Cultured microglia exposed to lipopolysaccharide (LPS) express outward K+ currents. These currents are due to the expression of new K+ channels detected by antibodies against Kv1.5, a shaker type delayed rectifier. We examined whether the K+ currents are involved in microglial activation. The amount of nitrite, converted from nitric oxide (NO), was measured as an indication of microglial activation [Chao, C. C., Hu, S., Molitor, T. W., Shaskan, E. G., and Peterson, P. K. (1992) J. Immunol. 149, 2730-2741]. Nitrite was detected starting from 24 h after LPS treatment and continuously increased over 4 days. Contrary to this, in the presence of 4-aminopyridine (4-AP, 2 mM), a blocker of outward K+ currents, nitrite production was reduced to less than 50%. However, the treatment of 4-AP 24 h after LPS did not reduce nitrite production. Other K+ channel blockers having a less blocking effect on outward K+ currents, such as 5 mM tetraethylammonium (TEA) and 1 mM Cs+, had little effect. The present study shows that the outward K+ channels induced by LPS are immunologically related to Kv1.5 and also suggests that these channels are required for microglial activation, particularly for the initiation of the activation process.