Ion channels related to neutrophil NADPH oxidase. (360G-Wellcome-081695_Z_06_Z)

The neutrophil leukocyte is the primary cell involved in the killing and digestion of bacteria and fungi. The NADPH oxidase is an electron transport chain in the wall of the phagocytic vacuole which is essential for the killing of the contained microbe, and when defective, causes severe immunodeficiency. The oxidase passes electrons onto O2 to produce reactive oxygen species (ROS) and these ROS were thought to be responsible for microbial killing. We have shown that this is not the case and tha t the microbes are killed by granule enzymes released into the vacuole from cytoplasmic granules, and that the oxidase activates these enzymes by altering the pH and ionic composition in the vacuole. The ion fluxes are driven by the requirement to compensate the charge generated across the phagosomal membrane by electron transport which was thought to be accomplished by H+ flux through proton channels. K+ flux through BKCa-like channels is essential for oxidase activity, and consequently, microb ial killing and Cl- fluxes compensate most of the charge. In addition Na+/H+ exchange is important for the regulation of pH. We propose to characterise these ion channels, and to elucidate the mechanisms underlying the coupling of these processes to the oxidase.