Type

Other / n/a

Authors

Jochen HM Prehn
Heinrich J Huber
Naser Monsefi
Beatrice D'Orsi
Niamh MC Connolly

Subjects

Pharmacology

Topics
bioenergy neuroprotection mathematical model physics sensitivity analysis physiology calcium transport enzyme activity glucose transport calcium cell level controlled study cell stress

Computational Analysis of AMPK-Mediated Neuroprotection Suggests Acute Excitotoxic Bioenergetics and Glucose Dynamics Are Regulated by a Minimal Set of Critical Reactions. (2016)

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.
Collections Ireland -> Royal College of Surgeons in Ireland -> Physiology and Medical Physics Articles
Ireland -> Royal College of Surgeons in Ireland -> Department of Physiology and Medical Physics

Full list of authors on original publication

Jochen HM Prehn, Heinrich J Huber, Naser Monsefi, Beatrice D'Orsi, Niamh MC Connolly

Experts in our system

1
Jochen H M Prehn
Royal College of Surgeons in Ireland
Total Publications: 206
 
2
Heinrich J Huber
Royal College of Surgeons in Ireland
Total Publications: 39
 
3
Beatrice D'Orsi
Royal College of Surgeons in Ireland
Total Publications: 14
 
4
Niamh M C Connolly
Royal College of Surgeons in Ireland
Total Publications: 14