The role of pH-sensitive TASK channels in central respiratory chemoreception
- 629 Downloads
A number of the subunits within the family of K2P background K+ channels are sensitive to changes in extracellular pH in the physiological range, making them likely candidates to mediate various pH-dependent processes. Based on expression patterns within several brainstem neuronal cell groups that are believed to function in CO2/H+ regulation of breathing, three TASK subunits—TASK-1, TASK-2, and TASK-3—were specifically hypothesized to contribute to this central respiratory chemoreflex. For the acid-sensitive TASK-1 and TASK-3 channels, despite widespread expression at multiple levels within the brainstem respiratory control system (including presumptive chemoreceptor populations), experiments in knockout mice provided no evidence for their involvement in CO2 regulation of breathing. By contrast, the alkaline-activated TASK-2 channel has a more restricted brainstem distribution and was localized to the Phox2b-expressing chemoreceptor neurons of the retrotrapezoid nucleus (RTN). Remarkably, in a Phox2b27Ala/+ mouse genetic model of congenital central hypoventilation syndrome (CCHS) that is characterized by reduced central respiratory chemosensitivity, selective ablation of Phox2b-expressing RTN neurons was accompanied by a corresponding loss of TASK-2 expression. Furthermore, genetic deletion of TASK-2 blunted RTN neuronal pH sensitivity in vitro, reduced alkaline-induced respiratory network inhibition in situ and diminished the ventilatory response to CO2/H+ in vivo. Notably, a subpopulation of RTN neurons from TASK-2−/− mice retained their pH sensitivity, at least in part due to a residual pH-sensitive background K+ current, suggesting that other mechanisms (and perhaps other K2P channels) for RTN neuronal pH sensitivity are yet to be identified.
KeywordsTASK subunits Potassium selective channels pH sensitivity Respiratory chmosensitivity
This work was supported by grants from the NIH (HL108609, DAB and HL074011, PGG), and from French National Agency for Research Grants (ANR RESPITASK, JB, CG and ANR-11-LABX-0015-01, JB) and from CNRS (JB, CG).
- 19.Gestreau C, Heitzmann D, Thomas J, Dubreuil V, Bandulik S, Reichold M, Bendahhou S, Pierson P, Sterner C, Peyronnet-Roux J, Benfriha C, Tegtmeier I, Ehnes H, Georgieff M, Lesage F, Brunet JF, Goridis C, Warth R, Barhanin J (2010) Task2 potassium channels set central respiratory CO2 and O2 sensitivity. Proc Natl Acad Sci U S A 107:2325–2330CrossRefPubMedCentralPubMedGoogle Scholar
- 23.Gonzalez JA, Jensen LT, Doyle SE, Miranda-Anaya M, Menaker M, Fugger L, Bayliss DA, Burdakov D (2009) Deletion of TASK1 and TASK3 channels disrupts intrinsic excitability but does not abolish glucose or pH responses of orexin/hypocretin neurons. Eur J Neurosci 30:57–64CrossRefPubMedCentralPubMedGoogle Scholar
- 29.Karschin C, Wischmeyer E, Preisig-Muller R, Rajan S, Derst C, Grzeschik KH, Daut J, Karschin A (2001) Expression pattern in brain of TASK-1, TASK-3, and a tandem pore domain K+ channel subunit, TASK-5, associated with the central auditory nervous system. Mol Cell Neurosci 18:632–648CrossRefPubMedGoogle Scholar
- 65.Warth R, Barriere H, Meneton P, Bloch M, Thomas J, Tauc M, Heitzmann D, Romeo E, Verrey F, Mengual R, Guy N, Bendahhou S, Lesage F, Poujeol P, Barhanin J (2004) Proximal renal tubular acidosis in TASK2 K+ channel-deficient mice reveals a mechanism for stabilizing bicarbonate transport. Proc Natl Acad Sci U S A 101:8215–8220CrossRefPubMedCentralPubMedGoogle Scholar