Proton Conduction through gp91phox

Previous Perspectives in the Journal of General Physiology have considered (a) the different advantages of two models of ion channel permeation and (b) whether ryanodine receptor adaptation might arise from flash photolysis. Each argument, over the choice of model or influence of technique, is an example of a classic scientific dispute. Here we turn to another hoary old problem—the identification of a “prime mover.” The specific problem we are dealing with here concerns the structure and function of the voltage-gated proton channel in mammalian neutrophils. We have presented evidence recently that a component of the NADPH oxidase, gp91 phox , functions as a proton channel and as such plays an essential role in neutrophil action (Henderson and Meech, 1999). The proposal has proved controversial because the evidence we provided was necessarily circumstantial. Each time this kind of controversy arises standard pieces of circumstantial evidence are assembled. The following is a list of the kinds of evidence that would generally be considered relevant: (a) Deletion: destruction of gp91 phox abolishes function. (b) Addition: recovery of function when gp91 phox is restored. (c) Modification: altered gp91 phox structure leads to altered function. (d) Location: gp91 phox is located at a site appropriate to its proposed function. (e) Quantity: gp91 phox is present in sufficient quantity to perform the function. (f) Conditions: gp91 phox is active under conditions appropriate to its proposed function. The key question is whether gp91 phox is a “prime mover,” i.e., a proton channel, or whether it simply acts as some kind of cofactor. It has been suggested that gp91 phox is not the proton channel itself but the modulator of a proton channel formed by a different, as yet unidentified protein (DeCoursey et al., 2001). The experimental basis for this suggestion comes from Xenopus oocytes where high levels of heterologous expression of many different membrane proteins induce the appearance of an endogenous chloride current (Shimbo et al., 1995; Tzounopoulos et al., 1995). The question is an important one because the proton channel poses an interesting problem in membrane permeation; if gp91 phox is the channel, further analysis of proton permeation becomes possible. Before we start to evaluate the evidence we have tried to summarize the key findings in this area over the past 20 yr. So new readers start here!