TASK-2 channels contribute to pH sensitivity of retrotrapezoid nucleus chemoreceptor neurons

Phox2b-expressing glutamatergic neurons of the retrotrapezoid nucleus (RTN) display properties expected of central respiratory chemoreceptors; they are directly activated by CO₂/H⁺ via an unidentified pH-sensitive background K⁺ channel and, in turn, facilitate brainstem networks that control breathing. Here, we used a knock-out mouse model to examine whether TASK-2 (K2P5), an alkaline-activated background K⁺ channel, contributes to RTN neuronal pH sensitivity. We made patch-clamp recordings in brainstem slices from RTN neurons that were identified by expression of GFP (directed by the Phox2b promoter) or β-galactosidase (from the gene trap used for TASK-2 knock-out). Whereas nearly all RTN cells from control mice were pH sensitive (95%, n=58 of 61), only 56% of GFP-expressing RTN neurons from TASK-2^-/- mice (n-49 of 88) could be classified as pH sensitive (>30% reduction in firing rate from pH 7.0 to pH 7.8); the remaining cells were pH insensitive (44%). Moreover, none of the recorded RTN neurons from TASK-2^-/- mice selected based on β-galactosidase activity (a subpopulation of GFP-expressing neurons) were pH sensitive. The alkaline-activated background K⁺ currents were reduced in amplitude in RTN neurons from TASK-2^-/- mice that retained some pH sensitivity but were absent from pH-insensitive cells. Finally, using a working heart- brainstem preparation, we found diminished inhibition of phrenic burst amplitude by alkalization in TASK-2^-/- mice, with apneic threshold shifted to higher pH levels. In conclusion, alkaline-activated TASK-2 channels contribute to pH sensitivity in RTN neurons, with effects on respiration in situ that are particularly prominent near apneic threshold.