First discovered… AMP-activated protein kinase (AMPK) was first named in 1988 although it had appeared in several earlier reports under a number of different aliases, e.g. HMG-CoA reductase kinase, acetyl-CoA carboxylase kinase. The name AMP-activated protein kinase was chosen after one of its physiological activators, AMP. Don't ever say… Cyclic-AMP dependent protein kinase in the same breath! AMPK and PKA may have similar-sounding names but they are regulated by different pathways and their downstream effects, although in some cases overlap, are quite distinct. What does it do? AMPK has been dubbed the cellular fuel gauge, because it is activated by a drop in the energy status of the cell. If ATP is used up faster than it can be re-synthesized, ATP levels fall and this leads to a rise in AMP. The increase in the AMP:ATP ratio triggers the activation of AMPK and leads to the phosphorylation of a large number of downstream targets. The overall effect of AMPK activation is to switch off energy-using pathways and switch on energy-generating pathways, thus helping to restore the energy balance within the cell. The conservation of AMPK throughout evolution emphasises its importance: homologs have been identified in all eukaryotic species examined to date, including plants. More recent findings have shown that AMPK is activated by stimuli that do not cause a change in the AMP:ATP ratio, such as hyperosmotic stress, indicating that the kinase may have other roles within the cell. What does it look like? AMPK is a heterotrimeric enzyme complex. The α subunit contains a typical serine/threonine kinase domain and a carboxy-terminal regulatory domain. The β subunit acts as a scaffold for binding the other two subunits and contains a glycogen-binding domain. The γ subunit contains four cystathionine-β-synthase (CBS) domains that play a role in binding AMP and ATP, allosteric effectors of the kinase. A range of isoforms of each of the subunits results in 12 possible combinations of the heterotrimeric complex in mammals. The physiological role of the different isoforms is not clear, although their differing tissue distributions suggest they have distinct roles in specific cells. How is it regulated? Activation of AMPK requires phosphorylation by an upstream kinase, which was recently identified as LKB1. Intriguingly, inactivating mutations in LKB1 cause a rare form of hereditary cancer, called Peutz-Jeghers syndrome. It is not yet clear whether AMPK is involved in the progression of this disease, but it does hint at the possibility that AMPK may be involved in cell proliferation. Can we live without it? Almost certainly not. Mice lacking either one of the catalytic α subunits are viable, but deleting both isoforms results in embryonic lethality. Interestingly, mice lacking LKB1 also die at around the same stage during development. Although a complete loss of AMPK activity is lethal, subtle changes in AMPK activity can lead to serious clinical consequences. Naturally occurring mutations within the γ2 regulatory subunit in humans cause cardiac hypertrophy associated with a form of arrhythmia known as Wolff–Parkinson–White syndrome, possibly by abolishing the normal activation of the kinase by AMP. Where can I find out more?