The modulation of intracellular Ca2+concentration ([Ca2+]i) by the pro-inflammatory cytokine interleukin-1β (IL-1β) was assessed in synaptosomes loaded with the Ca2+-sensitive dye, Fura-2AM. IL-1β was found to exert a biphasic effect on the KCl-induced rise in [Ca2+]i, extending an inhibitory effect at lower (3.5 ng/ml) concentrations, and a stimulatory effect at high (100 ng/ml) concentrations. The inhibitory action of IL-1β on [Ca2+]iwas sensitive to pertussis toxin (PTX; 2 μg/ml), indicating a role for a PTX-sensitive G-protein, but was unaffected by the p42 mitogen-activated protein kinase kinase (MAP kinase kinase) inhibitor, PD 098059 (2 μM). In contrast, the stimulatory action of higher concentrations of IL-1β on [Ca2+]iwas blocked by PD 098059 and unaffected by PTX. We conclude that the biphasic actions of IL-1β on the KCl-induced rise in [Ca2+]iare mediated through activation of alternative second messenger pathways.