Mathematical modeling of PI3K/Akt pathway in microglia

Poshtkohi, A., Wade, J., McDaid, L., Liu, J., Dallas, M. L. ORCID: https://orcid.org/0000-0002-5190-0522 and Bithell, A. (2024) Mathematical modeling of PI3K/Akt pathway in microglia. Neural Computation, 36 (4). pp. 645-676. ISSN 1530-888X doi: 10.1162/neco_a_01643

Abstract/Summary

The motility of microglia involves intracellular signaling pathways that are predominantly controlled by changes in cytosolic Ca2+ and activation of PI3K/Akt (phosphoinositide-3-kinase/protein kinase B). In this letter, 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 optimization techniques to fit the model to phosphorylated Akt (pAkt) experimental modeling/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.

Item Type	Article
URI	https://reading-clone.eprints-hosting.org/id/eprint/115781
Item Type	Article
Refereed	Yes
Divisions	Life Sciences > School of Chemistry, Food and Pharmacy > School of Pharmacy > Medicinal Chemistry Research Group
Uncontrolled Keywords	Cognitive Neuroscience, Arts and Humanities (miscellaneous)
Publisher	MIT Press
Download/View statistics	View download statistics for this item