The long-term objective is to understand the cellular and subcellular mechanisms of oxygen chemoreception in the carotid body. The working models is that glomus cell metabolism senses oxygen and the resultant metabolic changes lead to an alteration of the electric activity of the sensory fiber which innervates it. Multiple pathways may be involved in oxygen sensing. Accordingly, the specific aims are to measure the cellular oxygen stimulus and to measure its effect on the chemosensory discharge, intracellular (glomus cell) pH, Ca2+, plasma membrane ionic currents (K+, Na+ and Ca2+), glomus cell volume regulation and secretory activity of the glomus cells. In order to understand the mechanisms of coupling between the stimulus and chemosensory response in the carotid body at the cellular level, studies will be made with the whole carotid body and with single glomus cells in primary culture. Fluorescence and phosphorescence probes will be combined with quantitative imaging techniques to measure extra- and intracellular PO2 as well as intracellular pH and Ca2+; patch clamp techniques will be used to measure the various pathways for ion flux across the membrane and to measure increases in membrane capacitance reflecting exocytosis and secretory activity in single glomus cells. This multidiscplinary approach is made possible by bringing together investigators with expertise from different fields. Understanding of the mechanisms of oxygen detection and signalling in the carotid body are important for many health related questions. The mechanisms may be a prototype of oxygen sensing in other tissues (i.e. renal erythropoietin synthesis and release; regulation of coronary and pulmonary vascular resistance). The carotid body is the primary organ which elicits protective reflex ventilatory, autonomic and cardiovascular responses against oxygen deprivation in health (e.g. high altitude) and disease (pulmonary and cardiovascular).
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