![]() ![]() Metformin and other biguanides, such as the more potent analog phenformin 37, are thought to activate AMPK by acting as mild inhibitors of Complex I of the respiratory chain, which leads to a drop of intracellular ATP levels 38, 39. Metformin, the most widely prescribed Type 2 diabetes drug, has been shown to activate AMPK 35 and to do so in an LKB1 dependent manner 36. In addition to physiological AMP/ADP elevation from stresses such as low nutrients or prolonged exercise, AMPK can be activated in response to several pharmacological agents (see Figure 1). Many types of cellular stresses can lead to AMPK activation. Although only AMPKα1 and AMPKα2 are activated in response to energy stress, there is a significant amount of crosstalk and shared substrates between AMPK and the AMPK related kinases 15. This family of kinases includes the MARKs (1-4), SIKs (1-3), BRSK/SADs (1-2) and NUAKs (1-2) sub-families of kinases 34. In addition to regulating AMPKα1 and AMPKα2 phosphorylation, LKB1 phosphorylates and activates another twelve kinases related to AMPK 33. Genetic studies of tissue-specific deletion of LKB1 have revealed that LKB1 mediates the majority of AMPK activation in nearly every tissue type examined to date, though CAMKK2 appears to be particularly involved in AMPK activation in neurons and T cells 31, 32. Additional control via regulation of the localization of AMPK 26- 28 or LKB1 29, 30 remains an critical underexplored area for future research. However, the α1 subunit has been shown to localize to the nucleus under some conditions 24, and the myristoylation of the (β isoforms has been shown to be required for proper activation of AMPK and its localization to membranes 25. The expression of some of these isoforms is tissue restricted, and functional distinctions are reported for the two catalytic α subunits, particularly of AMP- and LKB1-responsiveness and nuclear localization of AMPKα2 compared to the α1 23. In mammals, there are two genes encoding the AMPK α catalytic subunit (α1 and α2), two β genes (β1 and β2) and three γ subunit genes (γ1, γ2 and γ3) 22. Additional studies have suggested the MAPKKK family member TAK1/MAP3K7 may also phosphorylate Thr172 but the contexts in which TAK1 might regulate AMPK in vivo, and whether that involves LKB1 still requires further investigation 20, 21. Importantly, AMPK can also be phosphorylated on Thr172 in response to calcium flux, independently of LKB1, via CAMKK2 (CAMKKβ) kinase, which is the closest mammalian kinase to LKB1 by sequence homology 16- 19. Interestingly, LKB1 is a tumor suppressor gene mutated in the inherited cancer disorder Peutz-Jeghers syndrome and in a significant fraction of lung and cervical cancers, suggesting that AMPK could play a role in tumor suppression 15. In addition to nucleotide binding, phosphorylation of Thr172 in the activation loop of AMPK is required for its activation, and several groups have demonstrated that the serine/threonine kinase LKB1 directly mediates this event 12- 14. Recent studies discovering that ADP can also bind the nucleotide binding pockets in the AMPK γ suggest it may be the physiological nucleotide for AMPK activation under a variety of cellular stresses 18- 11. Under lowered intracellular ATP levels, AMP or ADP can directly bind to the γ regulatory subunits, leading to a conformational change that protects the activating phosphorylation of AMPK 9, 10. AMPK is hypothesized to be activated by a two-pronged mechanism (for a full review, see 8). In most species, AMPK exists as an obligate heterotrimer, containing a catalytic subunit (a), and two regulatory subunits (β and γ). In higher eukaryotes like mammals, AMPK plays a general role in coordinating growth and metabolism, and specialized roles in metabolic control in dedicated tissues such as the liver, muscle and fat 7. elegans 4, Drosophila 5, and even the moss Physcomitrella patens 6 has revealed a conserved function of AMPK as a metabolic sensor, allowing for adaptive changes in growth, differentiation, and metabolism under conditions of low energy. Genetic analysis of AMPK orthologs in Arabidopsis 1, Saccharomyces cerevisiae 2, Dictyostelium 3, C. In response, AMPK promotes catabolic pathways to generate more ATP, and inhibits anabolic pathways. AMPK is a highly conserved sensor of intracellular adenosine nucleotide levels that is activated when even modest decreases in ATP production result in relative increases in AMP or ADP. One of the fundamental requirements of all cells is to balance ATP consumption and ATP generation. Core AMPK complex Components and Upstream Activators ![]()
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