Use of Cells Expressing γ Subunit Variants to Identify Diverse Mechanisms of AMPK Activation
By S. Hawley, Fiona A. Ross, C. Chevtzoff, K. Green, A. Evans, S. Fogarty, M. Towler, Laura J. Brown, O. Ogunbayo, D. Hardie. Cell Metabolism, 2010
818 citations recorded by the source corpus.
Summary A wide variety of agents activate AMPK, but in many cases the mechanisms remain unclear. We generated isogenic cell lines stably expressing AMPK complexes containing AMP-sensitive (wild-type, WT) or AMP-insensitive (R531G) γ2 variants. Mitochondrial poisons such as oligomycin and dinitrophenol only activated AMPK in WT cells, as did AICAR, 2-deoxyglucose, hydrogen peroxide, metformin, phenformin, galegine, troglitazone, phenobarbital, resveratrol, and berberine. Excluding AICAR, all of these also inhibited cellular energy metabolism, shown by increases in ADP:ATP ratio and/or by decreases in cellular oxygen uptake measured using an extracellular flux analyzer. By contrast, A769662, the Ca2+ ionophore, A23187, osmotic stress, and quercetin activated both variants to varying extents. A23187 and osmotic stress also increased cytoplasmic Ca2+, and their effects were inhibited by STO609, a CaMKK inhibitor. Our approaches distinguish at least six different mechanisms for AMPK activation and confirm that the widely used antidiabetic drug metformin activates AMPK by inhibiting mitochondrial respiration.
Subfields: Molecular Biology, Physiology, Surgery
View Paper: https://www.semanticscholar.org/paper/8c900fe7b77a1f64bd8991b7c19f7a70a87e9336
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Citations in the corpus
- AMP-activated protein kinase: an energy sensor that regulates all aspects of cell function. (2011, background): “Moreover, since metformin/phenformin and A-769662 activate AMPK by different mechanisms (Hawley et al. 2010), it seems unlikely that the observed delays in tumorigenesis (Huang et al. 2008) were ‘‘off-target,’’ AMPK-independent effects.”
- The hallmarks of aging. (2013, neutral): “There is compelling evidence that compounds such asmetformin and resveratrol are mild mitochondrial poisons that induce a lowenergy state characterized by increased AMP levels and activation of AMPK (Hawley et al., 2010).”
- Metformin: from mechanisms of action to therapies. (2014, positive): “This has been clearly evidenced in rat hepatoma cells H4IIE, where quinidine, a competitive OCT1 inhibitor, completely blocked AMPK activation by metformin, while AMPK activation by phenformin and galegine was not affected (Hawley et al., 2010).”
- The Ancient Drug Salicylate Directly Activates AMP-Activated Protein Kinase (2012, positive): “5 M perchloric acid and analyzed by capillary electrophoresis (1).”
- Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition) (2012, neutral): “Overexpression of a dominant negative mutant (R531G) of PRKAG2, the g-subunit isoform 2 of AMPK that is unable to bind AMP, makes it possible to analyze the relationship between AMP modulation (or alteration of energetic metabolism) and AMPK activity.(462,463) Activation of AMPK is also associated w”
- The mechanisms of action of metformin (2017, neutral): “(2)Metformin inhibits Complex I, preventingmitochondrial ATP production and, thus, increasing cytoplasmic ADP:ATP and AMP:ATP ratios (the latter by displacement of the adenylate kinase reaction); these changes activate AMPK [17].”
- Mechanisms of insulin resistance in obesity (2013, background): “) all inhibited mitochondrial function of ATP production in cellular models [64–67].”
- Metformin promotes antitumor immunity via endoplasmic reticulum-associated degradation of PD-L1 (2018, neutral): “Previous diabetes studies indicated that the AMP-activated protein kinase (AMPK) is a main effector of metformin (Zhou et al., 2001), and that metformin may indirectly activate AMPK by inducing stress conditions, such as mitochondrial malfunction that depletes ATP (Hawley et al., 2010).”
- The AMP-activated protein kinase (AMPK) signaling pathway coordinates cell growth, autophagy, & metabolism (2011, background): “, 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 level”
- Resveratrol Ameliorates Aging-Related Metabolic Phenotypes by Inhibiting cAMP Phosphodiesterases (2012, positive): “N IH -PA Author M anuscript N IH -PA Author M anuscript N IH -PA Author M anuscript activate AMPK by decreasing energy (Hawley et al., 2010), we examined whether the phosphorylation of AMPK and ACC by high concentration of resveratrol (300 μM) was also sensitive to STO609.”
- AMPK Phosphorylates and Inhibits SREBP Activity to Attenuate Hepatic Steatosis and Atherosclerosis in Diet-induced Insulin Resistant Mice (2011, neutral): “Moreover, Ser372 phosphorylation was enhanced by phenformin, which activates AMPK by inhibiting mitochondrial complex 1 inhibitor (Hawley et al., 2010), and the phosphorylation was ablated”
- SIRT1 is required for AMPK activation and the beneficial effects of resveratrol on mitochondrial function (2012, positive): “If resveratrol induces AMPK by acting as an ATPase or Complex III inhibitor (Gledhill et al., 2007; Hawley et al., 2010; Zini et al., 1999), then ATP levels should be lower in the resveratrol-treated mice, and AMPK activation should occur independently of SIRT1.”