During the Respiratory Burst, Do Phagocytes Need Proton Channels or Potassium Channels, or Both?

Abstract

The NADPH (reduced form of nicotinamide adenine dinucleotide phosphate) oxidase enzyme complex, a crucial component of innate immunity, produces superoxide anion (O 2 – ), which is a precursor to many reactive oxygen species. NADPH oxidase produces O 2 – by transferring electrons from intracellular NADPH across the membrane to extracellular (or phagosomal) oxygen and is thus electrogenic. It is widely believed that electroneutrality is preserved by proton flux through voltage-gated proton channels. A series of recent papers have challenged several key aspects of this view of the "respiratory burst." The most recent study solidifies the proposal that O 2 - and other reactive oxygen species produced by phagocytes are not toxic to microbes under physiological conditions. Further, an essential role for high-conductance, Ca 2+ -activated K + (maxi-K + ) channels in microbe killing is proposed. Finally, the results cast doubt on the widely held view that H + efflux through voltage-gated proton channels (i) is the main mechanism of charge compensation, and (ii) is essential to continuous O 2 - production by the NADPH oxidase. My analysis of the new data and of a large body of data in the literature indicates that the proposed role of maxi-K + channels in the respiratory burst is not yet credibly established. H + efflux through proton channels thus remains the most viable mechanism for charge compensation and continuous O 2 – production. The important question of the toxicity of reactive oxygen species in phagocytes and in other cells, which has long been simply taken for granted, is a widespread assumption that deserves critical study.