STIMULUS SECRETION COUPLING IN CAROTID BODY GLOMUS CELLS

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The primary sensor of the respiratory and cardiovascular systems for hypoxia are the carotid body chemoreceptors which increase their activity in response to a decrease in PaO2 or PHa. Sensitivity to these stimuli are weak at birth and increase over the first week or two of life. Hypoxia and acidity are likely transduced by glomus cells, secretory cells in apposition to the afferent nerve endings. Their role is essential to chemotransduction because chemosensitivity is lost following separation of the glomus cell from the nerve endings. Recent patch clamp recordings of isolated glomus cells revealed a K+ current which is inhibited by hypoxia. This inhibition is hypothesized to play an essential role in the transduction cascade of hypoxia, leading to depolarization, calcium influx and enhanced transmitter release. However, our preliminary question the validity of this mechanism because hypoxia often fails to alter membrane currents of glomus cells, in situ, and K+ blocking agents, although greatly effecting the cellular currents, may not block the nerve or secretory response of the organ. The proposed experiments address two basic questions regarding the transduction process. Firstly, what is the identity of glomus cell secretogues and which are liberated during hypoxia? This is addressed by examining: i) the importance of Na+, K+ and Ca+2 channels in initiating glomus cells secretion, ii) the relationship between Ca+2i and cell secretion and iii) the modulatory role of nucleotides and phosphorylases on secretory activity. Secondly, what change occurs in the level of or sensitivity to secretogues to account for the developmental increase in glomus cell stimulus/secretion coupling? The proposed experiments will employ a new and unique chemoreceptor model which allows for simultaneous single-fiber nerve recordings and either measurement of catecholamine release or patch-clamp recording of glomus cell. Patch-clamp data is used for assessment of vesicular fusion events by high-resolution monitoring of membrane capacitance. Catecholamine secretion is measured using carbon-fiber, Nafion coated microelectrodes combined with scanning or amperometric voltammetry. The anticipated results from this work will allow us to better understand the mechanisms of glomus cell hypoxia and acidity transduction and the basis for the maturational increase in sensitivity to these physiologic stimuli. This may lead to therapeutic strategies that can alter chemosensitivity and thereby improve treatment of apnea and hypoventilation in the neonate and older subject.