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

Abstract

Task2 K + channel expression in the central nervous system is surprisingly restricted to a few brainstem nuclei, including the retrotrapezoid (RTN) region. All Task2-positive RTN neurons were lost in mice bearing a Phox2b mutation that causes the human congenital central hypoventilation syndrome. In plethysmography, Task2 −/− mice showed disturbed chemosensory function with hypersensitivity to low CO 2 concentrations, leading to hyperventilation. Task2 probably is needed to stabilize the membrane potential of chemoreceptive cells. In addition, Task2 −/− mice lost the long-term hypoxia-induced respiratory decrease whereas the acute carotid-body-mediated increase was maintained. The lack of anoxia-induced respiratory depression in the isolated brainstemspinal cord preparation suggested a central origin of the phenotype. Task2 activation by reactive oxygen species generated during hypoxia could silence RTN neurons, thus contributing to respiratory depression. These data identify Task2 as a determinant of central O 2 chemoreception and demonstrate that this phenomenon is due to the activity of a small number of neurons located at the ventral medullary surface.breathing | central chemoreceptors | K2P | KCNK5 | ventral medullary surface S pontaneous breathing requires feedback controls in which detection of blood gases and pH is critical. At present, there is good understanding of the brainstem topology of respiratory centers, and functional measurements in vitro and in vivo have revealed the basic principles of the neuronal network required for respiratory rhythmogenesis and pattern generation. This network comprises several groups of respiratory neurons forming columns extending from the caudal ventrolateral medulla to the dorsolateral pons (1, 2). The activity of this network must be stable yet permanently adjusted to variations of O 2 , CO 2 , and pH during diverse physiological conditions, e.g., sleep, exercise, or high altitude (3). The precise physiological processes by which pH, CO 2 , and O 2 changes are sensed and translated into the appropriate respiratory neural output are important mechanisms that are still a matter of debate (4, 5). Changes in arterial CO 2 / pH are detected by peripheral chemoreceptors, mainly carotid bodies, and multiple chemoreceptive areas within the brainstem. Among the central chemoreceptive areas, two have attracted most attention: the raphe nuclei and the retrotrapezoid nucleus (RTN) (6, 7). The carotid bodies are the major sensors for acute O 2 changes. However, for longer periods of hypoxia, respiratory adaptation is substantially mediated by central mechanisms (8). The ventrolateral medullary surface comprising the RTN and the parafacial respiratory group (pFRG) has been proposed to contain intrinsically CO 2 -and O 2 -sensing neurons (9-12). Recently, a mouse model that carries a mutation of the transcription factor Phox2b, which causes congenital central hypoventilation syndrome in humans, was engineered. A specific loss of a population of Phox2b-expressing RTN/pFRG neurons ...

Separate Gating Mechanisms Mediate the Regulation of K2P Potassium Channel TASK-2 by Intra- and Extracellular pH

“…Addendum-Shortly after this paper was initially written, expression of TASK-2 was reported in the brainstem, including the retrotrapezoid nucleus. These TASK-2-positive cells were lost in Phox2b mutant mice that are a model for human congenital central hypoventilation syndrome (49). Retrotrapezoid nucleus neurons, whose development fails in Phox2b mutant mice, regulate breathing rate and intensity and active expiration and are therefore critical for the regulation of CO 2 (50).…”

“…Hypercapnia was shown to drive an acute ventilatory increase in WT but not in TASK-2-deficient mice (49). The authors hypothesize that active TASK-2 channels maintain a hyperpolarized condition of retrotrapezoid nucleus neurons, thus preventing a respiratory increase at low CO 2 (49). The strong ventilatory drive at high CO 2 could be the consequence of a decrease in TASK-2 channel activity.…”

“…Using a TASK-2 knock-out mouse, however, it is now shown that TASK-2 channels are important in mediating central CO 2 and O 2 chemosensitivity. Hypercapnia was shown to drive an acute ventilatory increase in WT but not in TASK-2-deficient mice (49). The authors hypothesize that active TASK-2 channels maintain a hyperpolarized condition of retrotrapezoid nucleus neurons, thus preventing a respiratory increase at low CO 2 (49).…”

Genetic Inactivation of Kcnj16 Identifies Kir5.1 as an Important Determinant of Neuronal PCO2/pH Sensitivity

“…The precise contribution of other pH-sensitive K ϩ channels (e.g. TASK) to chemosensation in these tissues remains controversial (35)(36)(37). Kir5.1 (and Kir4.1) are also expressed in some but not all of these other chemosensitive areas, indicating that the response to CO 2 is probably complex and involves a large degree of functional redundancy.…”

An Update on Channelopathies

“…The mice who fail to express potassium channels are insensitive to hypoxia and hypercapnia; they hypoventilate and die young. 123 This reintroduces the question of defining channelopathies. If a genetic syndrome does not encode a channel-forming protein and its product does seem to directly or indirectly bind channel proteins, but it nonetheless affects channel transcription, is it a channelopathy?…”