Computational Modeling of Purinergic Receptor Activation in Microglia

Abstract

Microglia function is orchestrated through highly-coupled signaling pathways that depend on calcium (Ca2+). In response to extracellular adenosine triphosphate (ATP), transient increases in intracellular Ca2+ can be driven through the activation of purinergic receptors, P2X and P2Y. Their activation is sufficient to promote physiological responses in microglia including cytokine release and morphological changes. Toward improving our understanding of how purinergic receptor activation drives cellular-scale responses, we developed a minimal computational model for P2X4, P2X7 and P2Y12 activation with concomitant changes in intracellular Ca2+ and K+ homeostasis. In addition to handling the intracellular cation transients, the model captures the subsequent modulation of intracellular signaling networks including G-protein signaling, the phospholipase C pathway and store operated calcium entry.These networks ultimately control the release of cytokines and changes in cellular morphology associated with microglial function. With this model, we probe the sensitivity of evoking these microglial functions with respect to purinergic receptor expression and their subcellular distribution, which are known to vary across microglia phenotypes.