Hypoglossal motoneurons contribute to the maintenance of upper airway patency and alterations in their function can lead to contribute to the maintenance of upper airway patency and alterations in their function can lead to obstructive apneas. Preliminary electrophysiological experiments have identified acid- and hypoxia-sensitive currents that contribute to cellular excitability in hypoglossal motoneurons. The response to acidosis and hypoxia suggests that these conditions inhibit a 'leak' K+ channel active under resting conditions. Further, hypoglossal motoneurons express TASK-1, a recently discovered leak K+ channel. The hypothesis that TASK-1 mediates acid- and hypoxia-sensitive currents in hypoglossal motoneurons is tested in this proposal by comparing properties of pH- and O2-sensitive currents in hypoglossal motoneurons (i.e., in terms of ionic selectivity, sensitivity to K+ channel blockers, inhibition by metabolic and respiratory acidosis and modulation by a neurotransmitter) to those of TASK-1 studied in a heterologous expression system (HEK 293T cells). In addition, expression levels of TASK-1, determined by in situ hybridization, are correlated with acid-sensitive current density throughout postnatal development.
The Specific Aims are: [1] Determine developmental changes in expression levels of TASK-1 mRNA and magnitude of an acid-sensitive current in hypoglossal motoneurons. [2] Characterize a pH-sensitive current in neonatal and adult hypoglossal motoneurons. [3] Determine hypoxia effects on pH-sensitive current in motoneurons and TASK-1 in HEK 293T cells. These studies will suggest a molecular basis for an acid-sensitive current native to hypoglossal motoneurons that could serve to enhance excitability during acidosis and hypoxia.
