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J Biol Chem, Vol. 275, Issue 11, 7684-7692, March 17, 2000
From the Accumulating evidence suggests that
neuroepithelial bodies are airway O2 sensors.
Recently, we have established the H-146 small cell lung carcinoma line
as a suitable model to study the biochemical basis of neuroepithelial
body cell chemotransduction. Here we explore the possibility that
hypoxic modulation of K+ channels is intimately linked to
activity of NADPH oxidase. Graded hypoxia caused graded inhibition of
whole cell K+ currents, which correlated well with membrane
depolarization. Pretreatment with the phorbol ester,
12-O-tetradecanoyl (TPA), inhibited K+ currents
at all potentials. Although 4
O2 Sensing by Airway Chemoreceptor-derived Cells
PROTEIN KINASE C ACTIVATION REVEALS FUNCTIONAL EVIDENCE FOR
INVOLVEMENT OF NADPH OXIDASE*
§,,¶
School of Biomedical Sciences and the
§ Institute for Cardiovascular Research, University of
Leeds, Leeds LS2 9JT, United Kingdom
-phorbol 12,13-didecanoate and TPA in
the presence of bisindolylmaleimide were also able to depress
K+ currents, only TPA could significantly ameliorate
hypoxic depression of these currents. Thus, protein kinase C (PKC)
activation modulates the sensitivity of these cells to changes in
pO2. Furthermore, because the addition of
H2O2, a downstream product of NADPH oxidase, could only activate K+ currents during hypoxia (when
endogenous H2O2 production is suppressed), it
appears likely that PKC modulates the affinity of NADPH oxidase for
O2 potentially via phosphorylation of the
p47phox subunit, which is present in these cells. These
data show that PKC is an important regulator of the
O2-transduction pathway and suggests that NADPH oxidase
represents a significant component of the airway O2 sensor.
*
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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