Perspectives on the Identity of the H+ Channel Involved in the Respiratory Burst

Olaf Sparre Andersen

Editor
The Journal of General Physiology

The purpose of the Perspectives in General Physiology is to provide a forum where scientific uncertainties or controversies can be discussed in an authoritative, yet open manner.

The Perspectives are solicited by the editors—often based on recommendations by the advisory editors or members of the editorial board, who may be asked to coordinate the process. To frame the issue, two or more experts are invited to present brief points of view on the problem, which are published consecutively in the Journal. The comments and opinions expressed in the Perspectives are those of the authors and not necessarily those of the Editors or the Editorial Board. The Perspectives are accompanied by a few editorial paragraphs that introduce the problem—and invite the submission of comments, in the form of letters-to-the-editor, which are published in a single, predetermined issue (usually four months after publication of the Perspective). After the letters-to-the-editor have been published, further responses are limited to full manuscripts.

In this issue of the Journal, L.M. Henderson and R.W. Meech (University of Bristol, UK); N. Touret and S. Grinstein (Hospital for Sick Children, Toronto, Canada); T.E. DeCoursey, D. Morgan, and V.V. Cherny (Rush Presbyterian St. Luke's Medical Center); and A. Maturana, K.-H. Krause, and N. Demaurex (University of Geneva, Switzerland) provide different perspectives on the role of gp91phox in the voltage-dependent proton current that is activated during the oxidative burst in phagocytic cells.

The generation of reactive oxygen species is essential for phagocytes' ability to kill ingested microorganisms. After phagocytosis, the cells' oxygen consumption increases and reactive oxygen species are generated by an NADPH-dependent reduction of oxygen to form superoxide anions in the phagosomal and extracellular compartments. The superoxide production is catalyzed by a membrane-spanning NADPH oxidase, which moves two electrons from inside the cell across the membrane so as to produce the superoxide anions in what is topologically an extracellular compartment. The NADPH is regenerated by the concomitant activation of the hexose-monophosphate pathway; but the electron transport across the membrane will be associated with a depolarization and intracellular acidification. If uncompensated, the changes in membrane potential and cell pH would be sufficient to terminate the respiratory burst, which is associated with the activation of an outward H+ current. But what is the molecular identity of this H+ current? Is the H+ path part of the same NADPH oxidase complex that catalyzes the transmembrane electron transport or are the movements of electrons and H+ catalyzed by independent, but possibly interacting, membrane proteins? Does the H+ move through a channel, in the usual sense of a water-filled pore in which the ion movement is uncoupled from membrane protein conformational changes, or is it necessary to invoke some more complicated permeation mechanism?

The main dispute centers around whether the gp91phox subunit of the membrane-spanning cytochrome b558 (composed of gp91phox and p22phox, where phox denotes phagocyte oxidase) encodes the H+ pathway, or not. There is considerable experimental evidence supporting either conclusion, and it is likely that the debate will continue for some time to come. The present Perspectives serve to identify the major issues that need to be resolved before a consensus can be reached.

Letters-to-the-editor related to these Perspectives will be published in the April 2003 issue of the Journal of General Physiology. Letters-to-the-editor should be received no later than February 15, 2003 in order to allow for editorial review. The letters may be no longer than two printed pages (approximately six double-spaced pages) and will be subject to editorial review. They may contain no more than one figure, no more than 15 references and no significant references to unpublished work. Letters should be prepared according to the Journal's instructions and can be submitted electronically at www.jgp.org, as an e-mail attachment to jgp{at}mail.rockefeller.edu.





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