Excitation states of metabolic networks predict dose-response fingerprinting and ligand pulse phase signalling

With a computational model of energy metabolism in an astrocyte, we show how a system of enzymes in a cascade can act as a functional unit of interdependent reactions, rather than merely a series of independent reactions. These systems may exist in multiple states, depending on the level of stimulation, and the effects of substrates at any point will depend on those states. Response trajectories of metabolites downstream from cAMP-stimulated glycogenolysis exhibit a host of non-linear dynamical response characteristics including hysteresis and response envelopes. Dose-dependent phase transitions predict a novel intracellular signalling mechanism and suggest a theoretical framework that could be relevant to single cell information processing, drug discovery or synthetic biology. Ligands may produce unique dose-response fingerprints depending on the state of the system, allowing selective output tuning. We conclude with the observation that state- and dose-dependent phase transitions, what we dub "ligand pulses" (LPs), may carry information and resemble action potentials (APs) generated from excitatory postsynaptic potentials. In our model, the relevant information from a cAMP-dependent glycolytic cascade in astrocytes could reflect the level of neuromodulatory input that signals an energy demand threshold. We propose that both APs and LPs represent specialized cases of molecular phase signalling with a common evolutionary root. (C) 2019 The Authors. Published by Elsevier Ltd.