Release of interleukin-1β (IL-1b) represents one of the earliest responses of brain macrophages (microglia) to brain injury and IL-1b itself contributes to brain damage (Allan et al. 2005). Stimulation of the murine microglia cell line BV-2 with lysophosphatidylcholine (LPC) caused rapid IL-1b release that occurred independently of P2X7 ATP receptor activation. Neither LPC-induced IL-1b release (n=3 experiments) nor LPC-stimulated intracellular Ca²⁺ increases (n=144 cells) were affected by inhibition of P2X7 ATP receptors with 500 µM oxidized ATP. Patch-clamp experiments revealed activation of non-selective cation currents and Ca²⁺-dependent K⁺ currents by 15 µM extracellular LPC. LPC-activated non-selective cation channels were permeable for monovalent and divalent cations. They were inhibited by 100 µM Gd³⁺ (n=11 cells), 100 µM La³⁺ (n=10 cells), 500 µM Zn²⁺ (n=4 cells) and Grammostola spatulata venom (diluted 1:2000; n=7 cells), but were unaffected by 100 µM diltiazem (n=7 cells), 50 µM LOE908MS (n=7 cells), 1 mM amiloride (n=7 cells) and 200 µM DIDS (n=7 cells). Ca²⁺ influx through non-selective cation channels was sufficient to elicit charybdotoxin (CTX)-sensitive Ca²⁺-dependent K⁺ currents (n=21 cells). Microglial IL-1b release was suppressed in Ca²⁺-free extracellular medium (n=4 experiments; p<0.001) or during inhibition of non-selective cation channels with Gd³⁺ or La³⁺ (n=4 experiments for each condition; p<0.001). It was also attenuated in the presence of 200 nM CTX (n=4 experiments; p<0.05), but was unaffected by margatoxin (n=3 experiments), suggesting that Ca²⁺-activated K⁺ channels rather than voltage-activated K⁺ channels are important for microglial IL-1b release. The K⁺ ionophore nigericin (10 µM) did not reverse suppressive effects of CTX on LPC-stimulated IL-1b release, demonstrating the importance of membrane hyperpolarization. In all experiments, the statistical significance of differences between experimental groups was evaluated by the Mann-Whitney U test. In summary, these data indicate that LPC-stimulated IL-1b release from microglia is a Ca²⁺– and voltage-dependent process. Inhibitors of non-selective cation channels and Ca²⁺-activated K⁺ channels may represent tools for IL-1b inhibition during neuroinflammatory and neurodegenerative diseases.