TASK Channels Determine pH Sensitivity in Select Respiratory Neurons But Do Not Contribute to Central Respiratory Chemosensitivity

Abstract

Central respiratory chemoreception is the mechanism by which the CNS maintains physiologically appropriate pH and PCO 2 via control of breathing. A prominent hypothesis holds that neural substrates for this process are distributed widely in the respiratory network, especially because many neurons that make up this network are chemosensitive in vitro. We and others have proposed that TASK channels (TASK-1, K 2P 3.1 and/or TASK-3, K 2P 9.1) may serve as molecular sensors for central chemoreception because they are highly expressed in multiple neuronal populations in the respiratory pathway and contribute to their pH sensitivity in vitro. To test this hypothesis, we examined the chemosensitivity of two prime candidate chemoreceptor neurons in vitro and tested ventilatory responses to CO 2 using TASK channel knock-out mice. The pH sensitivity of serotonergic raphe neurons was abolished in TASK channel knock-outs. In contrast, pH sensitivity of neurons in the mouse retrotrapezoid nucleus (RTN) was fully maintained in a TASK null background, and pharmacological evidence indicated that a K ϩ channel with properties distinct from TASK channels contributes to the pH sensitivity of rat RTN neurons. Furthermore, the ventilatory response to CO 2 was completely retained in single or double TASK knock-out mice. These data rule out a strict requirement for TASK channels or raphe neurons in central respiratory chemosensation. Furthermore, they indicate that a non-TASK K ϩ current contributes to chemosensitivity of RTN neurons, which are profoundly pH-sensitive and capable of driving respiratory output in response to local pH changes in vivo.

Task2 potassium channels set central respiratory CO 2 and O 2 sensitivity

“…Until recently, Task1 and Task3 pH-sensitive K + channels were thought to underlie this K + conductance of RTN neurons. A recent study using double Task1/3 knockout mice failed to confirm this hypothesis (21). In contrast, our results suggest that Task2 channels contribute to the hyperpolarizing K + conductance of RTN neurons.…”

“…Moreover, volatile anesthetics were proposed to depress respiratory neurons through activation of Task channels, leading to hyperpolarization and neuronal silencing. However, a critical role of Task channels in central CO 2 chemosensitivity was questioned because the hypercapnic response persisted in double-mutant Task1 −/− /Task3 −/− mice, although the chemosensitivity of raphe neurons, but not RTN neurons, was abolished (21).…”

TASK channel deletion in mice causes primary hyperaldosteronism

“…As described in ref. 27 (see also Methods), the second exon of each TASK channel gene was ''floxed'' (Fig. 1A), and knockin animals bearing floxed alleles were generated by standard procedures.…”

“…1B, Lower). As reported, TASK Ϫ/Ϫ knockout mice were viable and showed no obvious sensorimotor deficits in several standard behavioral tests (e.g., rotarod, wire hang, tail flick) (27). For these studies, we used adult male mice (Ϸ4 months old).…”

“…The derivation of TASK-1 and TASK-3 knockout mice has been described (27). In short, we used homologous recombination in R1 embryonic stem cells to insert loxP sites flanking the second exon of TASK-1 (Kcnk3, K 2P3.1, MGI ID 1100509) and TASK-3 (Kcnk9, K2P9.1, MGI ID 3521816).…”