NADPH oxidase is an O
2
sensor in airway chemoreceptors: Evidence from K
+
current modulation in wild-type and oxidase-deficient mice
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abstract
Pulmonary neuroepithelial bodies (NEBs) are presumed airway chemoreceptors that express the putative O
2
sensor protein NADPH oxidase and O
2
-sensitive K
+
channels K
+
(O
2
). Although there is a consensus that redox modulation of K
+
(O
2
) may be a common O
2
-sensing mechanism, the identity of the O
2
sensor and related coupling pathways are still controversial. To test whether NADPH oxidase is the O
2
sensor in NEB cells, we performed patch-clamp experiments on intact NEBs identified by neutral red staining in fresh lung slices from wild-type (WT) and oxidase-deficient (OD) mice. In OD mice, cytochrome
b558
and oxidase function was disrupted in the gp91
phox
subunit coding region by insertion of a neomycin phosphotransferase (neo) gene. Expression in NEB cells of neo mRNA, a marker for nonfunctional gp91
phox
, was confirmed by nonisotopic
in situ
hybridization. In WT cells, hypoxia (pO
2
= 15–20 mmHg; 1 mmHg = 133 Pa) caused a reversible inhibition (≈46%) of both Ca
2+
-independent and Ca
2+
-dependent K
+
currents. In contrast, hypoxia had no effect on K
+
current in OD cells, even though both K
+
current components were expressed. Diphenylene iodonium (1 μM), an inhibitor of the oxidase, reduced K
+
current by ≈30% in WT cells but had no effect in OD cells. Hydrogen peroxide (H
2
O
2
; 0.25 mM), a reactive oxygen species generated by functional NADPH oxidase, augmented K
+
current by >30% in both WT and OD cells; further, in WT cells, H
2
O
2
restored K
+
current amplitude in the presence of diphenylene iodonium. We conclude that NADPH oxidase acts as the O
2
sensor in pulmonary airway chemoreceptors.
