Subject: TASK K+ channel contribution in breathing adaptation to O2, CO2 and pH changes
Context of the study
The chemosensitivity is an essential property of the respiratory system to permanently adapt its activity to the needs of the body. Specialized sensors at the periphery (mainly carotid bodies) and at the central level (specialized nuclei in the brainstem) are involved in monitoring arterial blood CO2 and O2 pressures as well as pH. Defects of central chemoreception are implicated in respiratory pathologies such as sleep apnea syndromes, periodic breathing in high altitude and drug- or anesthesia-induced respiratory depression.
The congenital central hypoventilation syndrome is a severe hereditary form of central breathing chemosensitivity in human. The brainstem topology of respiratory nuclei is relatively well known. Yet, we don't precisely know what are the neurons directly involved in chemosensitivity and even less the exact molecular identities of the chemoreceptors. Background K+ channels (K2P) of the TASK family display functional characteristics including pH and reactive oxygen species (ROS) sensitivities that make them good CO2 and O2 sensors candidates.
In a recently published work, we have identified TASK2 as the molecular O2 sensor in
retrotrapezoid nucleus (RTN) and proposed that its activation by hypoxia generated ROS is the mechanism by which central hypoxia-induced ventilatory depression takes place (Gestreau et al 2010).
The project is aimed at the characterization of the molecular mechanisms regulating the CO2 and O2 sensing in the brainstem and involved in the adaptation of breathing to the blood gases relying on the unique model of TASK mutant mice. We have produced
mice invalidated for the three TASK channel genes task1 (kcnk3), task2 (kcnk5) and task3 (kcnk9) as well as double knockout task1-3 and task2-3. The postdoctoral
fellow will develop patch-clamp studies on brainstem slices from these mouse models.
Therefore, a good experience in electrophysiology, and possibly in electrophysiology on slices would be greatly appreciated.
Post starting January 2011
Duration 24 months
Contact Jacques Barhanin (jacques.barhanin@
Faculté des Sciences
Bâtiment Sciences Naturelles
06105 Nice, France
Gestreau, C., D. Heitzmann, J. Thomas, V. Dubreuil, S. Bandulik, M. Reichold, S. Bendahhou, P. Pierson, C. Sterner, J. Peyronnet-Roux, C. Benfriha, I. Tegtmeier, H. Ehnes, M. Georgieff, F. Lesage, J. F. Brunet, C. Goridis, R. Warth and J. Barhanin (2010). "Task2 potassium channels set central respiratory CO2 and O2 sensitivity. " Proc Natl Acad Sci U S A 107(5): 2325-30.
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