Carotid Body Chemoreception: Mechanism & Development

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DESCRIPTION (provided by applicant): The primary hypoxia sensor of the cardio-respiratory system is the carotid body, which is relatively insensitive at birth and matures over the first 1-2 weeks of life. Although the mechanism of chemotransduction remains obscure, glomus cells, secretory cells apposed to the afferent nerve endings, as well as the nerve endings themselves appear to form the critical chemoreceptive unit. Current models propose that hypoxia causes release of an excitatory transmitter, but identification of the purported excitatory transmitter has proven elusive and our previous results, as well those of other laboratories, demonstrate a dissociation between glomus cell secretion and afferent nerve activity. The proposed work outlines two steps in understanding the mechanism of transduction: firstly, to understand the mechanism of spike generation and secondly, to understand how the generation process is controlled by hypoxia. Towards the first aim, we demonstrate: i) that the spike generation process is highly sensitive to external Na+ perturbation or drugs which target Na+ channels, ii) chemoreceptor afferent neurons express a limited and consistent Na+ channel profile and iii) isolated, chemoreceptor afferent neurons are able to generate spontaneous action potentials which resemble the pattern as generated by the afferent nerve ending. Based on the preliminary results, our general hypothesis is that the nerve terminals are the site of action potential generation through an endogenous process, specifically, a persistent Na+ current. The proposed work: 1) uses RT-PCR and immunocytochemistry to identify Na+ channel isoforms at the soma and nerve terminals of chemoreceptor neurons; 2) examines the consequences of Na+ current perturbations on the respiratory response to hypoxia and chemoreceptor activity following drugs which target fast Na+ currents or loss (knockout) of isoforms Navl.6 and Navl.8; 3) examines the effects of disruption of Na+ channel underexpression/overexpression on the ability of the soma to generate spontaneous action potentials. The anticipated results will provide acceptance or rejection of this unique model of chemoreceptor transduction. If supported, the model should lead to a pharmacologic targeting of these processes for the improved treatment of apnea and/or dyspnea.