Mast cells (MCs) participate in a variety of diseases, such as asthma, inflammatory bowel disease, anaphylaxis and mastocytosis. Release of mediators from MCs occurs via degranulation, a response that requires an increase in intracellular Ca2+ activity and corresponding changes in membrane potential. The Ca2+ -activated K+ channel is expressed in MCs, and has been shown to be important for MC degranulation and migration. According to the electrophysiological properties, sensitivity to the specific opener and blockers and RT-PCR analysis the underlying channel protein is the intermediate conductance channel SK4 (IK1/KCa3.1). The present study aimed to directly confirm the molecular identity of the channel. To this end, MCs were isolated from bone marrow of SK4 knockout (sk4-/- ) mice and their wild- type (wt) littermates. Stimulation with IgE-antigen or with the Ca2+ ionophore ionomycin activated Ca2+ -activated K+ current in wt MCs, that was inhibitable by K+ channel blockers clotrimazole (1.5 mM) and TRAM-34 (300 nM). The Ca 2+ induced current was completely absent in sk4-/- MCs. Moreover, ionomycin- and IgE-antigen-induced degranulation was significantly blunted in sk4-/- MCs as compared to wt MCs. The results demonstrate the involvement of SK4 in the regulation and function of MCs.