Calcium signaling in microglial immune functions: current understanding and implications for disease

Microglia are the resident innate immune cells of the brain that play essential roles in immune surveillance, phagocytosis, and neuroinflammatory responses. A central regulator of these diverse functions is intracellular Ca²⁺ signaling, which connects extracellular cues to transcriptional and metabolic programs that shape microglial activation states. Recent advances have expanded understanding of the 'Ca²⁺ toolkit' in microglia, which includes P2X and P2Y receptors, Orai Ca²⁺ channels, transient receptor potential channels, inositol triphosphate receptors, and organellar Ca²⁺ handling systems. These pathways generate dynamic and spatially localized Ca²⁺ signals that regulate numerous effector functions, including process motility, cytokine production, phagocytosis, metabolism, and communication with other brain cells. Emerging evidence further identifies dysregulated Ca²⁺ signaling as a key driver of chronic neuroinflammation in brain disorders. Here, we review the major components of the microglial Ca²⁺ signaling toolkit, discuss their molecular mechanisms and physiological functions, and highlight contributions to neuroinflammatory diseases.