The large-conductance Ca2+-activated K+ channel is essential for innate immunity

Neutrophil leukocytes have a pivotal function in innate immunity. Dogma dictates that the lethal blow is delivered to microbes by reactive oxygen species (ROS) and halogens 1 , 2 , products of the NADPH oxidase, whose impairment causes immunodeficiency. However, recent evidence indicates that the microbes might be killed by proteases, activated by the oxidase through the generation of a hypertonic, K + -rich and alkaline environment in the phagocytic vacuole 3 . Here we show that K + crosses the membrane through large-conductance Ca 2+ -activated K + (BK Ca ) channels. Specific inhibitors of these channels, iberiotoxin and paxilline, blocked oxidase-induced 86 Rb + fluxes and alkalinization of the phagocytic vacuole, whereas NS1619, a BK Ca channel opener, enhanced both. Characteristic outwardly rectifying K + currents, reversibly inhibited by iberiotoxin, were demonstrated in neutrophils and eosinophils and the expression of the α-subunit of the BK channel was confirmed by western blotting. The channels were opened by the combination of membrane depolarization and elevated Ca 2+ concentration, both consequences of oxidase activity. Remarkably, microbial killing and digestion were abolished when the BK Ca channel was blocked, revealing an essential and unexpected function for this K + channel in the microbicidal process.