Mammalian γ2 AMPK regulates intrinsic heart rate.

Autor: Yavari A; Experimental Therapeutics, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DU, UK. arash.yavari@well.ox.ac.uk.; Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DU, UK. arash.yavari@well.ox.ac.uk.; The Wellcome Trust Centre for Human Genetics, Oxford, OX3 7BN, UK. arash.yavari@well.ox.ac.uk., Bellahcene M; Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DU, UK.; The Wellcome Trust Centre for Human Genetics, Oxford, OX3 7BN, UK., Bucchi A; Department of Biosciences, Università degli Studi di Milano, Milan, 20133, Italy.; Centro Interuniversitario di Medicina Molecolare e Biofisica Applicata, University of Milano, Milan, 20133, Italy., Sirenko S; Laboratory of Cardiovascular Science, Intramural Research Program, National Institute on Aging, NIH, Baltimore, MD, 21224, USA., Pinter K; Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DU, UK.; The Wellcome Trust Centre for Human Genetics, Oxford, OX3 7BN, UK., Herring N; Burdon Sanderson Cardiac Science Centre, Department of Physiology, Anatomy & Genetics, University of Oxford, Oxford, OX1 3PT, UK., Jung JJ; Department of Cardiac Surgery, Rostock University Medical Centre, 18057, Rostock, Germany.; Department Life, Light and Matter, Interdisciplinary Faculty, Rostock University, 18059, Rostock, Germany., Tarasov KV; Laboratory of Cardiovascular Science, Intramural Research Program, National Institute on Aging, NIH, Baltimore, MD, 21224, USA., Sharpe EJ; Department of Physiology and Biophysics, University of Colorado School of Medicine, Aurora, CO, 80045, USA., Wolfien M; Department of Systems Biology and Bioinformatics, University of Rostock, Rostock, 18051, Germany., Czibik G; Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DU, UK.; The Wellcome Trust Centre for Human Genetics, Oxford, OX3 7BN, UK., Steeples V; Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DU, UK.; The Wellcome Trust Centre for Human Genetics, Oxford, OX3 7BN, UK., Ghaffari S; Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DU, UK.; The Wellcome Trust Centre for Human Genetics, Oxford, OX3 7BN, UK., Nguyen C; Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DU, UK.; The Wellcome Trust Centre for Human Genetics, Oxford, OX3 7BN, UK., Stockenhuber A; Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DU, UK.; The Wellcome Trust Centre for Human Genetics, Oxford, OX3 7BN, UK., Clair JRS; Department of Physiology and Biophysics, University of Colorado School of Medicine, Aurora, CO, 80045, USA., Rimmbach C; Department of Cardiac Surgery, Rostock University Medical Centre, 18057, Rostock, Germany.; Department Life, Light and Matter, Interdisciplinary Faculty, Rostock University, 18059, Rostock, Germany., Okamoto Y; Laboratory of Cardiovascular Science, Intramural Research Program, National Institute on Aging, NIH, Baltimore, MD, 21224, USA., Yang D; Laboratory of Cardiovascular Science, Intramural Research Program, National Institute on Aging, NIH, Baltimore, MD, 21224, USA., Wang M; Laboratory of Cardiovascular Science, Intramural Research Program, National Institute on Aging, NIH, Baltimore, MD, 21224, USA., Ziman BD; Laboratory of Cardiovascular Science, Intramural Research Program, National Institute on Aging, NIH, Baltimore, MD, 21224, USA., Moen JM; Laboratory of Cardiovascular Science, Intramural Research Program, National Institute on Aging, NIH, Baltimore, MD, 21224, USA., Riordon DR; Laboratory of Cardiovascular Science, Intramural Research Program, National Institute on Aging, NIH, Baltimore, MD, 21224, USA., Ramirez C; Laboratory of Cardiovascular Science, Intramural Research Program, National Institute on Aging, NIH, Baltimore, MD, 21224, USA., Paina M; Department of Biosciences, Università degli Studi di Milano, Milan, 20133, Italy.; Centro Interuniversitario di Medicina Molecolare e Biofisica Applicata, University of Milano, Milan, 20133, Italy., Lee J; Laboratory of Cardiovascular Science, Intramural Research Program, National Institute on Aging, NIH, Baltimore, MD, 21224, USA., Zhang J; Laboratory of Cardiovascular Science, Intramural Research Program, National Institute on Aging, NIH, Baltimore, MD, 21224, USA., Ahmet I; Laboratory of Cardiovascular Science, Intramural Research Program, National Institute on Aging, NIH, Baltimore, MD, 21224, USA., Matt MG; Laboratory of Cardiovascular Science, Intramural Research Program, National Institute on Aging, NIH, Baltimore, MD, 21224, USA., Tarasova YS; Laboratory of Cardiovascular Science, Intramural Research Program, National Institute on Aging, NIH, Baltimore, MD, 21224, USA., Baban D; The Wellcome Trust Centre for Human Genetics, Oxford, OX3 7BN, UK., Sahgal N; The Wellcome Trust Centre for Human Genetics, Oxford, OX3 7BN, UK., Lockstone H; The Wellcome Trust Centre for Human Genetics, Oxford, OX3 7BN, UK., Puliyadi R; Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DU, UK.; The Wellcome Trust Centre for Human Genetics, Oxford, OX3 7BN, UK., de Bono J; Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DU, UK.; The Wellcome Trust Centre for Human Genetics, Oxford, OX3 7BN, UK., Siggs OM; The Wellcome Trust Centre for Human Genetics, Oxford, OX3 7BN, UK.; MRC Human Immunology Unit, Weatherall Institute for Molecular Medicine, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 9DS, UK., Gomes J; Department of Medicine, BHF Laboratories, The Rayne Institute, University College London, London, WC1E 6JJ, UK., Muskett H; Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DU, UK.; The Wellcome Trust Centre for Human Genetics, Oxford, OX3 7BN, UK., Maguire ML; Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DU, UK.; The Wellcome Trust Centre for Human Genetics, Oxford, OX3 7BN, UK., Beglov Y; Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DU, UK.; The Wellcome Trust Centre for Human Genetics, Oxford, OX3 7BN, UK., Kelly M; Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DU, UK.; The Wellcome Trust Centre for Human Genetics, Oxford, OX3 7BN, UK., Dos Santos PPN; Instituto de Pós-Graduação, Faculdade de Ciências Médicas de Minas Gerais, Belo Horizonte, 30.130-110, Brazil., Bright NJ; Cellular Stress Group, MRC London Institute of Medical Sciences, Imperial College London, London, W12 0NN, UK., Woods A; Cellular Stress Group, MRC London Institute of Medical Sciences, Imperial College London, London, W12 0NN, UK., Gehmlich K; Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DU, UK.; The Wellcome Trust Centre for Human Genetics, Oxford, OX3 7BN, UK., Isackson H; Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DU, UK., Douglas G; Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DU, UK.; The Wellcome Trust Centre for Human Genetics, Oxford, OX3 7BN, UK., Ferguson DJP; Nuffield Department of Clinical Laboratory Science, University of Oxford, Oxford, OX3 9DU, UK., Schneider JE; Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DU, UK.; The Wellcome Trust Centre for Human Genetics, Oxford, OX3 7BN, UK., Tinker A; Department of Medicine, BHF Laboratories, The Rayne Institute, University College London, London, WC1E 6JJ, UK.; The Heart Centre, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, London, EC1M 6BQ, UK., Wolkenhauer O; Department of Systems Biology and Bioinformatics, University of Rostock, Rostock, 18051, Germany.; Stellenbosch Institute of Advanced Study (STIAS), Wallenberg Research Centre at Stellenbosch University, Stellenbosch, 7602, South Africa., Channon KM; Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DU, UK.; The Wellcome Trust Centre for Human Genetics, Oxford, OX3 7BN, UK., Cornall RJ; The Wellcome Trust Centre for Human Genetics, Oxford, OX3 7BN, UK.; MRC Human Immunology Unit, Weatherall Institute for Molecular Medicine, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 9DS, UK., Sternick EB; Instituto de Pós-Graduação, Faculdade de Ciências Médicas de Minas Gerais, Belo Horizonte, 30.130-110, Brazil., Paterson DJ; Burdon Sanderson Cardiac Science Centre, Department of Physiology, Anatomy & Genetics, University of Oxford, Oxford, OX1 3PT, UK., Redwood CS; Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DU, UK., Carling D; Cellular Stress Group, MRC London Institute of Medical Sciences, Imperial College London, London, W12 0NN, UK., Proenza C; Department of Physiology and Biophysics, University of Colorado School of Medicine, Aurora, CO, 80045, USA., David R; Department of Cardiac Surgery, Rostock University Medical Centre, 18057, Rostock, Germany.; Department Life, Light and Matter, Interdisciplinary Faculty, Rostock University, 18059, Rostock, Germany., Baruscotti M; Department of Biosciences, Università degli Studi di Milano, Milan, 20133, Italy.; Centro Interuniversitario di Medicina Molecolare e Biofisica Applicata, University of Milano, Milan, 20133, Italy., DiFrancesco D; Department of Biosciences, Università degli Studi di Milano, Milan, 20133, Italy.; Centro Interuniversitario di Medicina Molecolare e Biofisica Applicata, University of Milano, Milan, 20133, Italy., Lakatta EG; Laboratory of Cardiovascular Science, Intramural Research Program, National Institute on Aging, NIH, Baltimore, MD, 21224, USA., Watkins H; Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DU, UK.; The Wellcome Trust Centre for Human Genetics, Oxford, OX3 7BN, UK., Ashrafian H; Experimental Therapeutics, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DU, UK. houman.ashrafian@cardiov.ox.ac.uk.; Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 9DU, UK. houman.ashrafian@cardiov.ox.ac.uk.; The Wellcome Trust Centre for Human Genetics, Oxford, OX3 7BN, UK. houman.ashrafian@cardiov.ox.ac.uk.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2017 Nov 02; Vol. 8 (1), pp. 1258. Date of Electronic Publication: 2017 Nov 02.
DOI: 10.1038/s41467-017-01342-5
Abstrakt: 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.
Databáze: MEDLINE