AMP-activated protein kinase: an ultrasensitive system for monitoring cellular energy charge

The AMP-activated protein kinase cascade is activated by elevation of AMP a nd depression of ATP when cellular energy charge is compromised, leading to inhibition of anabolic pathways and activation of catabolic pathways. Here we show that the system responds in intact cells in an ultrasensitive mann er over a critical range of nucleotide concentrations, in that only a 6-fol d increase in activating nucleotide is required in order for the maximal ac tivity of the kinase to progress from 10 % to 90 %, equivalent to a co-oper ative system with a Hill coefficient (h) of 2.5. Modelling suggests that th is sensitivity arises from two features of the system: (i) AMP acts at mult iple steps in the cascade (multistep sensitivity); and (ii) the upstream ki nase is initially saturated with the downstream kinase (zero-order ultrasen sitivity).