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Division of Molecular Physiology, University of Dundee, Wellcome Trust Biocentre, Dundee DD1 5EH, Scotland, United Kingdom
Address all correspondence and requests for reprints to: D. Grahame Hardie, Division of Molecular Physiology, University of Dundee, Wellcome Trust Biocentre, Dundee DD1 5EH, Scotland, United Kingdom. E-mail: d.g.hardie{at}dundee.ac.uk.
All cells must maintain a high ratio of cellular ATP:ADP to survive. Because of the adenylate kinase reaction (2ADP 
ATP + AMP), AMP rises whenever the ATP:ADP ratio falls, and a high cellular ratio of AMP:ATP is a signal that the energy status of the cell is compromised. The AMP-activated protein kinase (AMPK) is the downstream component of a protein kinase cascade that is switched on by a rise in the AMP:ATP ratio, via a complex mechanism that results in an exquisitely sensitive system. AMPK is switched on by cellular stresses that either interfere with ATP production (e.g. hypoxia, glucose deprivation, or ischemia) or by stresses that increase ATP consumption (e.g. muscle contraction). It is also activated by hormones that act via Gq-coupled receptors, and by leptin and adiponectin, via mechanisms that remain unclear. Once activated, the system switches on catabolic pathways that generate ATP, while switching off ATP-consuming processes that are not essential for short-term cell survival, such as the synthesis of lipids, carbohydrates, and proteins. The AMPK cascade is the probable target for the antidiabetic drug metformin, and current indications are that it is responsible for many of the beneficial effects of exercise in the treatment and prevention of type 2 diabetes and the metabolic syndrome.
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M. W. Sun, J. Y. Lee, P. I.W. de Bakker, N. P. Burtt, P. Almgren, L. Rastam, T. Tuomi, D. Gaudet, M. J. Daly, J. N. Hirschhorn, et al. Haplotype Structures and Large-Scale Association Testing of the 5' AMP-Activated Protein Kinase Genes PRKAA2, PRKAB1, and PRKAB2 With Type 2 Diabetes Diabetes, March 1, 2006; 55(3): 849 - 855. [Abstract] [Full Text] [PDF]
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C. LaRosa and S. M. Downs Stress Stimulates AMP-Activated Protein Kinase and Meiotic Resumption in Mouse Oocytes Biol Reprod, March 1, 2006; 74(3): 585 - 592. [Abstract] [Full Text] [PDF]
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 C. R. Hancock, E. Janssen, and R. L. Terjung Contraction-mediated phosphorylation of AMPK is lower in skeletal muscle of adenylate kinase-deficient mice J Appl Physiol, February 1, 2006; 100(2): 406 - 413. [Abstract] [Full Text] [PDF]
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S. J. Lessard, Z.-P. Chen, M. J. Watt, M. Hashem, J. J. Reid, M. A. Febbraio, B. E. Kemp, and J. A. Hawley Chronic rosiglitazone treatment restores AMPK{alpha}2 activity in insulin-resistant rat skeletal muscle Am J Physiol Endocrinol Metab, February 1, 2006; 290(2): E251 - E257. [Abstract] [Full Text] [PDF]
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T. L. Hilder, L. A. Baer, P. M. Fuller, C. A. Fuller, R. E. Grindeland, C. E. Wade, and L. M. Graves Insulin-independent pathways mediating glucose uptake in hindlimb-suspended skeletal muscle J Appl Physiol, December 1, 2005; 99(6): 2181 - 2188. [Abstract] [Full Text] [PDF]
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E. B. Taylor, J. D. Lamb, R. W. Hurst, D. G. Chesser, W. J. Ellingson, L. J. Greenwood, B. B. Porter, S. T. Herway, and W. W. Winder Endurance training increases skeletal muscle LKB1 and PGC-1{alpha} protein abundance: effects of time and intensity Am J Physiol Endocrinol Metab, December 1, 2005; 289(6): E960 - E968. [Abstract] [Full Text] [PDF]
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J. S. Fisher, J.-S. Ju, P. J. Oppelt, J. L. Smith, A. Suzuki, and H. Esumi Muscle contractions, AICAR, and insulin cause phosphorylation of an AMPK-related kinase Am J Physiol Endocrinol Metab, December 1, 2005; 289(6): E986 - E992. [Abstract] [Full Text] [PDF]
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S. Foroutan, J. Brillault, B. Forbush, and M. E. O'Donnell Moderate-to-severe ischemic conditions increase activity and phosphorylation of the cerebral microvascular endothelial cell Na+-K+-Cl- cotransporter Am J Physiol Cell Physiol, December 1, 2005; 289(6): C1492 - C1501. [Abstract] [Full Text] [PDF]
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M. P. Biju, Y. Akai, N. Shrimanker, and V. H. Haase Protection of HIF-1-deficient primary renal tubular epithelial cells from hypoxia-induced cell death is glucose dependent Am J Physiol Renal Physiol, December 1, 2005; 289(6): F1217 - F1226. [Abstract] [Full Text] [PDF]
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F. Ahmad, M. Arad, N. Musi, H. He, C. Wolf, D. Branco, A. R. Perez-Atayde, D. Stapleton, D. Bali, Y. Xing, et al. Increased {alpha}2 Subunit-Associated AMPK Activity and PRKAG2 Cardiomyopathy Circulation, November 15, 2005; 112(20): 3140 - 3148. [Abstract] [Full Text] [PDF]
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 K. Terai, Y. Hiramoto, M. Masaki, S. Sugiyama, T. Kuroda, M. Hori, I. Kawase, and H. Hirota AMP-Activated Protein Kinase Protects Cardiomyocytes against Hypoxic Injury through Attenuation of Endoplasmic Reticulum Stress Mol. Cell. Biol., November 1, 2005; 25(21): 9554 - 9575. [Abstract] [Full Text] [PDF]
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 Q. W. Shen, C. S. Jones, N. Kalchayanand, M. J. Zhu, and M. Du Effect of dietary {alpha}-lipoic acid on growth, body composition, muscle pH, and AMP-activated protein kinase phosphorylation in mice J Anim Sci, November 1, 2005; 83(11): 2611 - 2617. [Abstract] [Full Text] [PDF]
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P. F. Mount, R. E. Hill, S. A. Fraser, V. Levidiotis, F. Katsis, B. E. Kemp, and D. A. Power Acute renal ischemia rapidly activates the energy sensor AMPK but does not increase phosphorylation of eNOS-Ser1177 Am J Physiol Renal Physiol, November 1, 2005; 289(5): F1103 - F1115. [Abstract] [Full Text] [PDF]
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C. O. Randak and M. J. Welsh Adenylate Kinase Activity in ABC Transporters J. Biol. Chem., October 14, 2005; 280(41): 34385 - 34388. [Full Text] [PDF]
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M. Igata, H. Motoshima, K. Tsuruzoe, K. Kojima, T. Matsumura, T. Kondo, T. Taguchi, K. Nakamaru, M. Yano, D. Kukidome, et al. Adenosine Monophosphate-Activated Protein Kinase Suppresses Vascular Smooth Muscle Cell Proliferation Through the Inhibition of Cell Cycle Progression Circ. Res., October 14, 2005; 97(8): 837 - 844. [Abstract] [Full Text] [PDF]
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H. Sakoda, M. Fujishiro, J. Fujio, N. Shojima, T. Ogihara, A. Kushiyama, Y. Fukushima, M. Anai, H. Ono, M. Kikuchi, et al. Glycogen debranching enzyme association with {beta}-subunit regulates AMP-activated protein kinase activity Am J Physiol Endocrinol Metab, September 1, 2005; 289(3): E474 - E481. [Abstract] [Full Text] [PDF]
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S. Di Marco, R. Mazroui, P. Dallaire, S. Chittur, S. A. Tenenbaum, D. Radzioch, A. Marette, and I.-E. Gallouzi NF-{kappa}B-Mediated MyoD Decay during Muscle Wasting Requires Nitric Oxide Synthase mRNA Stabilization, HuR Protein, and Nitric Oxide Release Mol. Cell. Biol., August 1, 2005; 25(15): 6533 - 6545. [Abstract] [Full Text] [PDF]
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K. Godl, O. J. Gruss, J. Eickhoff, J. Wissing, S. Blencke, M. Weber, H. Degen, D. Brehmer, L. Orfi, Z. Horvath, et al. Proteomic Characterization of the Angiogenesis Inhibitor SU6668 Reveals Multiple Impacts on Cellular Kinase Signaling Cancer Res., August 1, 2005; 65(15): 6919 - 6926. [Abstract] [Full Text] [PDF]
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T. Tanaka, S. Hidaka, H. Masuzaki, S. Yasue, Y. Minokoshi, K. Ebihara, H. Chusho, Y. Ogawa, T. Toyoda, K. Sato, et al. Skeletal Muscle AMP-Activated Protein Kinase Phosphorylation Parallels Metabolic Phenotype in Leptin Transgenic Mice Under Dietary Modification Diabetes, August 1, 2005; 54(8): 2365 - 2374. [Abstract] [Full Text] [PDF]
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A. M Woollhead, J. W Scott, D. G. Hardie, and D. L Baines Phenformin and 5-aminoimidazole-4-carboxamide-1-{beta}-D-ribofuranoside (AICAR) activation of AMP-activated protein kinase inhibits transepithelial Na+ transport across H441 lung cells J. Physiol., August 1, 2005; 566(3): 781 - 792. [Abstract] [Full Text] [PDF]
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M. Daval, F. Diot-Dupuy, R. Bazin, I. Hainault, B. Viollet, S. Vaulont, E. Hajduch, P. Ferre, and F. Foufelle Anti-lipolytic Action of AMP-activated Protein Kinase in Rodent Adipocytes J. Biol. Chem., July 1, 2005; 280(26): 25250 - 25257. [Abstract] [Full Text] [PDF]
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E. Schulz, E. Anter, M.-H. Zou, and J. F. Keaney Jr Estradiol-Mediated Endothelial Nitric Oxide Synthase Association With Heat Shock Protein 90 Requires Adenosine Monophosphate-Dependent Protein Kinase Circulation, June 28, 2005; 111(25): 3473 - 3480. [Abstract] [Full Text] [PDF]
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E. B. Taylor, W. J. Ellingson, J. D. Lamb, D. G. Chesser, and W. W. Winder Long-chain acyl-CoA esters inhibit phosphorylation of AMP-activated protein kinase at threonine-172 by LKB1/STRAD/MO25 Am J Physiol Endocrinol Metab, June 1, 2005; 288(6): E1055 - E1061. [Abstract] [Full Text] [PDF]
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D. An, G. Kewalramani, D. Qi, T. Pulinilkunnil, S. Ghosh, A. Abrahani, R. Wambolt, M. Allard, S. M. Innis, and B. Rodrigues {beta}-Agonist stimulation produces changes in cardiac AMPK and coronary lumen LPL only during increased workload Am J Physiol Endocrinol Metab, June 1, 2005; 288(6): E1120 - E1127. [Abstract] [Full Text] [PDF]
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L. D. McCullough, Z. Zeng, H. Li, L. E. Landree, J. McFadden, and G. V. Ronnett Pharmacological Inhibition of AMP-activated Protein Kinase Provides Neuroprotection in Stroke J. Biol. Chem., May 27, 2005; 280(21): 20493 - 20502. [Abstract] [Full Text] [PDF]
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R. M. Crooke, M. J. Graham, K. M. Lemonidis, C. P. Whipple, S. Koo, and R. J. Perera An apolipoprotein B antisense oligonucleotide lowers LDL cholesterol in hyperlipidemic mice without causing hepatic steatosis J. Lipid Res., May 1, 2005; 46(5): 872 - 884. [Abstract] [Full Text] [PDF]
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D. S. Hittel, Y. Hathout, E. P. Hoffman, and J. A. Houmard Proteome Analysis of Skeletal Muscle From Obese and Morbidly Obese Women Diabetes, May 1, 2005; 54(5): 1283 - 1288. [Abstract] [Full Text] [PDF]
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M. Foretz, N. Ancellin, F. Andreelli, Y. Saintillan, P. Grondin, A. Kahn, B. Thorens, S. Vaulont, and B. Viollet Short-Term Overexpression of a Constitutively Active Form of AMP-Activated Protein Kinase in the Liver Leads to Mild Hypoglycemia and Fatty Liver Diabetes, May 1, 2005; 54(5): 1331 - 1339. [Abstract] [Full Text] [PDF]
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K.-i. Inokuma, Y. Ogura-Okamatsu, C. Toda, K. Kimura, H. Yamashita, and M. Saito Uncoupling Protein 1 Is Necessary for Norepinephrine-Induced Glucose Utilization in Brown Adipose Tissue Diabetes, May 1, 2005; 54(5): 1385 - 1391. [Abstract] [Full Text] [PDF]
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N. Ouchi, R. Shibata, and K. Walsh AMP-Activated Protein Kinase Signaling Stimulates VEGF Expression and Angiogenesis in Skeletal Muscle Circ. Res., April 29, 2005; 96(8): 838 - 846. [Abstract] [Full Text] [PDF]
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D. K. Kramer, L. Al-Khalili, S. Perrini, J. Skogsberg, P. Wretenberg, K. Kannisto, H. Wallberg-Henriksson, E. Ehrenborg, J. R. Zierath, and A. Krook Direct Activation of Glucose Transport in Primary Human Myotubes After Activation of Peroxisome Proliferator-Activated Receptor {delta} Diabetes, April 1, 2005; 54(4): 1157 - 1163. [Abstract] [Full Text] [PDF]
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J. V. Swinnen, A. Beckers, K. Brusselmans, S. Organe, J. Segers, L. Timmermans, F. Vanderhoydonc, L. Deboel, R. Derua, E. Waelkens, et al. Mimicry of a Cellular Low Energy Status Blocks Tumor Cell Anabolism and Suppresses the Malignant Phenotype Cancer Res., March 15, 2005; 65(6): 2441 - 2448. [Abstract] [Full Text] [PDF]
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