Purinergic mediated changes in Ca2+ mobilization and functional responses in microglia: Effects of low levels of ATP

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Abstract
Microglia, the immune effector cells of the brain, are stimulated by a diversity of agents to transiently increase levels of intracellular calcium ([Ca2+]i). Changes in [Ca2+]i induced by compounds such as adenosine triphosphate (ATP) serve important roles in cellular signal transduction linking stimuli with cellular functional responses. Purinergic responses in microglia, like that in other cells, are mediated by two families of receptors classified as P2Y and P2X. Activation of metabotropic receptors (P2YR) leads to increased [Ca2+]i due to depletion of intracellular stores, a process that can trigger activation of Ca2+ entry through plasmalemmal store‐operated channels (SOC). Activation of ionotropic receptors (P2XR) is associated with influx of Na+ and Ca2+ and efflux of K+ through nonselective cationic channels, leading to cellular depolarization. An intriguing property of purinergic stimulation of microglia is the dependence of cellular responses on agonist concentration. As one example, activation of the subtype P2X7R by higher levels of ATP (millimolar range), leads to a marked enhancement in microglial secretion of inflammatory mediators. Other members of the ionotropic P2XR family sensitive to lower levels of ATP, however, are also important in mediating microglial inflammatory responses in brain. At lower concentrations of ATP (100 μM), activation of SOC in human microglia is not only coupled to P2YR‐dependent depletion of internal stores, but is also modulated by ATP binding to a P2XR (not P2X7R). The modulation is consistent with a P2XR‐mediated influx of Na+ and inhibition of SOC by depolarization. In this review, a primary focus is placed on the effects of low concentrations of ATP (≤100 μM) to induce changes in [Ca2+]i and modify functional processes in microglia. In essence, responses mediated by purinergic receptors other than P2X7R are considered.