Cell Metab. 18, 556–566 (2013)

AMP-activated protein kinase (AMPK) senses falling cellular energy status and activates catabolic pathways while inhibiting anabolic pathways to restore energy homeostasis. AMPK is activated by the upstream kinases LKB1 and CAMKK-β, which phosphorylate Thr172. The nucleotides ADP and AMP (signals of low cellular energy) promote Thr172 phosphorylation, whereas AMP causes further allosteric activation. Recently, ADP had been proposed to be the primary physiological signal, as it is present at higher cellular concentrations than AMP. However, Gowans et al. found that AMP was tenfold more potent than ADP in inhibiting Thr172 dephosphorylation, whereas it was the sole enhancer of Thr172 phosphorylation by LKB1. They also found the effect of allosteric activation was larger (greater than tenfold), whereas the increase in Thr172 phosphorylation in intact cells was smaller (less than fourfold) than previously thought. The authors further examined the role of allosteric activation in intact cells. They administered two compounds: the metabolic inhibitor berberine, which increases AMP, and another allosteric activator, A769662, under conditions where Thr172 phosphorylation could not occur. Both compounds still markedly stimulated the phosphorylation of downstream targets, showing that allosteric activation is an important mechanism. These studies suggest that AMP is the primary signal activating the AMPK system and stress the importance of the allosteric mechanism.