Voltage-gated Proton “Channels”: a Spectator’s Viewpoint

A battle is raging over the molecular identity of the voltage-gated, H -selective conductance that has been recorded in activated and/or depolarized phagocytes. Having stepped out of this arena, we feel uncommitted to any particular viewpoint and hope to be able to provide below an unbiased opinion of what we feel has been established unambiguously, and what requires additional confirmation before conclusive statements can be issued. The innate immune system is the first line of defense against invading microorganisms. This immune response is performed by specialized cells, macrophages, neutrophils, eosinophils, and dendritic cells, that recognize, ingest, and destroy pathogenic organisms. These professional phagocytes have developed an arsenal of microbicidal strategies aimed at ridding the organism of potential infectious agents. After engulfment, the foreign organism is trapped in a specialized vesicle, called the phagosome, which acquires microbicidal ability as a result of a series of coordinated fission and fusion events with other endomembrane compartments, culminating in the formation of the phagolysosome. These maturation events include the incorporation of vacuolar proton pumps and other integral proteins into the phagosomal membrane, as well as the delivery of microbicidal and lytic enzymes into the vacuolar lumen. Generation of reactive oxygen species (ROS) in the phagosomal lumen is one of the key strategies used by phagocytes to kill ingested organisms. Superoxide is initially generated in phagosomes and at the cell surface by the two-electron reduction of molecular oxygen, a reaction catalyzed by the NADPH oxidase complex. The resulting superoxide anion can then be converted to more reactive radical molecules. Hydrogen peroxide is produced by dismutation and is itself a substrate of myeloperoxidase, which generates hypochlorous acid (HOCl) (Hampton et al., 1998). Superoxide can also generate the extremely reactive hydroxyl radicals via the Haber-Weiss reaction. The importance of the NADPH oxidase to the immune response is highlighted by the manifestation of chronic granulomatous disease (CGD). Patients with this genetic disorder lack a functional NADPH oxidase and, as a result, suffer from chronic susceptibility to infection by various bacterial strains, which can be lethal. The NADPH oxidase is composed of two transmembrane proteins, p22 phox and gp91 phox , that jointly form the cytochrome b 558 ; three cytosolic factors, p67 phox , p47 phox