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The role of pH-sensitive TASK channels in central respiratory chemoreception

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Abstract

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.

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References

  1. Bagriantsev SN, Peyronnet R, Clark KA, Honore E, Minor DL Jr (2011) Multiple modalities converge on a common gate to control K2P channel function. EMBO J 30:3594–3606

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  2. Bayliss DA, Barrett PQ (2008) Emerging roles for two-pore-domain potassium channels and their potential therapeutic impact. Trends Pharmacol Sci 29:566–575

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. Bayliss DA, Talley EM, Sirois JE, Lei Q (2001) TASK-1 is a highly modulated pH-sensitive ‘leak’ K+ channel expressed in brainstem respiratory neurons. Respir Physiol 129:159–174

    Article  CAS  PubMed  Google Scholar 

  4. Berg AP, Talley EM, Manger JP, Bayliss DA (2004) Motoneurons express heteromeric TWIK-related acid-sensitive K+ (TASK) channels containing TASK-1 (KCNK3) and TASK-3 (KCNK9) subunits. J Neurosci 24:6693–6702

    Article  CAS  PubMed  Google Scholar 

  5. Brohawn SG, del Marmol J, MacKinnon R (2012) Crystal structure of the human K2P TRAAK, a lipid- and mechano-sensitive K+ ion channel. Science 335:436–441

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. Buckler KJ (2010) Two-pore domain K+ channels and their role in chemoreception. Adv Exp Med Biol 661:15–30

    Article  CAS  PubMed  Google Scholar 

  7. Burdakov D, Jensen LT, Alexopoulos H, Williams RH, Fearon IM, O’Kelly I, Gerasimenko O, Fugger L, Verkhratsky A (2006) Tandem-pore K+ channels mediate inhibition of orexin neurons by glucose. Neuron 50:711–722

    Article  CAS  PubMed  Google Scholar 

  8. Chemin J, Girard C, Duprat F, Lesage F, Romey G, Lazdunski M (2003) Mechanisms underlying excitatory effects of group I metabotropic glutamate receptors via inhibition of 2P domain K+ channels. EMBO J 22:5403–5411

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Chesler M (2003) Regulation and modulation of pH in the brain. Physiol Rev 83:1183–1221

    Article  CAS  PubMed  Google Scholar 

  10. Clarke CE, Veale EL, Wyse K, Vandenberg JI, Mathie A (2008) The M1P1 loop of TASK3 K2P channels apposes the selectivity filter and influences channel function. J Biol Chem 283:16985–16992

    Article  CAS  PubMed  Google Scholar 

  11. Czirjak G, Fischer T, Spat A, Lesage F, Enyedi P (2000) TASK (TWIK-related acid-sensitive K+ channel) is expressed in glomerulosa cells of rat adrenal cortex and inhibited by angiotensin II. Mol Endocrinol 14:863–874

    CAS  PubMed  Google Scholar 

  12. Dean JB, Lawing WL, Millhorn DE (1989) CO2 decreases membrane conductance and depolarizes neurons in the nucleus tractus solitarii. Exp Brain Res 76:656–661

    Article  CAS  PubMed  Google Scholar 

  13. Depuy SD, Kanbar R, Coates MB, Stornetta RL, Guyenet PG (2011) Control of breathing by raphe obscurus serotonergic neurons in mice. J Neurosci 31:1981–1990

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Dubreuil V, Thoby-Brisson M, Rallu M, Persson K, Pattyn A, Birchmeier C, Brunet JF, Fortin G, Goridis C (2009) Defective respiratory rhythmogenesis and loss of central chemosensitivity in Phox2b mutants targeting retrotrapezoid nucleus neurons. J Neurosci 29:14836–14846

    Article  CAS  PubMed  Google Scholar 

  15. Enyedi P, Czirjak G (2010) Molecular background of leak K+ currents: two-pore domain potassium channels. Physiol Rev 90:559–605

    Article  CAS  PubMed  Google Scholar 

  16. Es-Salah-Lamoureux Z, Steele DF, Fedida D (2010) Research into the therapeutic roles of two-pore-domain potassium channels. Trends Pharmacol Sci 31:587–595

    Article  CAS  PubMed  Google Scholar 

  17. Feldman JL, Mitchell GS, Nattie EE (2003) Breathing: rhythmicity, plasticity, chemosensitivity. Annu Rev Neurosci 26:239–266

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Fink M, Duprat F, Lesage F, Reyes R, Romey G, Heurteaux C, Lazdunski M (1996) Cloning, functional expression and brain localization of a novel unconventional outward rectifier K+ channel. EMBO J 15(24):6854–6862

    PubMed Central  CAS  PubMed  Google Scholar 

  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 107:2325–2330

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Goldstein SA, Price LA, Rosenthal DN, Pausch MH (1996) ORK1, a potassium-selective leak channel with two pore domains cloned from Drosophila melanogaster by expression in Saccharomyces cerevisiae. Proc Natl Acad Sci U S A 93:13256–13261

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Goldstein SA, Bockenhauer D, O’Kelly I, Zilberberg N (2001) Potassium leak channels and the KCNK family of two-P-domain subunits. Nat Rev Neurosci 2:175–184

    Article  CAS  PubMed  Google Scholar 

  22. Goldstein SA, Bayliss DA, Kim D, Lesage F, Plant LD, Rajan S (2005) International Union of Pharmacology. LV. Nomenclature and molecular relationships of two-P potassium channels. Pharmacol Rev 57:527–540

    Article  CAS  PubMed  Google 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 30:57–64

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Gurney A, Manoury B (2009) Two-pore potassium channels in the cardiovascular system. Eur Biophys J 38:305–318

    Article  CAS  PubMed  Google Scholar 

  25. Guyenet PG, Stornetta RL, Bayliss DA (2010) Central respiratory chemoreception. J Comp Neurol 518:3883–3906

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Guyon A, Tardy MP, Rovere C, Nahon JL, Barhanin J, Lesage F (2009) Glucose inhibition persists in hypothalamic neurons lacking tandem-pore K+ channels. J Neurosci 29:2528–2533

    Article  CAS  PubMed  Google Scholar 

  27. Honore E (2007) The neuronal background K2P channels: focus on TREK1. Nat Rev Neurosci 8:251–261

    Article  CAS  PubMed  Google Scholar 

  28. Iceman KE, Richerson GB, Harris MB (2013) Medullary serotonin neurons are CO2 sensitive in situ. J Neurophysiol 110:2536–2544

    Article  PubMed Central  CAS  PubMed  Google 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 18:632–648

    Article  CAS  PubMed  Google Scholar 

  30. Kim D (2005) Physiology and pharmacology of two-pore domain potassium channels. Curr Pharm Des 11:2717–2736

    Article  CAS  PubMed  Google Scholar 

  31. Koizumi H, Smerin SE, Yamanishi T, Moorjani BR, Zhang R, Smith JC (2010) TASK channels contribute to the K+-dominated leak current regulating respiratory rhythm generation in vitro. J Neurosci 30:4273–4284

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. L’Hoste S, Poet M, Duranton C, Belfodil R, e Barriere H, Rubera I, Tauc M, Poujeol C, Barhanin J, Poujeol P (2007) Role of TASK2 in the control of apoptotic volume decrease in proximal kidney cells. J Biol Chem 282:36692–36703

    Article  PubMed  Google Scholar 

  33. Lazarenko RM, Fortuna MG, Shi Y, Mulkey DK, Takakura AC, Moreira TS, Guyenet PG, Bayliss DA (2010) Anesthetic activation of central respiratory chemoreceptor neurons involves inhibition of a THIK-1-like background K+ current. J Neurosci 30:9324–9334

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. Lazarenko RM, Willcox SC, Shu S, Berg AP, Jevtovic-Todorovic V, Talley EM, Chen X, Bayliss DA (2010) Motoneuronal TASK channels contribute to immobilizing effects of inhalational general anesthetics. J Neurosci 30:7691–7704

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  35. Lesage F (2003) Pharmacology of neuronal background potassium channels. Neuropharmacology 44:1–7

    Article  CAS  PubMed  Google Scholar 

  36. Lesage F, Barhanin J (2011) Molecular physiology of pH-sensitive background K2P channels. Physiology (Bethesda) 26:424–437

    Article  CAS  Google Scholar 

  37. Lesage F, Guillemare E, Fink M, Duprat F, Lazdunski M, Romey G, Barhanin J (1996) TWIK-1, a ubiquitous human weakly inward rectifying K+ channel with a novel structure. EMBO J 15:1004–1011

    PubMed Central  CAS  PubMed  Google Scholar 

  38. Lesage F, Reyes R, Fink M, Duprat F, Guillemare E, Lazdunski M (1996) Dimerization of TWIK-1 K+ channel subunits via a disulfide bridge. EMBO J 15:6400–6407

    PubMed Central  CAS  PubMed  Google Scholar 

  39. Lopes CM, Zilberberg N, Goldstein SA (2001) Block of Kcnk3 by protons. Evidence that 2-P-domain potassium channel subunits function as homodimers. J Biol Chem 276:24449–24452

    Article  CAS  PubMed  Google Scholar 

  40. Lotshaw DP (2007) Biophysical, pharmacological, and functional characteristics of cloned and native mammalian two-pore domain K+ channels. Cell Biochem Biophys 47:209–256

    Article  CAS  PubMed  Google Scholar 

  41. Mathie A (2007) Neuronal two-pore-domain potassium channels and their regulation by G protein-coupled receptors. J Physiol 578:377–385

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  42. Mathie A, Veale EL (2007) Therapeutic potential of neuronal two-pore domain potassium-channel modulators. Curr Opin Investig Drugs 8:555–562

    CAS  PubMed  Google Scholar 

  43. Mathie A, Al-Moubarak E, Veale EL (2010) Gating of two pore domain potassium channels. J Physiol 588:3149–3156

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  44. Millar JA, Barratt L, Southan AP, Page KM, Fyffe RE, Robertson B, Mathie A (2000) A functional role for the two-pore domain potassium channel TASK-1 in cerebellar granule neurons. Proc Natl Acad Sci U S A 97:3614–3618

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  45. Miller AN, Long SB (2012) Crystal structure of the human two-pore domain potassium channel K2P1. Science 335:432–436

    Article  CAS  PubMed  Google Scholar 

  46. Morton MJ, O’Connell AD, Sivaprasadarao A, Hunter M (2003) Determinants of pH sensing in the two-pore domain K+ channels TASK-1 and −2. Pflugers Arch 445:577–583

    CAS  PubMed  Google Scholar 

  47. Mulkey DK, Stornetta RL, Weston MC, Simmons JR, Parker A, Bayliss DA, Guyenet PG (2004) Respiratory control by ventral surface chemoreceptor neurons in rats. Nat Neurosci 7:1360–1369

    Article  CAS  PubMed  Google Scholar 

  48. Mulkey DK, Talley EM, Stornetta RL, Siegel AR, West GH, Chen X, Sen N, Mistry AM, Guyenet PG, Bayliss DA (2007) TASK channels determine pH sensitivity in select respiratory neurons but do not contribute to central respiratory chemosensitivity. J Neurosci 27:14049–14058

    Article  CAS  PubMed  Google Scholar 

  49. Nattie EE (2001) Central chemosensitivity, sleep, and wakefulness. Respir Physiol 129:257–268

    Article  CAS  PubMed  Google Scholar 

  50. Niemeyer MI, Gonzalez-Nilo FD, Zuniga L, Gonzalez W, Cid LP, Sepulveda FV (2007) Neutralization of a single arginine residue gates open a two-pore domain, alkali-activated K+ channel. Proc Natl Acad Sci U S A 104:666–671

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  51. Piechotta PL, Rapedius M, Stansfeld PJ, Bollepalli MK, Ehrlich G, Andres-Enguix I, Fritzenschaft H, Decher N, Sansom MS, Tucker SJ, Baukrowitz T (2011) The pore structure and gating mechanism of K2P channels. EMBO J 30:3607–3619

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  52. Putnam RW, Filosa JA, Ritucci NA (2004) Cellular mechanisms involved in CO2 and acid signaling in chemosensitive neurons. Am J Physiol Cell Physiol 287:C1493–C1526

    Article  CAS  PubMed  Google Scholar 

  53. Rajan S, Wischmeyer E, Xin Liu G, Preisig-Muller R, Daut J, Karschin A, Derst C (2000) TASK-3, a novel tandem pore domain acid-sensitive K+ channel. An extracellular histiding as pH sensor. J Biol Chem 275:16650–16657

    Article  CAS  PubMed  Google Scholar 

  54. Ramanantsoa N, Hirsch MR, Thoby-Brisson M, Dubreuil V, Bouvier J, Ruffault PL, Matrot B, Fortin G, Brunet JF, Gallego J, Goridis C (2011) Breathing without CO2 chemosensitivity in conditional Phox2b mutants. J Neurosci 31:12880–12888

    Article  CAS  PubMed  Google Scholar 

  55. Reyes R, Duprat F, Lesage F, Fink M, Salinas M, Farman N, Lazdunski M (1998) Cloning and expression of a novel pH-sensitive two pore domain K+ channel from human kidney. J Biol Chem 273:30863–30869

    Article  CAS  PubMed  Google Scholar 

  56. Sirois JE, Lei Q, Talley EM, Lynch C 3rd, Bayliss DA (2000) The TASK-1 two-pore domain K+ channel is a molecular substrate for neuronal effects of inhalation anesthetics. J Neurosci 20:6347–6354

    CAS  PubMed  Google Scholar 

  57. Talley EM, Lei Q, Sirois JE, Bayliss DA (2000) TASK-1, a two-pore domain K+ channel, is modulated by multiple neurotransmitters in motoneurons. Neuron 25:399–410

    Article  CAS  PubMed  Google Scholar 

  58. Talley EM, Solorzano G, Lei Q, Kim D, Bayliss DA (2001) CNS distribution of members of the two-pore-domain (KCNK) potassium channel family. J Neurosci 21:7491–7505

    CAS  PubMed  Google Scholar 

  59. Talley EM, Sirois JE, Lei Q, Bayliss DA (2003) Two-pore-Domain (KCNK) potassium channels: dynamic roles in neuronal function. Neuroscientist 9:46–56

    Article  CAS  PubMed  Google Scholar 

  60. Teran FA, Massey CA, Richerson GB (2014) Serotonin neurons and central respiratory chemoreception: where are we now? Prog Brain Res 209:207–233

    Article  PubMed  Google Scholar 

  61. Veasey SC, Fornal CA, Metzler CW, Jacobs BL (1995) Response of serotonergic caudal raphe neurons in relation to specific motor activities in freely moving cats. J Neurosci 15:5346–5359

    CAS  PubMed  Google Scholar 

  62. Veasey SC, Fornal CA, Metzler CW, Jacobs BL (1997) Single-unit responses of serotonergic dorsal raphe neurons to specific motor challenges in freely moving cats. Neuroscience 79:161–169

    Article  CAS  PubMed  Google Scholar 

  63. Vega-Saenz de Miera E, Lau DH, Zhadina M, Pountney D, Coetzee WA, Rudy B (2001) KT3.2 and KT3.3, two novel human two-pore K+ channels closely related to TASK-1. J Neurophysiol 86:130–142

    CAS  PubMed  Google Scholar 

  64. Wang S, Benamer N, Zanella S, Kumar NN, Shi Y, Bevengut M, Penton D, Guyenet PG, Lesage F, Gestreau C, Barhanin J, Bayliss DA (2013) TASK-2 channels contribute to pH sensitivity of retrotrapezoid nucleus chemoreceptor neurons. J Neurosci 33:16033–16044

    Article  PubMed Central  CAS  PubMed  Google 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 101:8215–8220

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  66. Washburn CP, Sirois JE, Talley EM, Guyenet PG, Bayliss DA (2002) Serotonergic raphe neurons express TASK channel transcripts and a TASK-like pH- and halothane-sensitive K+ conductance. J Neurosci 22:1256–1265

    CAS  PubMed  Google Scholar 

  67. Washburn CP, Bayliss DA, Guyenet PG (2003) Cardiorespiratory neurons of the rat ventrolateral medulla contain TASK-1 and TASK-3 channel mRNA. Respir Physiol Neurobiol 138:19–35

    Article  CAS  PubMed  Google Scholar 

  68. Williams RH, Jensen LT, Verkhratsky A, Fugger L, Burdakov D (2007) Control of hypothalamic orexin neurons by acid and CO2. Proc Natl Acad Sci U S A 104(25):10685–10690

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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Acknowledgments

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).

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Authors and Affiliations

  1. Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA, 22908-0735, USA

    Douglas A. Bayliss & Patrice G. Guyenet

  2. LP2M-CNRS-UNS UMR 7370, Faculté de Médecine, Université de Nice-Sophia Antipolis, 28 Avenue de Valombrose, 06107, Nice Cedex 2, France

    Jacques Barhanin

  3. Laboratories of Excellence, Ion Channel Science and Therapeutics, Nice, France

    Jacques Barhanin

  4. Aix-Marseille-Université, CNRS, Centre de Recherche en Neurobiologie et Neurophysiologie de Marseille–Unité Mixte de Recherche (UMR) 7286, 13344, Marseille, France

    Christian Gestreau

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Bayliss, D.A., Barhanin, J., Gestreau, C. et al. The role of pH-sensitive TASK channels in central respiratory chemoreception. Pflugers Arch - Eur J Physiol 467, 917–929 (2015). https://doi.org/10.1007/s00424-014-1633-9

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