Mathematical Modeling of PI3K/Akt Pathway in Microglia

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.