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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32HL010271-03
Application #
6388744
Study Section
Special Emphasis Panel (ZRG1-MDCN-3 (01))
Program Officer
Rothgeb, Ann E
Project Start
2001-07-01
Project End
Budget Start
2001-07-01
Budget End
2002-06-30
Support Year
3
Fiscal Year
2001
Total Cost
$43,772
Indirect Cost
Name
University of Virginia
Department
Pharmacology
Type
Schools of Medicine
DUNS #
001910777
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Bayliss, Douglas A; Sirois, Jay E; Talley, Edmund M (2003) The TASK family: two-pore domain background K+ channels. Mol Interv 3:205-19
Talley, Edmund M; Sirois, Jay E; Lei, Qiubo et al. (2003) Two-pore-Domain (KCNK) potassium channels: dynamic roles in neuronal function. Neuroscientist 9:46-56
Sirois, Jay E; Lynch 3rd, Carl; Bayliss, Douglas A (2002) Convergent and reciprocal modulation of a leak K+ current and I(h) by an inhalational anaesthetic and neurotransmitters in rat brainstem motoneurones. J Physiol 541:717-29
Washburn, Christopher P; Sirois, Jay E; Talley, Edmund M et al. (2002) Serotonergic raphe neurons express TASK channel transcripts and a TASK-like pH- and halothane-sensitive K+ conductance. J Neurosci 22:1256-65
Bayliss, D A; Talley, E M; Sirois, J E et al. (2001) TASK-1 is a highly modulated pH-sensitive 'leak' K(+) channel expressed in brainstem respiratory neurons. Respir Physiol 129:159-74
Sirois, J E; Lei, Q; Talley, E M et al. (2000) The TASK-1 two-pore domain K+ channel is a molecular substrate for neuronal effects of inhalation anesthetics. J Neurosci 20:6347-54
Talley, E M; Lei, Q; Sirois, J E et al. (2000) TASK-1, a two-pore domain K+ channel, is modulated by multiple neurotransmitters in motoneurons. Neuron 25:399-410