NADPH-oxidase and a hydrogen peroxide-sensitive K+ channel may function as an oxygen sensor complex in airway chemoreceptors and small cell lung carcinoma cell lines

Dashou Wang; Charlotte Youngson; Veronica Wong; Herman Yeger; Mary C. Dinauer; Eleazar Vega-Saenz De Miera; Bernardo Rudy; Ernest Cutz

doi:10.1073/pnas.93.23.13182

NADPH-oxidase and a hydrogen peroxide-sensitive K⁺ channel may function as an oxygen sensor complex in airway chemoreceptors and small cell lung carcinoma cell lines

Dashou Wang
, Charlotte Youngson
, Veronica Wong
, Herman Yeger
, Mary C. Dinauer
, Eleazar Vega-Saenz De Miera
, Bernardo Rudy
, Ernest Cutz

Research output: Contribution to journal › Article › peer-review

164 Scopus citations

Abstract

Pulmonary neuroepithelial bodies (NEB) are widely distributed throughout the airway mucosa of human and animal lungs. Based on the observation that NEB cells have a candidate oxygen sensor enzyme complex (NADPH oxidase) and an oxygen-sensitive K⁺ current, it has been suggested that NEB may function as airway chemoreceptors. Here we report that mRNAs for both the hydrogen peroxide sensitive voltage gated potassium channel subunit (KH₂O₂) KV3.3a and membrane components of NADPH oxidase (gp91(phox) and p22(phox)) are coexpressed in the NEB cells of fetal rabbit and neonatal human lungs. Using a microfluorometry and dihydrorhodamine 123 as a probe in assess H₂O₂ generation, NEB cells exhibited oxidase activity under basal conditions. The oxidase in NEB cells was significantly stimulated by exposure to phorbol esther (0.1 μM) and inhibited by diphenyliodonium (5 μM). Studies using whole-cell voltage clamp showed that the K⁺ current of cultured fetal rabbit NEB cells exhibited inactivating properties similar to KV3.3a transcripts expressed in Xenopus oocyte model. Exposure of NEB cells to hydrogen peroxide (H₂O2, the dismuted by-product of the oxidase) under normoxia resulted in an increase of the outward K⁺ current indicating that H₂O₂ could be the transmitter modulating the O₂-sensitive K⁺ channel. Expressed mRNAs or corresponding protein products for the NADPH oxidase membrane cytochrome b as well as mRNA encoding KV3.3a were identified in small cell lung carcinoma cell lines. The studies presented here provide strong evidence for an oxidase-O₂ sensitive potassium channel molecular complex operating as an O₂ sensor in NEB cells, which function as chemoreceptors in airways and in NEB related tumors. Such a complex may represent an evolutionary conserved biochemical link for a membrane bound O₂-signaling mechanism proposed for other cells and life forms.

Original language	English
Pages (from-to)	13182-13187
Number of pages	6
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	93
Issue number	23
DOIs	https://doi.org/10.1073/pnas.93.23.13182
State	Published - Nov 12 1996

Keywords

nonisotopic in situ hybridization
oxygen sensing
pulmonary neuroepithelial bodies
reactive oxygen intermediates

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10.1073/pnas.93.23.13182

Cite this

Wang, D., Youngson, C., Wong, V., Yeger, H., Dinauer, M. C., Vega-Saenz De Miera, E., Rudy, B., & Cutz, E. (1996). NADPH-oxidase and a hydrogen peroxide-sensitive K⁺ channel may function as an oxygen sensor complex in airway chemoreceptors and small cell lung carcinoma cell lines. Proceedings of the National Academy of Sciences of the United States of America, 93(23), 13182-13187. https://doi.org/10.1073/pnas.93.23.13182

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title = "NADPH-oxidase and a hydrogen peroxide-sensitive K+ channel may function as an oxygen sensor complex in airway chemoreceptors and small cell lung carcinoma cell lines",

abstract = "Pulmonary neuroepithelial bodies (NEB) are widely distributed throughout the airway mucosa of human and animal lungs. Based on the observation that NEB cells have a candidate oxygen sensor enzyme complex (NADPH oxidase) and an oxygen-sensitive K+ current, it has been suggested that NEB may function as airway chemoreceptors. Here we report that mRNAs for both the hydrogen peroxide sensitive voltage gated potassium channel subunit (KH2O2) KV3.3a and membrane components of NADPH oxidase (gp91(phox) and p22(phox)) are coexpressed in the NEB cells of fetal rabbit and neonatal human lungs. Using a microfluorometry and dihydrorhodamine 123 as a probe in assess H2O2 generation, NEB cells exhibited oxidase activity under basal conditions. The oxidase in NEB cells was significantly stimulated by exposure to phorbol esther (0.1 μM) and inhibited by diphenyliodonium (5 μM). Studies using whole-cell voltage clamp showed that the K+ current of cultured fetal rabbit NEB cells exhibited inactivating properties similar to KV3.3a transcripts expressed in Xenopus oocyte model. Exposure of NEB cells to hydrogen peroxide (H2O2, the dismuted by-product of the oxidase) under normoxia resulted in an increase of the outward K+ current indicating that H2O2 could be the transmitter modulating the O2-sensitive K+ channel. Expressed mRNAs or corresponding protein products for the NADPH oxidase membrane cytochrome b as well as mRNA encoding KV3.3a were identified in small cell lung carcinoma cell lines. The studies presented here provide strong evidence for an oxidase-O2 sensitive potassium channel molecular complex operating as an O2 sensor in NEB cells, which function as chemoreceptors in airways and in NEB related tumors. Such a complex may represent an evolutionary conserved biochemical link for a membrane bound O2-signaling mechanism proposed for other cells and life forms.",

keywords = "nonisotopic in situ hybridization, oxygen sensing, pulmonary neuroepithelial bodies, reactive oxygen intermediates",

author = "Dashou Wang and Charlotte Youngson and Veronica Wong and Herman Yeger and Dinauer, \{Mary C.\} and \{Vega-Saenz De Miera\}, Eleazar and Bernardo Rudy and Ernest Cutz",

year = "1996",

month = nov,

day = "12",

doi = "10.1073/pnas.93.23.13182",

language = "English",

volume = "93",

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journal = "Proceedings of the National Academy of Sciences of the United States of America",

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Wang, D, Youngson, C, Wong, V, Yeger, H, Dinauer, MC, Vega-Saenz De Miera, E, Rudy, B & Cutz, E 1996, 'NADPH-oxidase and a hydrogen peroxide-sensitive K⁺ channel may function as an oxygen sensor complex in airway chemoreceptors and small cell lung carcinoma cell lines', Proceedings of the National Academy of Sciences of the United States of America, vol. 93, no. 23, pp. 13182-13187. https://doi.org/10.1073/pnas.93.23.13182

NADPH-oxidase and a hydrogen peroxide-sensitive K⁺ channel may function as an oxygen sensor complex in airway chemoreceptors and small cell lung carcinoma cell lines. / Wang, Dashou; Youngson, Charlotte; Wong, Veronica et al.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 93, No. 23, 12.11.1996, p. 13182-13187.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - NADPH-oxidase and a hydrogen peroxide-sensitive K+ channel may function as an oxygen sensor complex in airway chemoreceptors and small cell lung carcinoma cell lines

AU - Wang, Dashou

AU - Youngson, Charlotte

AU - Wong, Veronica

AU - Yeger, Herman

AU - Dinauer, Mary C.

AU - Vega-Saenz De Miera, Eleazar

AU - Rudy, Bernardo

AU - Cutz, Ernest

PY - 1996/11/12

Y1 - 1996/11/12

N2 - Pulmonary neuroepithelial bodies (NEB) are widely distributed throughout the airway mucosa of human and animal lungs. Based on the observation that NEB cells have a candidate oxygen sensor enzyme complex (NADPH oxidase) and an oxygen-sensitive K+ current, it has been suggested that NEB may function as airway chemoreceptors. Here we report that mRNAs for both the hydrogen peroxide sensitive voltage gated potassium channel subunit (KH2O2) KV3.3a and membrane components of NADPH oxidase (gp91(phox) and p22(phox)) are coexpressed in the NEB cells of fetal rabbit and neonatal human lungs. Using a microfluorometry and dihydrorhodamine 123 as a probe in assess H2O2 generation, NEB cells exhibited oxidase activity under basal conditions. The oxidase in NEB cells was significantly stimulated by exposure to phorbol esther (0.1 μM) and inhibited by diphenyliodonium (5 μM). Studies using whole-cell voltage clamp showed that the K+ current of cultured fetal rabbit NEB cells exhibited inactivating properties similar to KV3.3a transcripts expressed in Xenopus oocyte model. Exposure of NEB cells to hydrogen peroxide (H2O2, the dismuted by-product of the oxidase) under normoxia resulted in an increase of the outward K+ current indicating that H2O2 could be the transmitter modulating the O2-sensitive K+ channel. Expressed mRNAs or corresponding protein products for the NADPH oxidase membrane cytochrome b as well as mRNA encoding KV3.3a were identified in small cell lung carcinoma cell lines. The studies presented here provide strong evidence for an oxidase-O2 sensitive potassium channel molecular complex operating as an O2 sensor in NEB cells, which function as chemoreceptors in airways and in NEB related tumors. Such a complex may represent an evolutionary conserved biochemical link for a membrane bound O2-signaling mechanism proposed for other cells and life forms.

AB - Pulmonary neuroepithelial bodies (NEB) are widely distributed throughout the airway mucosa of human and animal lungs. Based on the observation that NEB cells have a candidate oxygen sensor enzyme complex (NADPH oxidase) and an oxygen-sensitive K+ current, it has been suggested that NEB may function as airway chemoreceptors. Here we report that mRNAs for both the hydrogen peroxide sensitive voltage gated potassium channel subunit (KH2O2) KV3.3a and membrane components of NADPH oxidase (gp91(phox) and p22(phox)) are coexpressed in the NEB cells of fetal rabbit and neonatal human lungs. Using a microfluorometry and dihydrorhodamine 123 as a probe in assess H2O2 generation, NEB cells exhibited oxidase activity under basal conditions. The oxidase in NEB cells was significantly stimulated by exposure to phorbol esther (0.1 μM) and inhibited by diphenyliodonium (5 μM). Studies using whole-cell voltage clamp showed that the K+ current of cultured fetal rabbit NEB cells exhibited inactivating properties similar to KV3.3a transcripts expressed in Xenopus oocyte model. Exposure of NEB cells to hydrogen peroxide (H2O2, the dismuted by-product of the oxidase) under normoxia resulted in an increase of the outward K+ current indicating that H2O2 could be the transmitter modulating the O2-sensitive K+ channel. Expressed mRNAs or corresponding protein products for the NADPH oxidase membrane cytochrome b as well as mRNA encoding KV3.3a were identified in small cell lung carcinoma cell lines. The studies presented here provide strong evidence for an oxidase-O2 sensitive potassium channel molecular complex operating as an O2 sensor in NEB cells, which function as chemoreceptors in airways and in NEB related tumors. Such a complex may represent an evolutionary conserved biochemical link for a membrane bound O2-signaling mechanism proposed for other cells and life forms.

KW - nonisotopic in situ hybridization

KW - oxygen sensing

KW - pulmonary neuroepithelial bodies

KW - reactive oxygen intermediates

UR - https://www.scopus.com/pages/publications/0029841060

U2 - 10.1073/pnas.93.23.13182

DO - 10.1073/pnas.93.23.13182

M3 - Article

C2 - 8917565

AN - SCOPUS:0029841060

SN - 0027-8424

VL - 93

SP - 13182

EP - 13187

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 23

ER -

Wang D, Youngson C, Wong V, Yeger H, Dinauer MC, Vega-Saenz De Miera E et al. NADPH-oxidase and a hydrogen peroxide-sensitive K⁺ channel may function as an oxygen sensor complex in airway chemoreceptors and small cell lung carcinoma cell lines. Proceedings of the National Academy of Sciences of the United States of America. 1996 Nov 12;93(23):13182-13187. doi: 10.1073/pnas.93.23.13182

NADPH-oxidase and a hydrogen peroxide-sensitive K⁺ channel may function as an oxygen sensor complex in airway chemoreceptors and small cell lung carcinoma cell lines

Abstract

Keywords

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