Mathematical Modelling of PI3K/Akt Pathway in Microglia

Alireza Poshtkohi, John Wade, Liam McDaid, Junxiu Liu, Mark L Dallas, Angela Bithell

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Abstract

The motility of microglia involves intracellular signalling pathways that are predominantly controlled by changes in cytosolic Ca2+ and activation of PI3K/Akt (phosphoinositide-3-kinase/protein kinase B). Herein, we develop a novel biophysical model for cytosolic Ca2+ activation of the PI3K/Akt pathway in microglia where Ca2+ influx is mediated by both P2Y purinergic receptors (P2YR) and P2X purinergic receptors (P2XR). The model parameters are estimated by employing optimisation techniques to fit the model to phosphorylated Akt (pAkt) experimental modelling/in vitro data. The integrated model supports the hypothesis that Ca2+ influx via P2YR and P2XR can explain the experimentally reported biphasic transient responses in measuring pAkt levels. Our predictions reveal new quantitative insights into P2Rs on how they regulate Ca2+ and Akt in terms of physiological interactions and transient responses. It is shown that the upregulation of P2X receptors through a repetitive application of agonist results in a continual increase in the baseline [Ca2+] which causes the biphasic response to become a monophasic response which prolongs elevated levels of pAkt.
Original languageEnglish
Pages (from-to)645–676
Number of pages33
JournalNeural Computation
Volume36
Issue number4
DOIs
Publication statusPublished - 21 Mar 2024

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