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Title: The intimate and controversial relationship between voltage‐gated proton channels and the phagocyte NADPH oxidase
Summary

One of the most fascinating and exciting periods in my scientific career entailed dissecting the symbiotic relationship between two membrane transporters, the Nicotinamide adenine dinucleotide phosphate reduced form (NADPH) oxidase complex and voltage‐gated proton channels (HV1). By the time I entered this field, there had already been substantial progress toward understandingNADPHoxidase, but HV1 were known only to a tiny handful of cognoscenti around the world. Having identified the first proton currents in mammalian cells in 1991, I needed to find a clear function for these molecules if the work was to become fundable. The then‐recent discoveries of Henderson, Chappell, and colleagues in 1987–1988 that led them to hypothesize interactions of both molecules during the respiratory burst of phagocytes provided an excellent opportunity. In a nutshell, both transporters function by moving electrical charge across the membrane:NADPHoxidase moves electrons and HV1 moves protons. The consequences of electrogenicNADPHoxidase activity on both membrane potential and pH strongly self‐limit this enzyme. Fortunately, both consequences specifically activate HV1, and HV1 activity counteracts both consequences, a kind of yin–yang relationship. Notwithstanding a decade starting in 1995 when many believed the opposite, these are two separate molecules that function independently despite their being functionally interdependent in phagocytes. The relationship betweenNADPHoxidase and HV1 has become a paradigm that somewhat surprisingly has now extended well beyond the phagocyteNADPHoxidase – an industrial strength producer of reactive oxygen species (ROS) – to myriad other cells that produce orders of magnitude lessROSfor signaling purposes. These cells with their sevenNADPHoxidase (NOX) isoforms provide a vast realm of mechanistic obscurity that will occupy future studies for years to come.

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NSF-PAR ID:
10201815
Author(s) / Creator(s):
 
Publisher / Repository:
Wiley-Blackwell
Date Published:
Journal Name:
Immunological Reviews
Volume:
273
Issue:
1
ISSN:
0105-2896
Page Range / eLocation ID:
p. 194-218
Format(s):
Medium: X
Sponsoring Org:
National Science Foundation
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