title: Computational Analysis of AMPK-Mediated Neuroprotection Suggests Acute Excitotoxic Bioenergetics and Glucose Dynamics Are Regulated by a Minimal Set of Critical Reactions.
abstract: Loss of ionic homeostasis during excitotoxic stress depletes ATP levels and activates the AMP-activated protein kinase (AMPK), re-establishing energy production by increased expression of glucose transporters on the plasma membrane. Here, we develop a computational model to test whether this AMPK-mediated glucose import can rapidly restore ATP levels following a transient excitotoxic insult. We demonstrate that a highly compact model, comprising a minimal set of critical reactions, can closely resemble the rapid dynamics and cell-to-cell heterogeneity of ATP levels and AMPK activity, as confirmed by single-cell fluorescence microscopy in rat primary cerebellar neurons exposed to glutamate excitotoxicity. The model further correctly predicted an excitotoxicity-induced elevation of intracellular glucose, and well resembled the delayed recovery and cell-to-cell heterogeneity of experimentally measured glucose dynamics. The model also predicted necrotic bioenergetic collapse and altered calcium dynamics following more severe excitotoxic insults. In conclusion, our data suggest that a minimal set of critical reactions may determine the acute bioenergetic response to transient excitotoxicity and that an AMPK-mediated increase in intracellular glucose may be sufficient to rapidly recover ATP levels following an excitotoxic insult.
authors: Centre for Systems Medicine, Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, Dublin 2, Ireland.|Centre for the Study of Neurological Disorders, Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
authors: Niamh M C
authors: NM
authors: Connolly
authors: Centre for the Study of Neurological Disorders, Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
authors: Beatrice
authors: B
authors: D'Orsi
authors: Centre for Systems Medicine, Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
authors: Naser
authors: N
authors: Monsefi
authors: Department of Cardiovascular Sciences, KU Leuven, 3000 Leuven, Belgium.
authors: Heinrich J
authors: HJ
authors: Huber
authors: Centre for Systems Medicine, Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, Dublin 2, Ireland.|Centre for the Study of Neurological Disorders, Department of Physiology & Medical Physics, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
authors: Jochen H M
authors: JH
authors: Prehn
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D002531:Cerebellum / Q000378:metabolism*; D003198:Computer Simulation; D004734:Energy Metabolism; D005947:Glucose / Q000378:metabolism*; D051246:Glucose Transport Proteins, Facilitative / Q000378:metabolism; D006801:Humans; D008959:Models, Neurological; D009474:Neurons / Q000378:metabolism*; D051381:Rats
chemical_list: D051246:Glucose Transport Proteins, Facilitative; D000255:Adenosine Triphosphate; D055372:AMP-Activated Protein Kinases; D005947:Glucose