Regulation of the muscle‐specific AMP‐activated protein kinase α2β2γ3 complexes by AMP and implications of the mutations in the γ3‐subunit for the AMP dependence of the enzyme

@article{Lindgren2007RegulationOT,
  title={Regulation of the muscle‐specific AMP‐activated protein kinase $\alpha$2$\beta$2$\gamma$3 complexes by AMP and implications of the mutations in the $\gamma$3‐subunit for the AMP dependence of the enzyme},
  author={Kerstin Lindgren and Mattias Ormestad and M{\aa}rten Persson and Sofia Martinsson and L. Thomas Svensson and Margit Mahlapuu},
  journal={The FEBS Journal},
  year={2007},
  volume={274}
}
The AMP‐activated protein kinase is an evolutionarily conserved heterotrimer that is important for metabolic sensing in all eukaryotes. The muscle‐specific isoform of the regulatory γ‐subunit of the kinase, AMP‐activated protein kinase γ3, has a key role in glucose and fat metabolism in skeletal muscle, as suggested by metabolic characterization of humans, pigs and mice harboring substitutions in the AMP‐binding Bateman domains of γ3. We demonstrate that AMP‐activated protein kinase α2β2γ3… 
Animal Models to Study AMPK.
TLDR
This chapter updates the new development in the generation and application of animal models for the study of AMPK biology and discusses recent breakthroughs from studies in mice, flies, and worms showing how AMPK has a primary role in initiating or promoting pathological or beneficial impact on health.

References

SHOWING 1-10 OF 71 REFERENCES
The 5′-AMP-activated Protein Kinase γ3 Isoform Has a Key Role in Carbohydrate and Lipid Metabolism in Glycolytic Skeletal Muscle*
TLDR
The results validate the muscle-specific AMPK γ3 isoform as a therapeutic target for prevention and treatment of insulin resistance and identify the R225Q mutation associated with higher basal AMPK activity and diminished AMP dependence.
Muscle-specific overexpression of wild type and R225Q mutant AMP-activated protein kinase gamma3-subunit differentially regulates glycogen accumulation.
AMP-activated protein kinase (AMPK) is a heterotrimeric complex that works as an energy sensor to integrate nutritional and hormonal signals. The naturally occurring R225Q mutation in the
Characterization of AMP-activated protein kinase gamma-subunit isoforms and their role in AMP binding.
TLDR
Labelling studies, using the reactive AMP analogue 8-azido-[(32)P]AMP, indicate that the gamma subunit may participate directly in the binding of AMP within the complex.
Functional Analysis of Mutations in the γ2 Subunit of AMP-activated Protein Kinase Associated with Cardiac Hypertrophy and Wolff-Parkinson-White Syndrome*
TLDR
The results indicate that mutations in γ2 have different effects on AMPK function, suggesting that they may lead to abnormal development of the heart through distinct mechanisms.
N488I Mutation of the γ2-Subunit Results in Bidirectional Changes in AMP-Activated Protein Kinase Activity
TLDR
It is demonstrated that the mutation renders AMPK insensitive to the inhibitory and stimulatory effects of the regulatory nucleotides ATP and AMP, respectively, suggesting that the pathogenesis of the human disease may not be attributable to a simple loss- or gain-of-function.
Dissecting the Role of 5′-AMP for Allosteric Stimulation, Activation, and Deactivation of AMP-activated Protein Kinase*
TLDR
Results show a 1000-fold activation of AMPK by the combined effects of upstream kinase and saturating concentrations of AMP and evidence is provided that ZMP, a compound formed in 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside-treated cells to activate AMPK in vivo, allosterically activates purified AM PK in vitro, but compared with AMP, maximal activity is not reached.
N488I mutation of the gamma2-subunit results in bidirectional changes in AMP-activated protein kinase activity.
TLDR
It is demonstrated that the mutation renders AMPK insensitive to the inhibitory and stimulatory effects of the regulatory nucleotides ATP and AMP, respectively, suggesting that the pathogenesis of the human disease may not be attributable to a simple loss- or gain-of-function.
Intrasteric control of AMPK via the γ1 subunit AMP allosteric regulatory site
TLDR
It is proposed that ATP acts as an intrasteric inhibitor by bridging the α and γ subunits and that AMP functions to derepress AMPK activity.
Investigating the mechanism for AMP activation of the AMP-activated protein kinase cascade.
TLDR
It is demonstrated that AMP activates AMPK via two mechanisms: by direct allosteric activation and by protecting Thr172 from dephosphorylation, and a simple model for the regulation of AMPK in mammalian cells by LKB1 and CaMKKbeta is proposed.
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