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 mechanisms of chemotransduction remains obscure, the 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 transduction models propose that hypoxia causes release of an excitatory transmitter from glomus cells, perhaps due to inhibition of an oxygen sensitive K+ current. In the initial funding period the PI tested this hypothesis with a new experimental model which allowed for simultaneous recording of nerve activity, patch clamp recording of glomus cell currents and microvoltammetric detection of catecholamine release. Experimental results did not support the central role of K+ channels in oxygen sensing since TEA and 4-AP failed to stimulate secretion or nerve activity, leading the PI to speculate that chemosensitivity of the afferent nerve subserves an essential role in organ function. This is supported by new preliminary data demonstrating inherent chemosensitivity in the soma of chemoreceptor neurons. The proposed work focuses on developmental and hypoxia-induced changes in membrane currents of petrosal neurons. Specifically, the PI will: 1) Compare currents of chemoreceptor and non-chemoreceptor petrosal neurons during development. 2) Determine hypoxia-induced changes in these currents. 3) Examine the role of Na+ and Ca+2 channels in spike generation. These experiments utilize extracellular and intracellular (patch clamp) recordings of petrosal chemoreceptor and non-chemoreceptor neurons and analysis of spike interval trains from afferent axons. The anticipated results will allow for a better understanding of the mechanism of glomus cell/nerve ending transduction and maturation. This should lead to a pharmacologic targeting of these processes for the improved treatment of apnea and/or dyspnea.
