Abnormal respiration under hyperoxia in TASK-1/3 potassium channel double knockout mice

Despite intensive research, the exact function of TASK potassium channels in central and peripheral chemoreception is still under debate. In this study, we investigated the respiration of unrestrained TASK-3 (TASK-3(-/-)) and TASK-1/TASK-3 double knockout (TASK-1/3(-/-)) adult male mice in vivo using a plethysmographic device. Ventilation parameters of TASK-3(-/-) mice were normal under control condition (21% O2) and upon hypoxia and hypercapnia they displayed the physiological increase of ventilation. TASK-1/3(-/-) mice showed increased ventilation under control conditions. This increase of ventilation was caused by increased tidal volumes (VT), a phenomenon similarly observed in TASK-1(-/-) mice. Under acute hypoxia, TASK-1/3(-/-) mice displayed the physiological increase of the minute volume. Interestingly, this increase was not related to an increase of the respiratory frequency (fR), as observed in wild-type mice, but was caused by a strong increase of VT. This particular respiratory phenotype is reminiscent of the respiratory phenotype of carotid body-denervated rodents in the compensated state. Acute hypercapnia (5% CO2) stimulated ventilation in TASK-1/3(-/-) and wild-type mice to a similar extent; however, at higher CO2 concentrations (>5% CO2) the stimulation of ventilation was more pronounced in TASK-1/3(-/-) mice. At hyperoxia (100% O2), TASK-1(-/-), TASK-3(-/-) and wild-type mice showed the physiological small decrease of ventilation. In sharp contrast, TASK-1/3(-/-) mice exhibited an abnormal increase of ventilation under hyperoxia. In summary, these measurements showed a grossly normal respiration of TASK-3(-/-) mice and a respiratory phenotype of TASK-1/3(-/-) mice that was characterized by a markedly enhanced tidal volume, similar to the one observed in TASK-1(-/-) mice. The abnormal hyperoxia response, exclusively found in TASK-1/3(-/-) double mutant mice, indicates that both TASK-1 and TASK-3 are essential for the hyperoxia-induced hypoventilation. The peculiar respiratory phenotype of TASK-1/3 knockout mice is reminiscent of the respiration of animals with long-term carotid body dysfunction. Taken together, TASK-1 and TASK-3 appear to serve specific and distinct roles in the complex processes underlying chemoreception and respiratory control