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2016 ; 273
(1
): 194-218
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The intimate and controversial relationship between voltage-gated proton channels
and the phagocyte NADPH oxidase
#MMPMID27558336
DeCoursey TE
Immunol Rev
2016[Sep]; 273
(1
): 194-218
PMID27558336
show ga
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 (HV 1). By the time I entered this field, there
had already been substantial progress toward understanding NADPH oxidase, but HV
1 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: NADPH
oxidase moves electrons and HV 1 moves protons. The consequences of electrogenic
NADPH oxidase activity on both membrane potential and pH strongly self-limit this
enzyme. Fortunately, both consequences specifically activate HV 1, and HV 1
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 between NADPH oxidase
and HV 1 has become a paradigm that somewhat surprisingly has now extended well
beyond the phagocyte NADPH oxidase - an industrial strength producer of reactive
oxygen species (ROS) - to myriad other cells that produce orders of magnitude
less ROS for signaling purposes. These cells with their seven NADPH oxidase (NOX)
isoforms provide a vast realm of mechanistic obscurity that will occupy future
studies for years to come.