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. 2014 Feb;42(1):71-5.
doi: 10.1042/BST20130244.

AMPK: a cellular energy sensor primarily regulated by AMP

Graeme J Gowans  1 , D Grahame Hardie  1
Affiliations

AMPK: a cellular energy sensor primarily regulated by AMP

Graeme J Gowans et al. Biochem Soc Trans. 2014 Feb.

Abstract

AMPK (AMP-activated protein kinase) is a cellular energy sensor that monitors the ratio of AMP/ATP, and possibly also ADP/ATP, inside cells. Once activated by falling cellular energy levels, it acts to restore energy homoeostasis by switching on catabolic pathways that generate ATP, while switching off anabolic pathways and other processes consuming ATP. AMPK is switched on by increases in AMP via three mechanisms, all of which are antagonized by ATP: (i) promotion of phosphorylation of Thr172 by upstream activating kinases; (ii) inhibition of dephosphorylation of Thr172 by phosphatases; and (iii) allosteric activation of the phosphorylated kinase. Recently, it has been proposed that the first two mechanisms are also triggered by ADP, which might be the physiological signal rather than AMP, and that the third mechanism may not be physiologically significant. We have re-evaluated these questions, and found that only mechanism (ii) is mimicked by ADP, and that ADP is also less potent than AMP, which we still believe to be the primary signal. We have also provided evidence that mechanism (iii), i.e. allosteric activation by AMP, is a quantitatively significant mechanism in intact cells.

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Figures

Figure 1
Figure 1
Domain structure of the α, β and γ subunits of AMPK heterotrimers, drawn approximately to scale. KEY: AID, auto-inhibitory domain; α/β-CTD, α/β C-terminal domains; CBSx, CBS repeat, numbered in order from N-terminus.
Figure 2
Figure 2
Changes in ATP, ADP and AMP induced by treatment of G361 cells with berberine (100 µM, 1 hr). ATP and ADP were estimated by capillary electrophoresis, and AMP calculated by assuming that the adenylate kinase reaction was at equilibrium. Statistically significant differences from control without berberine (P <0.001) are shown.
Figure 3
Figure 3
Triple mechanism by which AMP (and ADP) contribute to AMPK activation. (1) binding of AMP to AMPK promotes Thr172 phosphorylation by LKB1, but not CaMKKβ; (2) binding of AMP (and ADP at higher concentrations) inhibits Thr172 dephosphorylation; (3) binding of AMP causes allosteric activation. All three effects of AMP (and the single effect of ADP) are antagonized by binding of ATP.
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