Research Groups > Genes and Metabolism Cellular Stress
Our research focuses on the role of the AMP-activated protein kinase (AMPK) cascade in regulating energy metabolism.
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 plays an important role in this homeostasis. AMPK is activated by a fall in ATP (concomitant with a rise in ADP and AMP) leading to the activation of catabolic pathways and the inhibition of anabolic pathways. Recent studies have shown that AMPK plays a role in the regulation of whole body energy metabolism, including the control of feeding and using transgenic models we have shown that deletion of AMPK in the hypothalamus leads to an obese phenotype.
Figure 1. Model showing the regulation of AMPK by adenine nucleotides
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The pivotal role of AMPK in controlling metabolism makes it an ideal target for therapeutic intervention in certain forms of diabetes and obesity. Mutations in the γ2 subunit of AMPK cause a severe heart defect in humans (glycogen storage cardiomyopathy associated with pre-ventricular excitation), indicating that AMPK plays a role in the normal development of the heart.
Figure 2. Summary of metabolic effects of AMPK
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AMPK is activated primarily by phosphorylation catalysed by upstream protein kinases, which include LKB1 and Ca2+/calmodulin dependent protein kinase kinase β. CaMKKβ is highly expressed in neuronal tissues and is implicated in hippocampal function. Inactivating mutations within LKB1 lead to a rare, dominantly inherited cancer predispostion syndrome in humans, termed Peutz-Jeghers Syndrome. Collectively, these findings suggest that AMPK may provide a link in human diseases whose underlying cause is due to defects in energy metabolism. Our current interests focus on understanding the regulation of AMPK using structure/function analyses and the physiological role of AMPK using transgenic models.
Figure 1. Model showing the regulation of AMPK by adenine nucleotides
Click the image to see a larger version
Click the image to see a larger version
Figure 2. Summary of metabolic effects of AMPK
Click the image to get a larger version
Click the image to get a larger version
Group head
David Carling (Professor)
Telephone 34313/32078
Email
Group members
Nicola Bright
Duncan Bull (Mr)
Telephone 38262
Email
David Carmena (Dr)
Telephone 33014
Email
Romain Laine (Mr)
Fiona Leiper (Dr)
Telephone 38262/32078
Email
Philip Muckett (Mr)
Telephone 38537/31770
Email
Naveenan Navaratnam (Dr)
Telephone 33014
Email
Alex Sardini (Dr)
Telephone 33014
Email
Alessandra Sorelli Hartmann (Miss)
Telephone 38265
Email
Daniel Stuckey (Dr)
Telephone 38262
Email
Angela Woods (Dr)
Telephone 32097/32078
Email
Huza Zhang (Mr)
Telephone 38262
Email
Jess Zhao (Ms)
Telephone 38262
Email
Visiting worker
Alicia Garcia (Dr)
Admin contact
Angela Whyte (Mrs)
Telephone 34318
Email
Contact details
Telephone: +44 (0) 20 8383 4313
Facsimile: +44 (0) 20 8383 8306
Facsimile: +44 (0) 20 8383 8306
Selected publications
Mayer, F. V., Heath, R., Underwood, E., Sanders, M. J., Carmena, D., McCartney, R. R., Leiper, F. C., Xiao, B., Jing, C., Walker, P. A., Haire, L. F., Ogrodowicz, R., Martin, S. R., Schmidt, M. C., Gamblin, S. J., Carling, D. (2011). ADP regulates SNF1, the saccharomyces cerevisiae homolog of AMP-activated protein kinase. Cell Metabolism 14, 707–714. Abstract
Xiao, B., Sanders, M. J., Underwood, E., Heath, R., Mayer, F. V., Carmena, D., Jing, C., Walker, P. A., Eccleston, J. F., Haire, L. F., Saiu, P., Howell, S. A., Aasland, R., Martin, S. R., Carling, D., Gamblin, S. J. (2011). Structure of mammalian AMPK and its regulation by ADP. Nature 472, 230–233. Abstract
Woods, A., Heslegrave, A., Muckett, P. J., Levene, A., Clements, M., Mobberley, M., Ryder, T. A., Abu-Hayyeh, S., Williamson, C., Goldin, R. D., Ashworth, A., Withers, D. J., Carling, D. (2011). LKB1 is required for hepatic bile acid transport and canalicular membrane integrity in mice. The Biochemical Journal 434, 49–60. Abstract
Thornton, C., Bright, N. J., Sastre, M., Muckett, P. J., Carling, D. (2011). AMP-activated protein kinase (AMPK) is a tau kinase, activated in response to Β-amyloid exposure. The Biochemical Journal, 434, 503–512. Abstract
Xiao, B., Sanders, M. J., Underwood, E., Heath, R., Mayer, F. V., Carmena, D., Jing, C., Walker, P. A., Eccleston, J. F., Haire, L. F., Saiu, P., Howell, S. A., Aasland, R., Martin, S. R., Carling, D., Gamblin, S. J. (2011). Structure of mammalian AMPK and its regulation by ADP. Nature 472, 230–233. Abstract
Woods, A., Heslegrave, A., Muckett, P. J., Levene, A., Clements, M., Mobberley, M., Ryder, T. A., Abu-Hayyeh, S., Williamson, C., Goldin, R. D., Ashworth, A., Withers, D. J., Carling, D. (2011). LKB1 is required for hepatic bile acid transport and canalicular membrane integrity in mice. The Biochemical Journal 434, 49–60. Abstract
Thornton, C., Bright, N. J., Sastre, M., Muckett, P. J., Carling, D. (2011). AMP-activated protein kinase (AMPK) is a tau kinase, activated in response to Β-amyloid exposure. The Biochemical Journal, 434, 503–512. Abstract
