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Mathematical Modeling of PI3K/Akt Pathway in Microglia.

Alireza Poshtkohi1, John Wade2, Liam McDaid3

  • 1School of Physics, Engineering and Computer Science, University of Hertfordshire, Hatfield, Hertfordshire, U.K. a.poshtkohi@herts.ac.uk.

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|March 8, 2024
PubMed
Summary

This study models how calcium (Ca2+) and purinergic receptors (P2Rs) activate the PI3K/Akt pathway in microglia. The model explains biphasic responses and reveals how P2X receptor upregulation alters calcium signaling and prolongs Akt activation.

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Area of Science:

  • Neuroscience
  • Cell Biology
  • Biophysics

Background:

  • Microglial motility is regulated by intracellular signaling pathways, primarily involving cytosolic calcium (Ca2+) and phosphoinositide-3-kinase/protein kinase B (PI3K/Akt) activation.
  • Purinergic receptors, specifically P2Y purinergic receptors (P2YR) and P2X purinergic receptors (P2XR), play a role in mediating Ca2+ influx.

Purpose of the Study:

  • To develop a novel biophysical model for cytosolic Ca2+ activation of the PI3K/Akt pathway in microglia.
  • To investigate the role of P2YR and P2XR in mediating Ca2+ influx and subsequent Akt activation.
  • To provide quantitative insights into the regulation of Ca2+ and Akt signaling by P2Rs.

Main Methods:

  • Development of a novel biophysical model for Ca2+ activation of the PI3K/Akt pathway.
  • Estimation of model parameters using optimization techniques to fit experimental data for phosphorylated Akt (pAkt).
  • In vitro experimental modeling and data analysis.

Main Results:

  • The integrated model successfully explains the experimentally observed biphasic transient responses in pAkt levels.
  • Ca2+ influx via P2YR and P2XR can account for these biphasic responses.
  • Upregulation of P2X receptors leads to increased baseline [Ca2+], transforming biphasic pAkt responses into monophasic, prolonged elevated levels.

Conclusions:

  • The developed model provides a quantitative framework for understanding P2R-mediated regulation of Ca2+ and Akt signaling in microglia.
  • The findings offer new insights into the physiological interactions and transient response dynamics of these pathways.
  • The study highlights how P2R modulation can significantly alter microglial signaling, impacting cellular responses.