NOX Family NADPH Oxidases : Do They Have Built-in Proton Channels?

Proton channels allow cells to extrude excess acid with a high efficiency and therefore are one of the important homeostatic mechanisms that maintain the intracellular pH in a range compatible with life. Proton currents are highly expressed in phagocytes where they are thought to contribute to charge and pH compensation during NADPH oxidase activation. By analogy with the cytochrome C oxidase of mitochondria, it therefore has been suggested that the phagocyte NADPH oxidase possesses a built-in proton channel. This concept is supported by a variety of arguments: (a) electrophysiologically and pharmacologically distinct proton currents can be observed in phagocytes upon NADPH oxidase activation and these currents are absent in phagocytes from patients lacking the NADPH oxidase); (b) expression of full-length or COOH-terminal truncated NOX proteins (the gp91^phox subunit of the phagocyte NADPH oxidase, or several of its recently cloned homologues) leads in many instances...