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AMP‐activated protein kinase: the energy charge hypothesis revisited

Hardie, D. Grahame, Hawley, Simon A.·2001·BioEssays

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Abstract

The AMP‐activated protein kinase cascade is a sensor of cellular energy charge, and its existence provides strong support for the energy charge hypothesis first proposed by Daniel Atkinson in the 1960s. The system is activated in an ultrasensitive manner by cellular stresses that deplete ATP (and consequently elevate AMP), either by inhibiting ATP production (e.g., hypoxia), or by accelerating ATP consumption (e.g., exercise in muscle). Once activated, it switches on catabolic pathways, both acutely by phosphorylation of metabolic enzymes and chronically by effects on gene expression, and switches off many ATP‐consuming processes. Recent work suggests that activation of AMPK is responsible for many of the effects of physical exercise, both the rapid metabolic effects and the adaptations that occur during training. Dominant mutations in regulatory subunit isoforms (γ2 and γ3) of AMPK, which appear to increase the basal activity in the absence of AMP, lead to hypertrophy of cardiac and skeletal muscle respectively. BioEssays 23:1112–1119, 2001. © 2001 John Wiley & Sons, Inc.

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(1995) · FEBS Letters · doi:10.1016/0014-5793(95)01368-7 · Cited by 595
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Show all 6 references

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Inoki, K., Zhu, T., & Guan, K.-L. (2003) · Cell · doi:10.1016/s0092-8674(03)00929-2 · Cited by 3,914
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Jäger, S., Handschin, C., St.-Pierre, J., & Spiegelman, B. M. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0705070104 · Cited by 2,491
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Authors: Hardie, D. G., & Hawley, S. A.
Venue: BioEssays
Publisher: Wiley
Published: 2001-11-29
Volume: 23
Issue: 12
Pages: 1112-1119
ISSN: 0265-9247 (ISSN-L)
1521-1878
DOI: 10.1002/bies.10009
OpenAlex: W2067522487
Cited by: 784
References: 6
FWCI: 2.36
Type: journal article
Language: en
Open access: closed

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AMP‐activated protein kinase: the energy charge hypothesis revisited

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