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  4. Excitation states of metabolic networks predict dose-response fingerprinting and ligand pulse phase signalling
 
research article

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

Coggan, Jay S.  
•
Keller, Daniel  
•
Markram, Henry  
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February 21, 2020
Journal Of Theoretical Biology

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.

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Type
research article
DOI
10.1016/j.jtbi.2019.110123
Web of Science ID

WOS:000509005400010

Author(s)
Coggan, Jay S.  
Keller, Daniel  
Markram, Henry  
Schurmann, Felix  
Magistretti, Pierre J.
Date Issued

2020-02-21

Published in
Journal Of Theoretical Biology
Volume

487

Article Number

110123

Subjects

Biology

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Mathematical & Computational Biology

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Life Sciences & Biomedicine - Other Topics

•

Mathematical & Computational Biology

•

enzyme cascade

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phase signalling

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ligand pulse

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dose-response fingerprinting

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synthetic biology

•

systems biology

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drug

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strategies

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dynamics

•

disease

Editorial or Peer reviewed

REVIEWED

Written at

EPFL

EPFL units
BBP-CORE  
Available on Infoscience
March 3, 2020
Use this identifier to reference this record
https://infoscience.epfl.ch/handle/20.500.14299/166694
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