Use of Cells Expressing γ Subunit Variants to Identify Diverse Mechanisms of AMPK Activation

被引:659
作者
Hawley, Simon A. [1 ]
Ross, Fiona A. [1 ]
Chevtzoff, Cyrille [1 ]
Green, Kevin A. [1 ]
Evans, Ashleigh [1 ]
Fogarty, Sarah [1 ]
Towler, Mhairi C. [1 ]
Brown, Laura J. [1 ]
Ogunbayo, Oluseye A. [2 ]
Evans, A. Mark [2 ]
Hardie, D. Grahame [1 ]
机构
[1] Univ Dundee, Coll Life Sci, Div Mol Physiol, Dundee DD1 5EH, Scotland
[2] Univ Edinburgh, Ctr Integrat Physiol, Coll Med & Vet Med, Edinburgh EH8 9XD, Midlothian, Scotland
基金
英国惠康基金;
关键词
DEPENDENT PROTEIN-KINASE; RESPIRATORY COMPLEX-I; UPSTREAM KINASE; METFORMIN; PHOSPHORYLATION; INHIBITION; BETA; RESVERATROL; HEART; SIRT1;
D O I
10.1016/j.cmet.2010.04.001
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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) gamma 2 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 ST0609, 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.
引用
收藏
页码:554 / 565
页数:12
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