| 10713079 |
O'Kelly I, Lewis A, Peers C, Kemp PJ: O (2) sensing by airway chemoreceptor-derived cells. J Biol Chem. 2000 Mar 17;275(11):7684-92.
Protein kinase c activation reveals functional evidence for involvement of NADPH oxidase.. Accumulating evidence suggests that neuroepithelial bodies are airway O (2) 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 4alpha-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 pO (2). Furthermore, because the addition of H (2) O (2), a downstream product of NADPH oxidase, could only activate K (+) currents during hypoxia (when endogenous H (2) O (2) production is suppressed), it appears likely that PKC modulates the affinity of NADPH oxidase for O (2) potentially via phosphorylation of the p47 (phox) subunit, which is present in these cells. These data show that PKC is an important regulator of the O (2)-transduction pathway and suggests that NADPH oxidase represents a significant component of the airway O (2) sensor. |
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