Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Perspective
  • Published:

AMP-activated protein kinase: nature's energy sensor

Nature Chemical Biology volume 7, pages 512–518 (2011)Cite this article

Subjects

Abstract

Maintaining sufficient levels of ATP (the immediate source of cellular energy) is essential for the proper functioning of all living cells. As a consequence, cells require mechanisms to balance energy demand with supply. In eukaryotic cells the AMP-activated protein kinase (AMPK) cascade has an important role in this homeostasis. AMPK is activated by a fall in ATP (concomitant with a rise in ADP and AMP), which leads to the activation of catabolic pathways and the inhibition of anabolic pathways. Here we review the role of AMPK as an energy sensor and consider the recent finding that ADP, as well as AMP, causes activation of mammalian AMPK. We also review recent progress in structural studies on phosphorylated AMPK that provides a mechanism for the regulation of AMPK in which AMP and ADP protect it against dephosphorylation. Finally, we briefly survey some of the outstanding questions concerning the regulation of AMPK.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Model summarizing some of the key features underlying the regulation of mammalian AMPK by adenine nucleotides.
Figure 2: Summary of the nucleotide binding properties of the four CBS domains in AMPKγ1 subunit.
Figure 3: Important interactions involved in the regulation of mammalian AMPK.

Similar content being viewed by others

References

  1. Boyer, P.D. et al. Oxidative phosphorylation and photophosphorylation. Annu. Rev. Biochem. 46, 955–966 (1977).

    Article  CAS  Google Scholar 

  2. Carling, D., Zammit, V.A. & Hardie, D.G. A common bicyclic protein kinase cascade inactivates the regulatory enzymes of fatty acid and cholesterol biosynthesis. FEBS Lett. 223, 217–222 (1987).

    Article  CAS  Google Scholar 

  3. Hardie, D.G., Carling, D. & Sim, A.T.R. The AMP-activated protein kinase: a multisubstrate regulator of lipid metabolism. Trends Biochem. Sci. 14, 20–23 (1989).

    Article  CAS  Google Scholar 

  4. Carlson, C.A. & Kim, K.H. Regulation of hepatic acetyl-CoA carboxylase by phosphorylation and dephosphorylation. J. Biol. Chem. 248, 378–380 (1973).

    CAS  PubMed  Google Scholar 

  5. Yeh, L.A., Lee, K. & Kim, K. Regulation of rat liver acetyl-CoA carboxylase. Regulation of phosphorylation and inactivation of acetyl-CoA carboxylase by adenylate energy charge. J. Biol. Chem. 255, 2308–2314 (1980).

    CAS  PubMed  Google Scholar 

  6. Beg, Z.H., Allmann, D.W. & Gibson, D.M. Modulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity with cAMP and wth protein fractions of rat liver cytosol. Biochem. Biophys. Res. Commun. 54, 1362–1369 (1973).

    Article  CAS  Google Scholar 

  7. Harwood, H.J. Jr., Brandt, K.G. & Rodwell, V.W. Allosteric activation of rat liver cytosolic 3-hydroxy-3-methylglutaryl coenzyme A reductase kinase by nucleoside diphosphates. J. Biol. Chem. 259, 2810–2815 (1984).

    CAS  PubMed  Google Scholar 

  8. Ingebritsen, T.S., Parker, R.A. & Gibson, D.M. Regulation of liver hydroxymethylglutaryl-CoA reductase by a bicyclic phosphorylation system. J. Biol. Chem. 256, 1138–1144 (1981).

    CAS  PubMed  Google Scholar 

  9. Hardie, D.G., Carling, D. & Carlson, M. The AMP-activated/SNF1 protein kinase subfamily: metabolic sensors of the eukaryotic cell? Annu. Rev. Biochem. 67, 821–855 (1998).

    Article  CAS  Google Scholar 

  10. Munday, M.R., Campbell, D.G., Carling, D. & Hardie, D.G. Identification by amino acid sequencing of three major regulatory phosphorylation sites on rat acetyl-CoA carboxylase. Eur. J. Biochem. 175, 331–338 (1988).

    Article  CAS  Google Scholar 

  11. Cantó, C. & Auwerx, J. AMP-activated protein kinase and its downstream transcriptional pathways. Cell. Mol. Life Sci. 67, 3407–3423 (2010).

    Article  Google Scholar 

  12. Jansen, M., Ten Klooster, J.P., Offerhaus, G.J. & Clevers, H. LKB1 and AMPK family signaling: the intimate link between cell polarity and energy metabolism. Physiol. Rev. 89, 777–798 (2009).

    Article  CAS  Google Scholar 

  13. Kahn, B.B., Alquier, T., Carling, D. & Hardie, D.G. AMP-activated protein kinase: Ancient energy gauge provides clues to modern understanding of metabolism. Cell Metab. 1, 15–25 (2005).

    Article  CAS  Google Scholar 

  14. Lage, R., Diéguez, C., Vidal-Puig, A. & López, M. AMPK: a metabolic gauge regulating whole-body energy homeostasis. Trends Mol. Med. 14, 539–549 (2008).

    Article  CAS  Google Scholar 

  15. Steinberg, G.R. & Kemp, B.E. AMPK in health and disease. Physiol. Rev. 89, 1025–1078 (2009).

    Article  CAS  Google Scholar 

  16. Viollet, B. et al. AMPK inhibition in health and disease. Crit. Rev. Biochem. Mol. Biol. 45, 276–295 (2010).

    Article  CAS  Google Scholar 

  17. Zhang, B.B., Zhou, G. & Li, C. AMPK: an emerging drug target for diabetes and the metabolic syndrome. Cell Metab. 9, 407–416 (2009).

    Article  Google Scholar 

  18. Carling, D. et al. Mammalian AMP-activated protein kinase is homologous to yeast and plant protein kinases involved in the regulation of carbon metabolism. J. Biol. Chem. 269, 11442–11448 (1994).

    CAS  PubMed  Google Scholar 

  19. Mitchelhill, K.I. et al. Mammalian AMP-activated protein kinase shares structural and functional homology with the catalytic domain of yeast Snf1 protein kinase. J. Biol. Chem. 269, 2361–2364 (1994).

    CAS  PubMed  Google Scholar 

  20. Stapleton, D. et al. Mammalian AMP-activated protein kinase subfamily. J. Biol. Chem. 271, 611–614 (1996).

    Article  CAS  Google Scholar 

  21. Carlson, M., Osmond, B. & Botstein, D. Mutants of yeast defective in sucrose utilization. Genetics 98, 25–40 (1981).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Carlson, M., Osmond, B., Neigeborn, L. & Botstein, D. A suppressor of SNF1 mutations causes constitutive high-level invertase synthesis in yeast. Genetics 107, 19–32 (1984).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Celenza, J.L. & Carlson, M. A yeast gene that is essential for release from glucose repression encodes a protein kinase. Science 233, 1175–1180 (1986).

    Article  CAS  Google Scholar 

  24. Stapleton, D. et al. Mammalian 5′-AMP–activated protein kinase non-catalytic subunits are homologs of proteins that interact with yeast Snf1 protein kinase. J. Biol. Chem. 269, 29343–29346 (1994).

    CAS  PubMed  Google Scholar 

  25. Woods, A. et al. Characterization of AMP-activated protein kinase beta and gamma subunits. Assembly of the heterotrimeric complex in vitro. J. Biol. Chem. 271, 10282–10290 (1996).

    Article  CAS  Google Scholar 

  26. Carlson, M. Glucose repression in yeast. Curr. Opin. Microbiol. 2, 202–207 (1999).

    Article  CAS  Google Scholar 

  27. Hardie, D.G. Role of the AMP-activated protein kinase in the metabolic syndrome and in heart disease. FEBS Lett. 582, 81–89 (2008).

    Article  CAS  Google Scholar 

  28. Carling, D., Clarke, P.R., Zammit, V.A. & Hardie, D.G. Purification and characterisation of the AMP-activated protein kinase. Eur. J. Biochem. 186, 129–136 (1989).

    Article  CAS  Google Scholar 

  29. Neumann, D., Woods, A., Carling, D., Wallimann, T. & Schlattner, U. Mammalian AMP-activated protein kinase: functional, heterotrimeric complexes by co-expression of subunits in Escherichia coli. Protein Expr. Purif. 30, 230–237 (2003).

    Article  CAS  Google Scholar 

  30. Beg, Z.H., Stonik, J.A. & Brewer, H.B. Jr. Characterization and regulation of reductase kinase, a protein kinase that modulates the enzymic activity of 3-hydroxy-3-methylglutaryl-coenzyme A reductase. Proc. Natl. Acad. Sci. USA 76, 4375–4379 (1979).

    Article  CAS  Google Scholar 

  31. Davies, S.P., Helps, N.R., Cohen, P.T. & Hardie, D.G. 5′-AMP inhibits dephosphorylation, as well as promoting phosphorylation, of the AMP-activated protein kinase. Studies using bacterially expressed human protein phosphatase-2C α and native bovine protein phosphatase-2AC. FEBS Lett. 377, 421–425 (1995).

    Article  CAS  Google Scholar 

  32. Hawley, S.A. et al. 5′-AMP activates the AMP-activated protein kinase cascade and Ca2+/calmodulin activates the calmodulin-dependent protein kinase-I cascade, via 3 independent mechanisms. J. Biol. Chem. 270, 27186–27191 (1995).

    Article  CAS  Google Scholar 

  33. Hardie, D.G. & Carling, D. The AMP-activated protein kinase—fuel gauge of the mammalian cell? Eur. J. Biochem. 246, 259–273 (1997).

    Article  CAS  Google Scholar 

  34. Hawley, S.A. et al. Characterization of the AMP-activated protein kinase kinase from rat liver and identification of threonine 172 as the major site at which it phosphorylates AMP-activated protein kinase. J. Biol. Chem. 271, 27879–27887 (1996).

    Article  CAS  Google Scholar 

  35. Sanders, M.J., Grondin, P.O., Hegarty, B.D., Snowden, M.A. & Carling, D. Investigating the mechanism for AMP activation of the AMP-activated protein kinase cascade. Biochem. J. 403, 139–148 (2007).

    Article  CAS  Google Scholar 

  36. Suter, M. et al. Dissecting the role of AMP for allosteric stimulation, activation and deactivation of AMP-activated protein kinase. J. Biol. Chem. 281, 32207–32216 (2006).

    Article  CAS  Google Scholar 

  37. Hong, S.P., Leiper, F.C., Woods, A., Carling, D. & Carlson, M. Activation of yeast Snf1 and mammalian AMP-activated protein kinase by upstream kinases. Proc. Natl. Acad. Sci. USA 100, 8839–8843 (2003).

    Article  CAS  Google Scholar 

  38. Sutherland, C.M. et al. Elm1p is one of three upstream kinases for the Saccharomyces cerevisiae SNF1 complex. Curr. Biol. 13, 1299–1305 (2003).

    Article  CAS  Google Scholar 

  39. Hawley, S.A. et al. Complexes between the LKB1 tumor suppressor, STRAD α/β and MO25 α/β are upstream kinases in the AMP-activated protein kinase cascade. J. Biol. 2, 28 (2003).

    Article  Google Scholar 

  40. Woods, A. et al. LKB1 is the upstream kinase in the AMP-activated protein kinase cascade. Curr. Biol. 13, 2004–2008 (2003).

    Article  CAS  Google Scholar 

  41. Hawley, S.A. et al. Calmodulin-dependent protein kinase kinase-β is an alternative upstream kinase for AMP-activated protein kinase. Cell Metab. 2, 9–19 (2005).

    Article  CAS  Google Scholar 

  42. Woods, A. et al. Ca2+/calmodulin-dependent protein kinase kinase-β acts upstream of AMP-activated protein kinase in mammalian cells. Cell Metab. 2, 21–33 (2005).

    Article  CAS  Google Scholar 

  43. Stahmann, N., Woods, A., Carling, D. & Heller, R. Thrombin activates AMP-activated protein kinase in endothelial cells via a pathway involving Ca2+/calmodulin-dependent protein kinase kinase β. Mol. Cell. Biol. 26, 5933–5945 (2006).

    Article  CAS  Google Scholar 

  44. Tamás, P. et al. Regulation of the energy sensor AMP-activated protein kinase by antigen receptor and Ca2+ in T lymphocytes. J. Exp. Med. 203, 1665–1670 (2006).

    Article  Google Scholar 

  45. Thornton, C., Sardini, A. & Carling, D. Muscarinic receptor activation of AMP-activated protein kinase inhibits orexigenic neuropeptide mRNA expression. J. Biol. Chem. 283, 17116–17122 (2008).

    Article  CAS  Google Scholar 

  46. Hong, S.P., Momcilovic, M. & Carlson, M. Function of mammalian LKB1 and Ca2+/calmodulin-dependent protein kinase kinase α as Snf1-activating kinases in yeast. J. Biol. Chem. 28, 21804–21809 (2005).

    Article  Google Scholar 

  47. Sanz, P., Alms, G.R., Haystead, T.A. & Carlson, M. Regulatory interactions between the Reg1-Glc7 protein phosphatase and the Snf1 protein kinase. Mol. Cell. Biol. 20, 1321–1328 (2000).

    Article  CAS  Google Scholar 

  48. Haystead, T.A.J. et al. Effects of the tumour promoter okadaic acid on intracellular protein phosphorylation and metabolism. Nature 337, 78–81 (1989).

    Article  CAS  Google Scholar 

  49. Moore, F., Weekes, J. & Hardie, D.G. Evidence that AMP triggers phosphorylation as well as direct allosteric activation of rat liver AMP-activated protein kinase. A sensitive mechanism to protect the cell against ATP depletion. Eur. J. Biochem. 199, 691–697 (1991).

    Article  CAS  Google Scholar 

  50. Voss, M. et al. Ppm1E is an in cellulo AMP-activated protein kinase phosphatase. Cell. Signal. 23, 114–124 (2011).

    Article  CAS  Google Scholar 

  51. Garcia-Haro, L. et al. The PP1–R6 protein phosphatase holoenzyme is involved in the glucose-induced dephosphorylation and inactivation of AMP-activated protein kinase, a key regulator of insulin secretion, in MIN6 cells. FASEB J. 24, 5080–5091 (2010).

    Article  Google Scholar 

  52. Cheung, P.C., Salt, I.P., Davies, S.P., Hardie, D.G. & Carling, D. Characterization of AMP-activated protein kinase gamma-subunit isoforms and their role in AMP binding. Biochem. J. 346, 659–669 (2000).

    Article  CAS  Google Scholar 

  53. Bateman, A. The structure of a domain common to archaebacteria and the homocystinuria disease protein. Trends Biochem. Sci. 22, 12–13 (1997).

    Article  CAS  Google Scholar 

  54. Kemp, B.E. Bateman domains and adenosine derivatives form a binding contract. J. Clin. Invest. 113, 182–184 (2004).

    Article  CAS  Google Scholar 

  55. Scott, J.W. et al. CBS domains form energy-sensing modules whose binding of adenosine ligands is disrupted by disease mutations. J. Clin. Invest. 113, 274–284 (2004).

    Article  CAS  Google Scholar 

  56. Milan, D. et al. A mutation in PRKAG3 associated with excess glycogen content in pig skeletal muscle. Science 288, 1248–1251 (2000).

    Article  CAS  Google Scholar 

  57. Blair, E., Redwood, C., Ashrafian, H., Ostman-Smith, I. & Watkins, H. Mutations in the γ2 subunit of AMP-activated protein kinase cause familial hypertrophic cardiomyopathy: evidence for the central role of energy compromise in disease pathogenesis. Hum. Mol. Genet. 10, 1215–1220 (2001).

    Article  CAS  Google Scholar 

  58. Gollob, M.H. et al. Identification of a gene responsible for familial Wolff-Parkinson-White syndrome. N. Engl. J. Med. 344, 1823–1831 (2001); erratum 345, 552 (2001).

    Article  CAS  Google Scholar 

  59. Arad, M., Seidman, C.E. & Seidman, J.G. AMP-activated protein kinase in the heart: role during health and disease. Circ. Res. 100, 474–488 (2007).

    Article  CAS  Google Scholar 

  60. Townley, R. & Shapiro, L. Crystal structures of the adenylate sensor from fission yeast AMP-activated protein kinase. Science 315, 1726–1729 (2007).

    Article  CAS  Google Scholar 

  61. Xiao, B. et al. Structural basis for AMP binding to mammalian AMP-activated protein kinase. Nature 449, 496–500 (2007).

    Article  CAS  Google Scholar 

  62. Amodeo, G.A., Rudolph, M.J. & Tong, L. Crystal structure of the heterotrimer core of Saccharomyces cerevisiae AMPK homologue SNF1. Nature 449, 492–495 (2007).

    Article  CAS  Google Scholar 

  63. Kemp, B.E., Oakhill, J.S. & Scott, J.W. AMPK structure and regulation from three angles. Structure 15, 1161–1163 (2007).

    Article  CAS  Google Scholar 

  64. Jin, X., Townley, R. & Shapiro, L. Structural insight into AMPK regulation: ADP comes into play. Structure 15, 1285–1295 (2007).

    Article  CAS  Google Scholar 

  65. Chen, Z.P. et al. Effect of exercise intensity on skeletal muscle AMPK signaling in humans. Diabetes 52, 2205–2212 (2003).

    Article  CAS  Google Scholar 

  66. Frederich, M. & Balschi, J.A. The relationship between AMP-activated protein kinase activity and AMP concentration in the isolated perfused rat heart. J. Biol. Chem. 277, 1928–1932 (2002).

    Article  CAS  Google Scholar 

  67. Hellsten, Y., Richter, E., Kiens, B. & Bangsbo, J. AMP deamination and purine exchange in human skeletal muscle during and after intense exercise. J. Physiol. (Lond.) 520, 909–920 (1999).

    Article  CAS  Google Scholar 

  68. Veech, R.L., Lawson, J.W.R., Cornell, N.W. & Krebs, H.A. Cytosolic phosphorylation potential. J. Biol. Chem. 254, 6538–6547 (1979).

    CAS  PubMed  Google Scholar 

  69. Xiao, B. et al. Structure of mammalian AMPK and its regulation by ADP. Nature 472, 230–233 (2011).

    Article  CAS  Google Scholar 

  70. Brown, M.S., Brunschede, G.Y. & Goldstein, J.L. Inactivation of 3-hyroxy-3-methylglutaryl coenzyme A reductase in vitro. J. Biol. Chem. 250, 2502–2509 (1975).

    CAS  PubMed  Google Scholar 

  71. Corkey, B.E., Duszynski, J., Rich, T.L., Matschinsky, B. & Williamson, J.R. Regulation of free and bound magnesium in rat hepatocytes and isolated mitochondria. J. Biol. Chem. 261, 2567–2574 (1986).

    CAS  PubMed  Google Scholar 

  72. Oakhill, J.S. et al. β subunit myristoylation is the gatekeeper for initiating metabolic stress sensing by AMP-activated protein kinase (AMPK). Proc. Natl. Acad. Sci. U.S.A. 107, 19237–19241 (2010).

    Article  CAS  Google Scholar 

  73. Göransson, O. et al. Mechanism of action of A-769662, a valuable tool for activation of AMP-activated protein kinase. J. Biol. Chem. 282, 32549–32560 (2007).

    Article  Google Scholar 

  74. Pang, T. et al. Conserved a-helix acts as autoinhibitory sequence in AMP-activated protein kinase a subunits. J. Biol. Chem. 282, 495–506 (2007).

    Article  CAS  Google Scholar 

  75. Chen, L. et al. Structural insight into the autoinhibition mechanism of AMP-activated protein kinase. Nature 459, 1146–1149 (2009).

    Article  CAS  Google Scholar 

  76. Fogarty, S. et al. Calmodulin-dependent protein kinase kinase-β activates AMPK without forming a stable complex: synergistic effects of Ca2+ and AMP. Biochem. J. 426, 109–118 (2010).

    Article  CAS  Google Scholar 

  77. Hudson, E.R. et al. A novel domain in AMP-activated protein kinase causes glycogen storage bodies similar to those seen in hereditary cardiac arrhythmias. Curr. Biol. 13, 861–866 (2003).

    Article  CAS  Google Scholar 

  78. Polekhina, G. et al. AMPK β subunit targets metabolic stress sensing to glycogen. Curr. Biol. 13, 867–871 (2003).

    Article  CAS  Google Scholar 

  79. McBride, A., Ghilagaber, S., Nikolaev, A. & Hardie, D.G. The glycogen-binding domain on the AMPK β subunit allows the kinase to act as a glycogen sensor. Cell Metab. 9, 23–34 (2009).

    Article  CAS  Google Scholar 

  80. Sanders, M.J. et al. Defining the mechanism of activation of AMP-activated protein kinase by the small molecule A-769662, a member of the thienopyridone family. J. Biol. Chem. 282, 32539–32548 (2007).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank all members of the D.C. and S.J.G. groups for helpful comments. Work in the authors' laboratories was supported by the MRC.

Author information

Authors and Affiliations

  1. Medical Research Council (MRC) Clinical Sciences Centre, Cellular Stress Group, Hammersmith Hospital Campus, Imperial College, London, UK

    David Carling & Faith V Mayer

  2. MRC National Institute for Medical Research, London, UK

    Matthew J Sanders & Steven J Gamblin

Authors
  1. David Carling
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Faith V Mayer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Matthew J Sanders
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Steven J Gamblin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to David Carling.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Carling, D., Mayer, F., Sanders, M. et al. AMP-activated protein kinase: nature's energy sensor. Nat Chem Biol 7, 512–518 (2011). https://doi.org/10.1038/nchembio.610

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nchembio.610

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing