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The Journal of Neuroscience, April 15, 2009, 29(15):4903-4910; doi:10.1523/JNEUROSCI.4768-08.2009

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Behavioral/Systems/Cognitive
NADPH Oxidase Is Required for the Sensory Plasticity of the Carotid Body by Chronic Intermittent Hypoxia

Y.- J. Peng,¹ J. Nanduri,¹ G. Yuan,¹ N. Wang,¹ E. Deneris,³ S. Pendyala,² V. Natarajan,² G. K. Kumar,¹ and N. R. Prabhakar¹

¹Center for Systems Biology of Oxygen Sensing and ²Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Chicago, Chicago, Illinois 60637, and ³Department of Neuroscience, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106

Correspondence should be addressed to Nanduri R. Prabhakar, Center for Systems Biology of Oxygen Sensing, Department of Medicine, The University of Chicago, 5841 S. Maryland Avenue, MC 5068, Chicago, IL 60637. Email: nprabhak{at}medicine.bsd.uchicago.edu

Respiratory motoneuron response to hypoxia is reflex in nature and carotid body sensory receptor constitutes the afferent limb of this reflex. Recent studies showed that repetitive exposures to hypoxia evokes long term facilitation of sensory nerve discharge (sLTF) of the carotid body in rodents exposed to chronic intermittent hypoxia (CIH). Although studies with anti-oxidants suggested the involvement of reactive oxygen species (ROS)-mediated signaling in eliciting sLTF, the source of and the mechanisms associated with ROS generation have not yet been investigated. We tested the hypothesis that ROS generated by NADPH oxidase (NOX) mediate CIH-evoked sLTF. Experiments were performed on ex vivo carotid bodies from rats and mice exposed either to 10 d of CIH or normoxia. Acute repetitive hypoxia evoked a 12-fold increase in NOX activity in CIH but not in control carotid bodies, and this effect was associated with upregulation of NOX2 mRNA and protein, which was primarily localized to glomus cells of the carotid body. sLTF was prevented by NOX inhibitors and was absent in mice deficient in NOX2. NOX activation by CIH required 5-HT release and activation of 5-HT₂ receptors coupled to PKC signaling. Studies with ROS scavengers revealed that H₂O₂ generated from O₂·^– contributes to sLTF. Priming with H₂O₂ elicited sLTF of carotid bodies from normoxic control rats and mice, similar to that seen in CIH-treated animals. These observations reveal a novel role for NOX-induced ROS signaling in mediating sensory plasticity of the carotid body.

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Received Oct. 3, 2008; revised Nov. 15, 2008; accepted Feb. 28, 2009.

Correspondence should be addressed to Nanduri R. Prabhakar, Center for Systems Biology of Oxygen Sensing, Department of Medicine, The University of Chicago, 5841 S. Maryland Avenue, MC 5068, Chicago, IL 60637. Email: nprabhak{at}medicine.bsd.uchicago.edu

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