan/p/fastq Contact: james.taylor@emory.edu; anton@bx.psu.edu Supplementary information: Supplementary data are available at Bioinformatics online.
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            WikiPathways: Pathway Editing for the People

            WikiPathways provides a collaborative platform for creating, updating, and sharing pathway diagrams and serves as an example of content curation by the biology community.
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              UCP2 mediates ghrelin's action on NPY/AgRP neurons by lowering free radicals.

              The gut-derived hormone ghrelin exerts its effect on the brain by regulating neuronal activity. Ghrelin-induced feeding behaviour is controlled by arcuate nucleus neurons that co-express neuropeptide Y and agouti-related protein (NPY/AgRP neurons). However, the intracellular mechanisms triggered by ghrelin to alter NPY/AgRP neuronal activity are poorly understood. Here we show that ghrelin initiates robust changes in hypothalamic mitochondrial respiration in mice that are dependent on uncoupling protein 2 (UCP2). Activation of this mitochondrial mechanism is critical for ghrelin-induced mitochondrial proliferation and electric activation of NPY/AgRP neurons, for ghrelin-triggered synaptic plasticity of pro-opiomelanocortin-expressing neurons, and for ghrelin-induced food intake. The UCP2-dependent action of ghrelin on NPY/AgRP neurons is driven by a hypothalamic fatty acid oxidation pathway involving AMPK, CPT1 and free radicals that are scavenged by UCP2. These results reveal a signalling modality connecting mitochondria-mediated effects of G-protein-coupled receptors on neuronal function and associated behaviour.
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                Author and article information

                Contributors
                arash.yavari@well.ox.ac.uk
                houman.ashrafian@cardiov.ox.ac.uk
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                2 November 2017
                2 November 2017
                2017
                : 8
                : 1258
                Affiliations
                [1 ]ISNI 0000 0004 1936 8948, GRID grid.4991.5, Experimental Therapeutics, Radcliffe Department of Medicine, University of Oxford, ; Oxford, OX3 9DU UK
                [2 ]ISNI 0000 0004 1936 8948, GRID grid.4991.5, Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, ; Oxford, OX3 9DU UK
                [3 ]ISNI 0000 0004 1936 8948, GRID grid.4991.5, The Wellcome Trust Centre for Human Genetics, ; Oxford, OX3 7BN UK
                [4 ]ISNI 0000 0004 1757 2822, GRID grid.4708.b, Department of Biosciences, , Università degli Studi di Milano, ; Milan, 20133 Italy
                [5 ]ISNI 0000 0004 1757 2822, GRID grid.4708.b, Centro Interuniversitario di Medicina Molecolare e Biofisica Applicata, University of Milano, ; Milan, 20133 Italy
                [6 ]ISNI 0000 0000 9372 4913, GRID grid.419475.a, Laboratory of Cardiovascular Science, Intramural Research Program, National Institute on Aging, NIH, ; Baltimore, MD 21224 USA
                [7 ]ISNI 0000 0004 1936 8948, GRID grid.4991.5, Burdon Sanderson Cardiac Science Centre, Department of Physiology, Anatomy & Genetics, University of Oxford, ; Oxford, OX1 3PT UK
                [8 ]ISNI 0000000121858338, GRID grid.10493.3f, Department of Cardiac Surgery, , Rostock University Medical Centre, ; 18057 Rostock, Germany
                [9 ]ISNI 0000000121858338, GRID grid.10493.3f, Department Life, Light and Matter, , Interdisciplinary Faculty, Rostock University, ; 18059 Rostock, Germany
                [10 ]ISNI 0000 0001 0703 675X, GRID grid.430503.1, Department of Physiology and Biophysics, , University of Colorado School of Medicine, ; Aurora, CO 80045 USA
                [11 ]ISNI 0000000121858338, GRID grid.10493.3f, Department of Systems Biology and Bioinformatics, , University of Rostock, ; Rostock, 18051 Germany
                [12 ]ISNI 0000 0004 1936 8948, GRID grid.4991.5, MRC Human Immunology Unit, Weatherall Institute for Molecular Medicine, Nuffield Department of Medicine, University of Oxford, ; Oxford, OX3 9DS UK
                [13 ]Department of Medicine, BHF Laboratories, The Rayne Institute, University College London, London, WC1E 6JJ UK
                [14 ]ISNI 0000 0004 0413 0953, GRID grid.419130.e, Instituto de Pós-Graduação, Faculdade de Ciências Médicas de Minas Gerais, ; Belo Horizonte, 30.130-110 Brazil
                [15 ]ISNI 0000 0001 2113 8111, GRID grid.7445.2, Cellular Stress Group, MRC London Institute of Medical Sciences, Imperial College London, ; London, W12 0NN UK
                [16 ]ISNI 0000 0004 1936 8948, GRID grid.4991.5, Nuffield Department of Clinical Laboratory Science, University of Oxford, ; Oxford, OX3 9DU UK
                [17 ]ISNI 0000 0001 2171 1133, GRID grid.4868.2, The Heart Centre, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, ; London, EC1M 6BQ UK
                [18 ]ISNI 0000 0001 2214 904X, GRID grid.11956.3a, Stellenbosch Institute of Advanced Study (STIAS), Wallenberg Research Centre at Stellenbosch University, ; Stellenbosch, 7602 South Africa
                Author information
                http://orcid.org/0000-0001-7799-4670
                http://orcid.org/0000-0002-1887-4772
                http://orcid.org/0000-0003-2840-4851
                http://orcid.org/0000-0003-4019-1844
                http://orcid.org/0000-0001-5045-819X
                http://orcid.org/0000-0003-0999-5684
                http://orcid.org/0000-0002-7322-1790
                Article
                1342
                10.1038/s41467-017-01342-5
                5668267
                29097735
                db0df3da-86bb-44fa-9584-6eabf8a20d48
                © The Author(s) 2017

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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                : 12 June 2017
                : 8 September 2017
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