O2-CHEMOSENSING BY REATIVE OXYGEN SPECIES/NADPH OXIDASE

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DESCRIPTION (provided by applicant): O2-sensing in the carotid body occurs in neuroectoderm-derived type I glomus cells where hypoxia elicits a complex chemotransduction cascade involving membrane depolarization, Ca 2+ entry and the release of excitatory neurotransmitters. Efforts to understand the exquisite O2-sensitivity of these cells focus primarily on the relationship between PO2 and the activity of K+-channels. A current hypothesis proposes that coupling between local PO2 and the open-closed state of K+-channels is mediated by a phagocytic-like multisubunit enzyme, NADPH oxidase, which produces reactive oxygen species (ROS) in proportion to the prevailing PO2. In O2-sensitive cells contained in lung neuroepithelial bodies (NEB), experiments have confirmed that ROS levels decrease in hypoxia, and that E M and K+-channel activity are indeed controlled by ROS produced by NADPH oxidase. However, recent studies in our laboratory suggest that ROS generated by a non-phagocytic form of NADPH oxidase, are important contributors to chemotransduction, but that their role in type I cells differs fundamentally from the mechanism utilized by NEB. We propose to test the hypothesis that in response to hypoxia, NADPH oxidase activity is increased in type I cells, and further, that increased ROS levels generated in response to low-O2 facilitate membrane re-polarization via the activation of a subset of K+-channels. In addition, we will examine the hypothesis that a non-phagocytic NADPH oxidase mediates adaptive morphological and physiological adjustments induced by exposure of the carotid body to chronic hypoxia (CH), a condition that occurs clinically in sleep apnea and chronic obstructive pulmonary disease (COPD). Studies will include: I. An examination of the sources and mechanisms of ROS production in type I cells, II. Evaluation of the involvement of NADPH oxidase and ROS in the carotid body response to acute hypoxia; III. The expression of NADPH oxidase subunits in the carotid body; and the effects of CH; and IV. The role of NADPH oxidase and ROS in carotid body adaptation to CH.