Abstract
Regulation of cytosolic calcium (Ca2+) dynamics is fundamental to microglial function. Temporal and spatial Ca2+ fluxes are induced from a complicated signal transduction pathway linked to brain ionic homeostasis. In this paper, we develop a novel biophysical model of Ca2+ and sodium (Na+) dynamics in human microglia and evaluate the contribution of purinergic receptors (P2XRs) to both intracellular Ca2+ and Na+ levels in response to agonist/ATP binding. This is the first comprehensive model that integrates P2XRs to predict intricate Ca2+ and Na+ transient responses in microglia. Specifically, a novel compact biophysical model is proposed for the capture of whole-cell patch-clamp currents associated with P2X4 and P2X7 receptors, which is composed of only four state variables. The entire model shows that intricate intracellular ion dynamics arise from the coupled interaction between P2X4 and P2X7 receptors, the Na+/Ca2+ exchanger (NCX), Ca2+ extrusion by the plasma membrane Ca2+ ATPase (PMCA), and Ca2+ and Na+ leak channels. Both P2XRs are modelled as two separate adenosine triphosphate (ATP) gated Ca2+ and Na+ conductance channels, where the stoichiometry is the removal of one Ca2+ for the hydrolysis of one ATP molecule. Two unique sets of model parameters were determined using an evolutionary algorithm to optimise fitting to experimental data for each of the receptors. This allows the proposed model to capture both human P2X7 and P2X4 data (hP2X7 and hP2X4). The model architecture enables a high degree of simplicity, accuracy and predictability of Ca2+ and Na+ dynamics thus providing quantitative insights into different behaviours of intracellular Na+ and Ca2+ which will guide future experimental research. Understanding the interactions between these receptors and other membrane-bound transporters provides a step forward in resolving the qualitative link between purinergic receptors and microglial physiology and their contribution to brain pathology.
Highlights
Microglia have attracted wide attention owing to their ability to undergo a variety of morphological configurations in health and disease [1,2,3]
We develop a theoretical foundation for studying P2X-mediated calcium and sodium signalling in human microglial cells
Recent studies highlight the importance for increasing our understanding of microglia physiology, since their functions play critical roles in both normal physiological and pathological dynamics of the brain
Summary
Microglia have attracted wide attention owing to their ability to undergo a variety of morphological configurations in health and disease [1,2,3]. Restructuring of the actin cytoskeleton for directed motility in microglia consists of a complex molecular cascade that involves several membrane-coupled receptors [5]. These receptors enable the microglia to detect subtle concentration changes in their environment in order to begin either process extension or whole-cell chemotaxis. Three major families of purinergic receptors are found in human, rat and mouse microglia. These include adenosine receptors (A1, A2A, A2B and A3), P2X receptors (P2XRs) (P2X1, P2X4 and P2X7) and P2Y receptors (P2Y2, P2Y6 and P2Y12-14) [7]. The main goal of this paper is to develop a biologically faithful model of ATP-triggered P2XR Ca2+ and sodium (Na+) signalling transduction and plasma membrane electrophysiology in microglia
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