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Minireview: The AMP-Activated Protein Kinase Cascade: The Key Sensor of Cellular Energy Status

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.

	Abstract

Top Abstract Introduction Regulation of AMPK Regulation of the AMPK... Downstream Targets for AMPK... Relevance to Type 2... References

 
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.

	Introduction

Top Abstract Introduction Regulation of AMPK Regulation of the AMPK... Downstream Targets for AMPK... Relevance to Type 2... References

 
ALL LIVING CELLS must continuously maintain a high, nonequilibrium ratio of ATP to ADP (which are analogous to the chemicals in an electrical cell or battery) to survive. Catabolism charges up the battery by converting ADP and phosphate to ATP, whereas almost all other cellular processes tend to discharge the battery by directly or indirectly converting ATP to ADP and phosphate (or AMP and pyrophosphate). The fact that the ATP:ADP ratio in cells usually remains almost constant indicates that the mechanisms that maintain these processes in balance are very efficient. What is more surprising is that the identity of the key player in this process, the AMP-activated protein kinase (AMPK), has become apparent only in the last few years. With hindsight, its discovery can be traced back to two independent observations first reported in 1973. Gibson and co-workers (1) reported that a crude preparation of 3-hydroxy-3-methyl-CoA reductase, the key regulatory enzyme of cholesterol synthesis, became inactivated in a time-dependent manner upon incubation with MgATP, while Carlson and Kim (2) reported similar observations with acetyl-CoA carboxylase. Both groups correctly surmised that this was due to the action of a protein kinase, but it was to be another 14 yr before the current author provided evidence that these were both functions of the same protein kinase (3), which we renamed AMPK (4, 5).

	Regulation of AMPK

Top Abstract Introduction Regulation of AMPK Regulation of the AMPK... Downstream Targets for AMPK... Relevance to Type 2... References

 
AMPK is a heterotrimeric complex comprising a catalytic -subunit and regulatory ß- and -subunits (6). Each subunit exists as alternate isoforms encoded by two or three genes (1, 2, ß1, ß2, 1, 2, 3), and all twelve different combinations of isoforms appear to be able to form complexes. The predominant isoforms in most cells are 1, ß1, and 1, but liver cells also significantly express 2 (7), whereas skeletal and cardiac muscles also express 2, ß2, 2, and 3 (8, 9, 10). Although much remains to be learned, differences in function between the isoforms are already known. First, the degree of AMP dependence depends on the identity of both the - and -subunits, with stimulation varying from only 50% for the 13 combination to more than 5-fold for the 22 combination (10). Second, 2 complexes appear to be enriched in the nucleus, whereas 1 complexes are largely cytoplasmic and appear to be largely excluded from the nucleus (11, 12, 13, 14).

As its name suggests, AMPK is allosterically activated by AMP, but, more importantly, it is also activated by phosphorylation by one or more upstream kinases at a threonine residue within the activation loop of the -subunit kinase domain, without which there is no detectable activity (15, 16). This phosphorylation is promoted by AMP both by stimulating phosphorylation by the upstream kinase (17) and by inhibiting dephosphorylation by protein phosphatases (18). This complex mechanism renders the cascade ultrasensitive, i.e. over the critical range of concentrations, a small rise in AMP produces a large increase in the final output (19). The effects of AMP are also antagonized by high concentrations of ATP, so that the system responds to rises in the AMP:ATP ratio rather than to rises in AMP alone. If the function of the AMPK system is indeed to monitor cellular energy status, a pertinent question is why it should respond to the AMP:ATP ratio rather than the ADP:ATP ratio. The likely answer is that all eukaryotic cells contain a very active adenylate kinase enzyme that maintains the reaction catalyzed (2ADP ATP + AMP) close to equilibrium at all times. This means that the AMP:ATP ratio varies approximately as the square of the ADP:ATP ratio (20), and the former is therefore a much more sensitive indicator of cellular energy status than the latter.

	Regulation of the AMPK in Vivo

Top Abstract Introduction Regulation of AMPK Regulation of the AMPK... Downstream Targets for AMPK... Relevance to Type 2... References

 
The AMPK system is therefore activated by any stress that causes a rise in the cellular AMP:ATP ratio, either by interfering with ATP production or by increasing ATP consumption. Stresses of the former type include heat shock and metabolic poisoning in isolated hepatocytes (21), and hypoxia and ischemia in perfused heart muscle (22, 23). These are all pathological stresses, but the kinase is also regulated by more physiological stimuli. In pancreatic ß-cells, low glucose activates AMPK in the same range of concentrations over which it inhibits insulin release (13, 24). Finally, a physiological metabolic stress that activates AMPK by increasing ATP consumption is exercise in skeletal muscle, the original finding of which (25) triggered a greatly increased interest in the system. AMPK is activated by exercise or contraction in rodent (25, 26, 27) and human (28, 29) muscle, and activation is dependent on both the duration and the intensity of exercise (30, 31).

AMPK is also allosterically inhibited by physiological concentrations of phosphocreatine (32), consistent with the proposed physiological role of the kinase as a sensor of cellular energy status. Another rapidly mobilized store of energy in many tissues is glycogen. The ß-subunits of AMPK contain a central conserved domain that has recently been recognized as a glycogen-binding domain (GBD) (33, 34). In both rat (35) and human (36) muscle, a high glycogen content represses AMPK activation, suggesting that the AMPK system may monitor the availability of this longer term store of energy as well as that of ATP and phosphocreatine. It is tempting to suggest that the GBD is responsible for this, although there is no direct evidence for this at present. An alternative role for the GBD, which is not necessarily mutually exclusive, is that it localizes the kinase with one of its substrates, i.e. glycogen synthase. Consistent with this, overexpression of AMPK in cultured cells has been found to cause the accumulation of AMPK in unusually large glycogen granules that also contain glycogen synthase (33).

Homologs of the -, ß-, and -subunits of AMPK are present even in the most primitive, unicellular eukaryotes such as Giardia lamblia (6), and it seems likely that the system primarily evolved to regulate cellular function in response to fluctuations in energy status, rather than to hormonal stimuli. Nevertheless, it has recently been found that some hormones do regulate the system. AMPK is activated by receptors coupled to phospholipase C via the G protein Gq (37), and by the adipocytokines leptin (38) and adiponectin (39). The mechanism for AMPK activation by these hormones remains unclear, and in particular, it is not known whether they act by increasing the AMP:ATP ratio or via some more novel mechanism.

	Downstream Targets for AMPK Activation

Top Abstract Introduction Regulation of AMPK Regulation of the AMPK... Downstream Targets for AMPK... Relevance to Type 2... References

 
Much of what has been learned about the downstream targets for AMPK in intact cells and in vivo has come from the use of the compound 5-aminoimidazole-4-carboxamide (AICA) riboside. This adenosine analog is taken up into cells and converted by adenosine kinase to the monophosphorylated nucleotide 5-aminoimidazole-4-carboxamide-1-D-ribofuranosyl-5'-monophosphate (ZMP). ZMP mimics all of the activating effects of AMP on the AMPK system, although it is much less potent than AMP itself (40). Nevertheless, in most cells, it accumulates to sufficiently high concentrations that it activates AMPK without disturbing cellular levels of AMP, ADP, or ATP (40, 41). An important caveat in the use of AICA riboside is that ZMP does affect certain other AMP-regulated enzymes (42, 43). Recently, it has been found that the antidiabetic drug metformin activates AMPK (44) by a mechanism that involves phosphorylation by the upstream kinase but with no alteration in the cellular AMP:ATP ratio (45, 46). Because AICA riboside and metformin activate AMPK by different mechanisms, if both agents produce the same physiological effect, one can have more confidence that it is mediated by AMPK activation. For a complete analysis of the effects of AMPK on a physiological process, it is also necessary to identify the actual target protein for AMPK phosphorylation, identify the sites phosphorylated, and show that these are phosphorylated in intact cells or in vivo in response to AMPK activation. At present, this level of analysis has been achieved only in a few cases.

In general, activation of AMPK switches on catabolic pathways that generate ATP, while switching off anabolic pathways and any other nonessential processes that consume ATP. It achieves this both by direct phosphorylation of regulatory proteins involved in the process, and by indirect effects on gene expression. A full discussion of the targets for AMPK is beyond the scope of this minireview, but a summary of those that are reasonably well established is shown in Fig. 1. The interested reader should consult earlier reviews for detailed citations (6, 20, 47), and only a few more recently established examples are discussed below.

View larger version (34K): [in this window] [in a new window]   FIG. 1. Known physiological target proteins and pathways regulated by the AMPK system (modified from Ref. 6 ). The list is not exhaustive: other targets have been proposed, but in some cases the evidence is not yet conclusive. ACC, Acetyl-coenzyme A carboxylase [ACC1 () and ACC2 (ß) isoforms]; HMGR, 3-hydroxy-3-methylglutaryl-coenzyme A reductase; GPAT, glycerol phosphate acyl transferase; GS, glycogen synthase; EF2, elongation factor-2; mTOR, mammalian target of rapamycin; p70S6K, p70 ribosomal protein S6 kinase; HSL, hormone-sensitive lipase; CFTR, cystic fibrosis transmembrane regulator; PFK2, 6-phosphofructo-2-kinase; eNOS, endothelial nitric oxide synthase; IRS1, insulin receptor substrate-1; PI-3-kinase, phosphatidylinositol 3-kinase; GLUT1 and -4, glucose transporter 1 and 4; PEPCK, phosphoenolpyruvate carboxykinase; G6Pase, glucose-6-phosphatase; FAS, fatty acid synthase.

In most cases, the direct target proteins for AMPK responsible for the effects on gene expression are not known. However, AMPK phosphorylates the carbohydrate response element binding protein at Ser⁵⁶⁸, which inhibits its DNA binding activity and may be involved in the regulation of expression of the liver pyruvate kinase gene (58). It also phosphorylates the transcriptional coactivator p300 at Ser⁸⁹, and this reduces its interaction with nuclear hormone receptors such as peroxisome proliferator-activated receptor- (59). Moreover, AMPK activation has been shown to reduce the expression of several important transcription factors, including sterol regulatory element binding protein-1c (44), hepatocyte nuclear factor-4 (60), CCAAT/enhancer binding protein-, and peroxisome proliferator-activated receptor- (61). AMPK directly phosphorylates hepatocyte nuclear factor-4, and this seems to have a 2-fold effect, both reducing its ability to form homodimers and bind DNA, and stimulating its degradation (62).

	Relevance to Type 2 Diabetes and the Metabolic Syndrome

Top Abstract Introduction Regulation of AMPK Regulation of the AMPK... Downstream Targets for AMPK... Relevance to Type 2... References

 
Via mechanisms indicated in Fig. 1, AMPK activation causes many metabolic changes that would be beneficial in subjects with type 2 diabetes and the metabolic syndrome, such as increased glucose uptake and metabolism by muscle and other tissues, decreased glucose production by the liver, and decreased synthesis and increased oxidation of fatty acids. Indeed, experiments with animal models of type 2 diabetes and the metabolic syndrome show that activation of AMPK using 5-aminoimidazole-4-carboxamide 1-ß-D-ribofuranoside riboside can reverse many of the metabolic defects of these animals in vivo (63, 64, 65, 66). The AMPK system is the probable target of the major antidiabetic drug metformin (44, 45, 46) and may even be one target for another antidiabetic drug, rosiglitazone (45). It is responsible for the increased fat oxidation in response to the adipocyte-derived hormones, leptin (38) and adiponectin (39), thus promoting their action to prevent fat accumulation in other tissues. It is also activated by exercise, which is known to have beneficial effects in the treatment and prevention of type 2 diabetes. Given the inexorable rise in the incidence of type 2 diabetes and the metabolic syndrome in modern society, these recent findings help to explain the intense current interest in the AMPK system.

	Footnotes

 
This work was supported by a program grant from the Wellcome Trust, an RTD contract (QLG1-CT-2001-01488) from the European Commission, and a project grant from Diabetes UK.

Abbreviations: AICA, 5-Aminoimidazole-4-carboxamide; AMPK, AMP-activated protein kinase; GBD, glycogen-binding domain; ZMP, 5-aminoimidazole-4-carboxamide-1-D-ribofuranosyl-5'-monophosphate.

Received July 31, 2003.

Accepted for publication August 25, 2003.

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Top Abstract Introduction Regulation of AMPK Regulation of the AMPK... Downstream Targets for AMPK... Relevance to Type 2... References

 

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				N. G. Abraham, J. Cao, D. Sacerdoti, X. Li, and G. Drummond Heme oxygenase: the key to renal function regulation Am J Physiol Renal Physiol, November 1, 2009; 297(5): F1137 - F1152. [Abstract] [Full Text] [PDF]

				Y. Wang, Y. Xie, D. Wygle, H. H. Shen, E. E. Puscheck, and D. A. Rappolee A Major Effect of Simulated Microgravity on Several Stages of Preimplantation Mouse Development is Lethality Associated With Elevated Phosphorylated SAPK/JNK Reproductive Sciences, October 1, 2009; 16(10): 947 - 959. [Abstract] [PDF]

				G. Libby, L. A. Donnelly, P. T. Donnan, D. R. Alessi, A. D. Morris, and J. M.M. Evans New Users of Metformin Are at Low Risk of Incident Cancer: A cohort study among people with type 2 diabetes Diabetes Care, September 1, 2009; 32(9): 1620 - 1625. [Abstract] [Full Text] [PDF]

				V. Ljubicic and D. A. Hood Specific attenuation of protein kinase phosphorylation in muscle with a high mitochondrial content Am J Physiol Endocrinol Metab, September 1, 2009; 297(3): E749 - E758. [Abstract] [Full Text] [PDF]

				Y. Wang, L. Tao, Y. Yuan, W. B. Lau, R. Li, B. L. Lopez, T. A. Christopher, R. Tian, and X.-L. Ma Cardioprotective effect of adiponectin is partially mediated by its AMPK-independent antinitrative action Am J Physiol Endocrinol Metab, August 1, 2009; 297(2): E384 - E391. [Abstract] [Full Text] [PDF]

				S. J. Peterson, D. H. Kim, M. Li, V. Positano, L. Vanella, L. F. Rodella, F. Piccolomini, N. Puri, A. Gastaldelli, C. Kusmic, et al. The L-4F mimetic peptide prevents insulin resistance through increased levels of HO-1, pAMPK, and pAKT in obese mice J. Lipid Res., July 1, 2009; 50(7): 1293 - 1304. [Abstract] [Full Text] [PDF]

				M. M. Rogge The Role of Impaired Mitochondrial Lipid Oxidation in Obesity Biol Res Nurs, April 1, 2009; 10(4): 356 - 373. [Abstract] [PDF]

				S. Rodriguez-Nieto and M. Sanchez-Cespedes BRG1 and LKB1: tales of two tumor suppressor genes on chromosome 19p and lung cancer Carcinogenesis, April 1, 2009; 30(4): 547 - 554. [Abstract] [Full Text] [PDF]

				Y. Zang, L.-F. Yu, F.-J. Nan, L.-Y. Feng, and J. Li AMP-activated Protein Kinase Is Involved in Neural Stem Cell Growth Suppression and Cell Cycle Arrest by 5-Aminoimidazole-4-carboxamide-1-{beta}-D-ribofuranoside and Glucose Deprivation by Down-regulating Phospho-retinoblastoma Protein and Cyclin D J. Biol. Chem., March 6, 2009; 284(10): 6175 - 6184. [Abstract] [Full Text] [PDF]

				R. G. Jones and C. B. Thompson Tumor suppressors and cell metabolism: a recipe for cancer growth Genes & Dev., March 1, 2009; 23(5): 537 - 548. [Abstract] [Full Text] [PDF]

				A. Nicolai, M. Li, D. H. Kim, S. J. Peterson, L. Vanella, V. Positano, A. Gastaldelli, R. Rezzani, L. F. Rodella, G. Drummond, et al. Heme Oxygenase-1 Induction Remodels Adipose Tissue and Improves Insulin Sensitivity in Obesity-Induced Diabetic Rats Hypertension, March 1, 2009; 53(3): 508 - 515. [Abstract] [Full Text] [PDF]

				Y. Wang, E. Gao, L. Tao, W. B. Lau, Y. Yuan, B. J. Goldstein, B. L. Lopez, T. A. Christopher, R. Tian, W. Koch, et al. AMP-Activated Protein Kinase Deficiency Enhances Myocardial Ischemia/Reperfusion Injury but Has Minimal Effect on the Antioxidant/Antinitrative Protection of Adiponectin Circulation, February 17, 2009; 119(6): 835 - 844. [Abstract] [Full Text] [PDF]

				S. Gundewar, J. W. Calvert, S. Jha, I. Toedt-Pingel, S. Yong Ji, D. Nunez, A. Ramachandran, M. Anaya-Cisneros, R. Tian, and D. J. Lefer Activation of AMP-Activated Protein Kinase by Metformin Improves Left Ventricular Function and Survival in Heart Failure Circ. Res., February 13, 2009; 104(3): 403 - 411. [Abstract] [Full Text] [PDF]

				A. M. Bair, P. B. Thippegowda, M. Freichel, N. Cheng, R. D. Ye, S. M. Vogel, Y. Yu, V. Flockerzi, A. B. Malik, and C. Tiruppathi Ca2+ Entry via TRPC Channels Is Necessary for Thrombin-induced NF-{kappa}B Activation in Endothelial Cells through AMP-activated Protein Kinase and Protein Kinase C{delta} J. Biol. Chem., January 2, 2009; 284(1): 563 - 574. [Abstract] [Full Text] [PDF]

				J.-L. Chen, H. H. Lin, K.-J. Kim, A. Lin, H. J. Forman, and D. K. Ann Novel Roles for Protein Kinase C{delta}-dependent Signaling Pathways in Acute Hypoxic Stress-induced Autophagy J. Biol. Chem., December 5, 2008; 283(49): 34432 - 34444. [Abstract] [Full Text] [PDF]

				B. B. Hasinoff, D. Patel, and K. A. O'Hara Mechanisms of Myocyte Cytotoxicity Induced by the Multiple Receptor Tyrosine Kinase Inhibitor Sunitinib Mol. Pharmacol., December 1, 2008; 74(6): 1722 - 1728. [Abstract] [Full Text] [PDF]

				W. Yin, A. P. Signore, M. Iwai, G. Cao, Y. Gao, and J. Chen Rapidly Increased Neuronal Mitochondrial Biogenesis After Hypoxic-Ischemic Brain Injury Stroke, November 1, 2008; 39(11): 3057 - 3063. [Abstract] [Full Text] [PDF]

				M. Zakikhani, R. J.O. Dowling, N. Sonenberg, and M. N. Pollak The Effects of Adiponectin and Metformin on Prostate and Colon Neoplasia Involve Activation of AMP-Activated Protein Kinase Cancer Prevention Research, October 1, 2008; 1(5): 369 - 375. [Abstract] [Full Text] [PDF]

				J. Feng, M. Zhang, S. Zheng, P. Xie, and A. Ma Effects of High Temperature on Multiple Parameters of Broilers In Vitro and In Vivo Poult. Sci., October 1, 2008; 87(10): 2133 - 2139. [Abstract] [Full Text] [PDF]

				E. Schulz, J. Dopheide, S. Schuhmacher, S. R. Thomas, K. Chen, A. Daiber, P. Wenzel, T. Munzel, and J. F. Keaney Jr Suppression of the JNK Pathway by Induction of a Metabolic Stress Response Prevents Vascular Injury and Dysfunction Circulation, September 23, 2008; 118(13): 1347 - 1357. [Abstract] [Full Text] [PDF]

				X. Zhao, J. W. Zmijewski, E. Lorne, G. Liu, Y.-J. Park, Y. Tsuruta, and E. Abraham Activation of AMPK attenuates neutrophil proinflammatory activity and decreases the severity of acute lung injury Am J Physiol Lung Cell Mol Physiol, September 1, 2008; 295(3): L497 - L504. [Abstract] [Full Text] [PDF]

				T. Pang, Z.-S. Zhang, M. Gu, B.-Y. Qiu, L.-F. Yu, P.-R. Cao, W. Shao, M.-B. Su, J.-Y. Li, F.-J. Nan, et al. Small Molecule Antagonizes Autoinhibition and Activates AMP-activated Protein Kinase in Cells J. Biol. Chem., June 6, 2008; 283(23): 16051 - 16060. [Abstract] [Full Text] [PDF]

				V. Poitout and R. P. Robertson Glucolipotoxicity: Fuel Excess and {beta}-Cell Dysfunction Endocr. Rev., May 1, 2008; 29(3): 351 - 366. [Abstract] [Full Text] [PDF]

				Y. Zang, L.-F. Yu, T. Pang, L.-P. Fang, X. Feng, T.-Q. Wen, F.-J. Nan, L.-Y. Feng, and J. Li AICAR Induces Astroglial Differentiation of Neural Stem Cells via Activating the JAK/STAT3 Pathway Independently of AMP-activated Protein Kinase J. Biol. Chem., March 7, 2008; 283(10): 6201 - 6208. [Abstract] [Full Text] [PDF]

				R. P. Taylor, G. J. Parker, M. W. Hazel, Y. Soesanto, W. Fuller, M. J. Yazzie, and D. A. McClain Glucose Deprivation Stimulates O-GlcNAc Modification of Proteins through Up-regulation of O-Linked N-Acetylglucosaminyltransferase J. Biol. Chem., March 7, 2008; 283(10): 6050 - 6057. [Abstract] [Full Text] [PDF]

				J. W. Calvert, S. Gundewar, S. Jha, J. J.M. Greer, W. H. Bestermann, R. Tian, and D. J. Lefer Acute Metformin Therapy Confers Cardioprotection Against Myocardial Infarction Via AMPK-eNOS-Mediated Signaling Diabetes, March 1, 2008; 57(3): 696 - 705. [Abstract] [Full Text] [PDF]

				R. Okoshi, T. Ozaki, H. Yamamoto, K. Ando, N. Koida, S. Ono, T. Koda, T. Kamijo, A. Nakagawara, and H. Kizaki Activation of AMP-activated Protein Kinase Induces p53-dependent Apoptotic Cell Death in Response to Energetic Stress J. Biol. Chem., February 15, 2008; 283(7): 3979 - 3987. [Abstract] [Full Text] [PDF]

				L. H. Young AMP-Activated Protein Kinase Conducts the Ischemic Stress Response Orchestra Circulation, February 12, 2008; 117(6): 832 - 840. [Full Text] [PDF]

				M. E. Spurlock and N. K. Gabler The Development of Porcine Models of Obesity and the Metabolic Syndrome J. Nutr., February 1, 2008; 138(2): 397 - 402. [Abstract] [Full Text] [PDF]

				M. S. Kim, G. Kewalramani, P. Puthanveetil, V. Lee, U. Kumar, D. An, A. Abrahani, and B. Rodrigues Acute Diabetes Moderates Trafficking of Cardiac Lipoprotein Lipase Through p38 Mitogen-Activated Protein Kinase Dependent Actin Cytoskeleton Organization Diabetes, January 1, 2008; 57(1): 64 - 76. [Abstract] [Full Text] [PDF]

				D. Zheng, A. Perianayagam, D. H. Lee, M. D. Brannan, L. E. Yang, D. Tellalian, P. Chen, K. Lemieux, A. Marette, J. H. Youn, et al. AMPK activation with AICAR provokes an acute fall in plasma [K+] Am J Physiol Cell Physiol, January 1, 2008; 294(1): C126 - C135. [Abstract] [Full Text] [PDF]

				N. Arai, H. Masuzaki, T. Tanaka, T. Ishii, S. Yasue, N. Kobayashi, T. Tomita, M. Noguchi, T. Kusakabe, J. Fujikura, et al. Ceramide and Adenosine 5'-Monophosphate-Activated Protein Kinase Are Two Novel Regulators of 11{beta}-Hydroxysteroid Dehydrogenase Type 1 Expression and Activity in Cultured Preadipocytes Endocrinology, November 1, 2007; 148(11): 5268 - 5277. [Abstract] [Full Text] [PDF]

				S. D. Mason, H. Rundqvist, I. Papandreou, R. Duh, W. J. McNulty, R. A. Howlett, I. M. Olfert, C. J. Sundberg, N. C. Denko, L. Poellinger, et al. HIF-1{alpha} in endurance training: suppression of oxidative metabolism Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2007; 293(5): R2059 - R2069. [Abstract] [Full Text] [PDF]

				S. I. Anghel, E. Bedu, C. D. Vivier, P. Descombes, B. Desvergne, and W. Wahli Adipose Tissue Integrity as a Prerequisite for Systemic Energy Balance: A CRITICAL ROLE FOR PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR {gamma} J. Biol. Chem., October 12, 2007; 282(41): 29946 - 29957. [Abstract] [Full Text] [PDF]

				M. N. Galardo, M. F. Riera, E. H. Pellizzari, S. B. Cigorraga, and S. B. Meroni The AMP-activated protein kinase activator, 5-aminoimidazole-4-carboxamide-1-b-D-ribonucleoside, regulates lactate production in rat Sertoli cells J. Mol. Endocrinol., October 1, 2007; 39(4): 279 - 288. [Abstract] [Full Text] [PDF]

				C. T. Putman, K. J. B. Martins, M. E. Gallo, G. D. Lopaschuk, J. A. Pearcey, I. M. MacLean, R. J. Saranchuk, and D. Pette {alpha}-Catalytic subunits of 5'AMP-activated protein kinase display fiber-specific expression and are upregulated by chronic low-frequency stimulation in rat muscle Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2007; 293(3): R1325 - R1334. [Abstract] [Full Text] [PDF]

				A. S. Jeyapalan, R. A. Orellana, A. Suryawan, P. M. J. O'Connor, H. V. Nguyen, J. Escobar, J. W. Frank, and T. A. Davis Glucose stimulates protein synthesis in skeletal muscle of neonatal pigs through an AMPK- and mTOR-independent process Am J Physiol Endocrinol Metab, August 1, 2007; 293(2): E595 - E603. [Abstract] [Full Text] [PDF]

				B. Drogat, P. Auguste, D. T. Nguyen, M. Bouchecareilh, R. Pineau, J. Nalbantoglu, R. J. Kaufman, E. Chevet, A. Bikfalvi, and M. Moenner IRE1 Signaling Is Essential for Ischemia-Induced Vascular Endothelial Growth Factor-A Expression and Contributes to Angiogenesis and Tumor Growth In vivo Cancer Res., July 15, 2007; 67(14): 6700 - 6707. [Abstract] [Full Text] [PDF]

				A. Caretti, S. Morel, G. Milano, M. Fantacci, P. Bianciardi, R. Ronchi, G. Vassalli, L. K. von Segesser, and M. Samaja Heart HIF-1{alpha} and MAP Kinases During Hypoxia: Are They Associated In Vivo? Experimental Biology and Medicine, July 1, 2007; 232(7): 887 - 894. [Abstract] [Full Text] [PDF]

				R.-Y. Su, Y. Chao, T.-Y. Chen, D.-Y. Huang, and W.-W. Lin 5-Aminoimidazole-4-carboxamide riboside sensitizes TRAIL- and TNF{alpha}-induced cytotoxicity in colon cancer cells through AMP-activated protein kinase signaling Mol. Cancer Ther., May 1, 2007; 6(5): 1562 - 1571. [Abstract] [Full Text] [PDF]

				R. Shin, S. Alvarez, A. Y. Burch, J. M. Jez, and D. P. Schachtman Phosphoproteomic identification of targets of the Arabidopsis sucrose nonfermenting-like kinase SnRK2.8 reveals a connection to metabolic processes PNAS, April 10, 2007; 104(15): 6460 - 6465. [Abstract] [Full Text] [PDF]

				M. A. Mayes, M. F. Laforest, C. Guillemette, R. B. Gilchrist, and F. J. Richard Adenosine 5'-Monophosphate Kinase-Activated Protein Kinase (PRKA) Activators Delay Meiotic Resumption in Porcine Oocytes Biol Reprod, April 1, 2007; 76(4): 589 - 597. [Abstract] [Full Text] [PDF]

				R. Townley and L. Shapiro Crystal Structures of the Adenylate Sensor from Fission Yeast AMP-Activated Protein Kinase Science, March 23, 2007; 315(5819): 1726 - 1729. [Abstract] [Full Text] [PDF]

				M. Arad, C. E. Seidman, and J.G. Seidman AMP-Activated Protein Kinase in the Heart: Role During Health and Disease Circ. Res., March 2, 2007; 100(4): 474 - 488. [Abstract] [Full Text] [PDF]

				C. J Bailey Treating insulin resistance: future prospects Diabetes and Vascular Disease Research, March 1, 2007; 4(1): 20 - 31. [Abstract] [PDF]

				C. LaRosa and S. M. Downs Meiotic Induction by Heat Stress in Mouse Oocytes: Involvement of AMP-Activated Protein Kinase and MAPK Family Members Biol Reprod, March 1, 2007; 76(3): 476 - 486. [Abstract] [Full Text] [PDF]

				C. Blume, P. M. Benz, U. Walter, J. Ha, B. E. Kemp, and T. Renne AMP-activated Protein Kinase Impairs Endothelial Actin Cytoskeleton Assembly by Phosphorylating Vasodilator-stimulated Phosphoprotein J. Biol. Chem., February 16, 2007; 282(7): 4601 - 4612. [Abstract] [Full Text] [PDF]

				R. L. Jacobs, S. Lingrell, J. R. B. Dyck, and D. E. Vance Inhibition of Hepatic Phosphatidylcholine Synthesis by 5-Aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside Is Independent of AMP-activated Protein Kinase Activation J. Biol. Chem., February 16, 2007; 282(7): 4516 - 4523. [Abstract] [Full Text] [PDF]

				G. Boudry, C. I. Cheeseman, and M. H. Perdue Psychological stress impairs Na+-dependent glucose absorption and increases GLUT2 expression in the rat jejunal brush-border membrane Am J Physiol Regulatory Integrative Comp Physiol, February 1, 2007; 292(2): R862 - R867. [Abstract] [Full Text] [PDF]

				C. Lopez-Lopez, M. O. Dietrich, F. Metzger, H. Loetscher, and I. Torres-Aleman Disturbed Cross Talk between Insulin-Like Growth Factor I and AMP-Activated Protein Kinase as a Possible Cause of Vascular Dysfunction in the Amyloid Precursor Protein/Presenilin 2 Mouse Model of Alzheimer's Disease J. Neurosci., January 24, 2007; 27(4): 824 - 831. [Abstract] [Full Text] [PDF]

				K. A. Al-Regaiey, M. M. Masternak, M. S. Bonkowski, J. A. Panici, J. J. Kopchick, and A. Bartke Effects of Caloric Restriction and Growth Hormone Resistance on Insulin-Related Intermediates in the Skeletal Muscle J. Gerontol. A Biol. Sci. Med. Sci., January 1, 2007; 62(1): 18 - 26. [Abstract] [Full Text] [PDF]

				N. Fujii, N. Jessen, and L. J. Goodyear AMP-activated protein kinase and the regulation of glucose transport Am J Physiol Endocrinol Metab, November 1, 2006; 291(5): E867 - E877. [Abstract] [Full Text] [PDF]

				J. Li, D. L. Coven, E. J. Miller, X. Hu, M. E. Young, D. Carling, A. J. Sinusas, and L. H. Young Activation of AMPK {alpha}- and {gamma}-isoform complexes in the intact ischemic rat heart Am J Physiol Heart Circ Physiol, October 1, 2006; 291(4): H1927 - H1934. [Abstract] [Full Text] [PDF]

				D. An and B. Rodrigues Role of changes in cardiac metabolism in development of diabetic cardiomyopathy Am J Physiol Heart Circ Physiol, October 1, 2006; 291(4): H1489 - H1506. [Abstract] [Full Text] [PDF]

				D. K. Singh, L. Li, and T. D. Porter Policosanol Inhibits Cholesterol Synthesis in Hepatoma Cells by Activation of AMP-Kinase J. Pharmacol. Exp. Ther., September 1, 2006; 318(3): 1020 - 1026. [Abstract] [Full Text] [PDF]

				A. Beckers, S. Organe, L. Timmermans, F. Vanderhoydonc, L. Deboel, R. Derua, E. Waelkens, K. Brusselmans, G. Verhoeven, and J. V. Swinnen Methotrexate enhances the antianabolic and antiproliferative effects of 5-aminoimidazole-4-carboxamide riboside. Mol. Cancer Ther., September 1, 2006; 5(9): 2211 - 2217. [Abstract] [Full Text] [PDF]

				M. Zang, S. Xu, K. A. Maitland-Toolan, A. Zuccollo, X. Hou, B. Jiang, M. Wierzbicki, T. J. Verbeuren, and R. A. Cohen Polyphenols Stimulate AMP-Activated Protein Kinase, Lower Lipids, and Inhibit Accelerated Atherosclerosis in Diabetic LDL Receptor-Deficient Mice. Diabetes, August 1, 2006; 55(8): 2180 - 2191. [Abstract] [Full Text] [PDF]

				E. Elia, V. Sander, C.G. Luchetti, M.E. Solano, G. Di Girolamo, C. Gonzalez, and A.B. Motta The mechanisms involved in the action of metformin in regulating ovarian function in hyperandrogenized mice Mol. Hum. Reprod., August 1, 2006; 12(8): 475 - 481. [Abstract] [Full Text] [PDF]

				L. Tosca, S. Crochet, P. Ferre, F. Foufelle, S. Tesseraud, and J. Dupont AMP-activated protein kinase activation modulates progesterone secretion in granulosa cells from hen preovulatory follicles. J. Endocrinol., July 1, 2006; 190(1): 85 - 97. [Abstract] [Full Text] [PDF]

				H. Motoshima, B. J. Goldstein, M. Igata, and E. Araki AMPK and cell proliferation - AMPK as a therapeutic target for atherosclerosis and cancer J. Physiol., July 1, 2006; 574(1): 63 - 71. [Abstract] [Full Text] [PDF]

				A. M. Evans AMP-activated protein kinase and the regulation of Ca2+ signalling in O2-sensing cells J. Physiol., July 1, 2006; 574(1): 113 - 123. [Abstract] [Full Text] [PDF]

				J. Yang and G. D. Holman Long-Term Metformin Treatment Stimulates Cardiomyocyte Glucose Transport through an AMP-Activated Protein Kinase-Dependent Reduction in GLUT4 Endocytosis Endocrinology, June 1, 2006; 147(6): 2728 - 2736. [Abstract] [Full Text] [PDF]

				I. Aymerich, F. Foufelle, P. Ferre, F. J. Casado, and M. Pastor-Anglada Extracellular adenosine activates AMP-dependent protein kinase (AMPK) J. Cell Sci., April 15, 2006; 119(8): 1612 - 1621. [Abstract] [Full Text] [PDF]

				B. Guigas, L. Bertrand, N. Taleux, M. Foretz, N. Wiernsperger, D. Vertommen, F. Andreelli, B. Viollet, and L. Hue 5-Aminoimidazole-4-Carboxamide-1-{beta}-D-Ribofuranoside and Metformin Inhibit Hepatic Glucose Phosphorylation by an AMP-Activated Protein Kinase-Independent Effect on Glucokinase Translocation. Diabetes, April 1, 2006; 55(4): 865 - 874. [Abstract] [Full Text] [PDF]

				Y. Andersson, H. Le, S. Juell, and O. Fodstad AMP-activated protein kinase protects against anti-epidermal growth factor receptor-Pseudomonas exotoxin A immunotoxin-induced MA11 breast cancer cell death. Mol. Cancer Ther., April 1, 2006; 5(4): 1050 - 1059. [Abstract] [Full Text] [PDF]

				E. B. Taylor, W. J. Ellingson, J. D. Lamb, D. G. Chesser, C. L. Compton, and W. W. Winder Evidence against regulation of AMP-activated protein kinase and LKB1/STRAD/MO25 activity by creatine phosphate Am J Physiol Endocrinol Metab, April 1, 2006; 290(4): E661 - E669. [Abstract] [Full Text] [PDF]

				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]

				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]

				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]

				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]

				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]

				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]

				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]

				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]

				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]

				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]

				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]

				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]

				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]

				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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