Advertisement

Ca2+-dependent large conductance K+ currents in thalamocortical relay neurons of different rat strains

  • Petra EhlingEmail author
  • Manuela Cerina
  • Patrick Meuth
  • Tatyana Kanyshkova
  • Pawan Bista
  • Philippe Coulon
  • Sven G. Meuth
  • Hans-Christian Pape
  • Thomas Budde
Ion Channels, Receptors and Transporters

Abstract

Mutations in genes coding for Ca2+ channels were found in patients with childhood absence epilepsy (CAE) indicating a contribution of Ca2+-dependent mechanisms to the generation of spike-wave discharges (SWD) in humans. Since the involvement of Ca2+ signals remains unclear, the aim of the present study was to elucidate the function of a Ca2+-dependent K+ channel (BKCa) under physiological conditions and in the pathophysiological state of CAE. The activation of BKCa channels is dependent on both voltage and intracellular Ca2+ concentrations. Moreover, these channels exhibit an outstandingly high level of regulatory heterogeneity that builds the basis for the influence of BKCa channels on different aspects of neuronal activity. Here, we analyse the contribution of BKCa channels to firing of thalamocortical relay neurons, and we test the hypothesis that BKCa channel activity affects the phenotype of a genetic rat model of CAE. We found that the activation of the β2-adrenergic receptor/protein kinase A pathway resulted in BKCa channel inhibition. Furthermore, BKCa channels affect the number of action potentials fired in a burst and produced spike frequency adaptation during tonic activity. The latter result was confirmed by a computer modelling approach. We demonstrate that the β2-adrenergic inhibition of BKCa channels prevents spike frequency adaptation and, thus, might significantly support the tonic firing mode of thalamocortical relay neurons. In addition, we show that BKCa channel functioning differs in epileptic WAG/Rij and thereby likely contributes to highly synchronised, epileptic network activity.

Keywords

BKCa channels Thalamic firing modes Computer modelling Spike frequency adaptation WAG/Rij rat Absence epilepsy 

Notes

Acknowledgments

This work was funded by Deutsche Forschungsgemeinschaft (DFG; BU 1019/11-1) and Interdisziplinäres Zentrum für Klinische Forschung (IZKF; Bud3/010/10; http://campus.uni-muenster.de/home.html). Thanks are due to E. Nass and K. Foraita for excellent technical assistance.

Supplementary material

424_2012_1188_MOESM1_ESM.docx (23 kb)
ESM 1 (DOCX 23 kb)
424_2012_1188_MOESM2_ESM.pdf (19 kb)
ESM 2 (PDF 18 kb)
424_2012_1188_MOESM3_ESM.pdf (20 kb)
ESM 3 (PDF 20 kb)
424_2012_1188_MOESM4_ESM.pdf (39 kb)
ESM 4 (PDF 39 kb)

References

  1. 1.
    Biella G, Meis S, Pape H-C (2001) Modulation of a Ca2+-dependent K+-current by intracellular cAMP in rat thalamocortical relay neurons. Thalamus Relat Syst 1:157–167CrossRefGoogle Scholar
  2. 2.
    Bista P, Meuth S, Kanyshkova T, Cerina M, Pawlowski M, Ehling P, Landgraf P, Borsotto M, Heurteaux C, Pape H-C, Baukrowitz T, Budde T (2012) Identification of the muscarinic pathway underlying cessation of sleep-related burst activity in rat thalamocortical relay neurons. Pflügers Archiv Eur J Physiol 463(1):89–102. doi: 10.1007/s00424-011-1056-9 CrossRefGoogle Scholar
  3. 3.
    Blumenfeld H, Klein J, Schridde U, Vestal M, Rice T, Khera D, Bashyal C, Giblin K, Paul-Laughinghouse C, Wang F, Phadke A, Mission J, Agarwal R, Englot D, Motelow J, Nersesyan H, Waxman S, Levin A (2008) Early treatment suppresses the development of spike-wave epilepsy in a rat model. Epilepsia 49(3):400–409PubMedCrossRefGoogle Scholar
  4. 4.
    Broicher T, Kanyshkova T, Landgraf P, Rankovic V, Meuth P, Meuth S, Pape H-C, Budde T (2007) Specific expression of low-voltage-activated calcium channel isoforms and splice variants in thalamic local circuit interneurons. Mol Cell Neurosci 36(2):132–145PubMedCrossRefGoogle Scholar
  5. 5.
    Broicher T, Kanyshkova T, Meuth P, Pape H-C, Budde T (2008) Correlation of T-channel coding gene expression, IT, and the low threshold Ca2+ spike in the thalamus of a rat model of absence epilepsy. Mol Cell Neurosci 39(3):384–399. doi: 10.1016/j.mcn.2008.07.012 PubMedCrossRefGoogle Scholar
  6. 6.
    Broicher T, Seidenbecher T, Meuth P, Munsch T, Meuth S, Kanyshkova T, Pape H-C, Budde T (2007) T-current related effects of antiepileptic drugs and a Ca2+ channel antagonist on thalamic relay and local circuit interneurons in a rat model of absence epilepsy. Neuropharmacology 53(3):431–446PubMedCrossRefGoogle Scholar
  7. 7.
    Budde T, Biella G, Munsch T, Pape H (1997) Lack of regulation by intracellular Ca2+ of the hyperpolarization-activated cation current in rat thalamic neurones. J Physiol 503(Pt 1):79–85PubMedCrossRefGoogle Scholar
  8. 8.
    Budde T, Caputi L, Kanyshkova T, Staak R, Abrahamczik C, Munsch T, Pape H-C (2005) Impaired regulation of thalamic pacemaker channels through an imbalance of subunit expression in absence epilepsy. J Neurosci Off J Soc Neurosci 25(43):9871–9882CrossRefGoogle Scholar
  9. 9.
    Budde T, Mager R, Pape H-C (1992) Different types of potassium outward current in relay neurons acutely isolated from the rat lateral geniculate nucleus. Eur J Neurosci 4(8):708–722PubMedCrossRefGoogle Scholar
  10. 10.
    Budde T, Sieg F, Braunewell K, Gundelfinger E, Pape H (2000) Ca2+-induced Ca2+ release supports the relay mode of activity in thalamocortical cells. Neuron 26(2):483–492PubMedCrossRefGoogle Scholar
  11. 11.
    Chen L, Tian L, MacDonald S, McClafferty H, Hammond M, Huibant J-M, Ruth P, Knaus H-G, Shipston M (2005) Functionally diverse complement of large conductance calcium- and voltage-activated potassium channel (BK) alpha-subunits generated from a single site of splicing. J Biol Chem 280(39):33599–33609PubMedCrossRefGoogle Scholar
  12. 12.
    Chen Y, Lu J, Pan H, Zhang Y, Wu H, Xu K, Liu X, Jiang Y, Bao X, Yao Z, Ding K, Lo W, Qiang B, Chan P, Shen Y, Wu X (2003) Association between genetic variation of CACNA1H and childhood absence epilepsy. Ann Neurol 54(2):239–243PubMedCrossRefGoogle Scholar
  13. 13.
    Coenen A, Van Luijtelaar E (2003) Genetic animal models for absence epilepsy: a review of the WAG/Rij strain of rats. Behav Genet 33(6):635–655PubMedCrossRefGoogle Scholar
  14. 14.
    Coulon P, Budde T, Pape H-C (2012) The sleep relay—the role of the thalamus in central and decentral sleep regulation. Pflügers Archiv Eur J Physiol 463(1):53–71CrossRefGoogle Scholar
  15. 15.
    Danober L, Deransart C, Depaulis A, Vergnes M, Marescaux C (1998) Pathophysiological mechanisms of genetic absence epilepsy in the rat. Prog Neurobiol 55(1):27–57PubMedCrossRefGoogle Scholar
  16. 16.
    Depaulis A, van Luijtelaar G (2006) Genetic models of absence epilepsy in the rat. In: Pitkänen A, Schwrtzkroin P, Moshé S (eds) Models of seizures and epilepsy. Elsevier, San DiegoGoogle Scholar
  17. 17.
    Destexhe A, Bal T, McCormick D, Sejnowski T (1996) Ionic mechanisms underlying synchronized oscillations and propagating waves in a model of ferret thalamic slices. J Neurophysiol 76(3):2049–2070PubMedGoogle Scholar
  18. 18.
    Eichhorn B, Dobrev D (2007) Vascular large conductance calcium-activated potassium channels: functional role and therapeutic potential. Naunyn Schmiedeberg's Arch Pharmacol 376(3):145–155CrossRefGoogle Scholar
  19. 19.
    Ghatta S, Nimmagadda D, Xu X, O'Rourke S (2006) Large-conductance, calcium-activated potassium channels: structural and functional implications. Pharmacol Ther 110(1):103–116PubMedCrossRefGoogle Scholar
  20. 20.
    Gribkoff VK, Starrett JE, Dworetzky SI (2001) Maxi-K potassium channels: form, function, and modulation of a class of endogenous regulators of intracellular calcium. Neuroscientist 7(2):166–177PubMedCrossRefGoogle Scholar
  21. 21.
    Gu N, Vervaeke K, Storm J (2007) BK potassium channels facilitate high-frequency firing and cause early spike frequency adaptation in rat CA1 hippocampal pyramidal cells. J Physiol 580(Pt.3):859–882PubMedCrossRefGoogle Scholar
  22. 22.
    Guyon A, Vergnes M, Leresche N (1993) Thalamic low threshold calcium current in a genetic model of absence epilepsy. NeuroReport 4(11):1231–1234PubMedCrossRefGoogle Scholar
  23. 23.
    Hall S, Armstrong D (2000) Conditional and unconditional inhibition of calcium-activated potassium channels by reversible protein phosphorylation. J Biol Chem 275(6):3749–3754PubMedCrossRefGoogle Scholar
  24. 24.
    Hines M, Carnevale N (1997) The NEURON simulation environment. Neural Comput 9(6):1179–1209PubMedCrossRefGoogle Scholar
  25. 25.
    Houweling A, Sejnowski T (1997) MyFirstNeuron. Oxford University Press, New YorkGoogle Scholar
  26. 26.
    Huguenard J, Prince D (1991) Slow inactivation of a TEA-sensitive K current in acutely isolated rat thalamic relay neurons. J Neurophysiol 66(4):1316–1328PubMedGoogle Scholar
  27. 27.
    Inoue M, Peeters B, van Luijtelaar E, Vossen J, Coenen A (1990) Spontaneous occurrence of spike-wave discharges in five inbred strains of rats. Physiol Behav 48(1):199–201PubMedCrossRefGoogle Scholar
  28. 28.
    Kanyshkova T, Meuth P, Bista P, Liu Z, Ehling P, Caputi L, Doengi M, Chetkovich D, Pape H-C, Budde T (2012) Differential regulation of HCN channel isoform expression in thalamic neurons of epileptic and non-epileptic rat strains. Neurobiol Dis 45(1):450–461. doi: 10.1016/j.nbd.2011.08.032 PubMedCrossRefGoogle Scholar
  29. 29.
    Khan R, Smith S, Morrison J, Ashford M (1993) Properties of large-conductance K+ channels in human myometrium during pregnancy and labour. Proc Biol Sci R Soc 251(1330):9–15CrossRefGoogle Scholar
  30. 30.
    Kuisle M, Wanaverbecq N, Brewster A, Frère S, Pinault D, Baram T, Lüthi A (2006) Functional stabilization of weakened thalamic pacemaker channel regulation in rat absence epilepsy. J Physiol 575(Pt 1):83–100PubMedCrossRefGoogle Scholar
  31. 31.
    Leresche N, Parri H, Erdemli G, Guyon A, Turner J, Williams S, Asprodini E, Crunelli V (1998) On the action of the anti-absence drug ethosuximide in the rat and cat thalamus. J Neurosci: Off J Soc Neurosci 18(13):4842–4853Google Scholar
  32. 32.
    MacDonald S, Ruth P, Knaus H-G, Shipston M (2006) Increased large conductance calcium-activated potassium (BK) channel expression accompanied by STREX variant downregulation in the developing mouse CNS. BMC Dev Biol 6:37PubMedCrossRefGoogle Scholar
  33. 33.
    Mahmoud S, McCobb D (2004) Regulation of Slo potassium channel alternative splicing in the pituitary by gonadal testosterone. J Neuroendocrinol 16(3):237–243PubMedCrossRefGoogle Scholar
  34. 34.
    McCormick D (1992) Neurotransmitter actions in the thalamus and cerebral cortex and their role in neuromodulation of thalamocortical activity. Prog Neurobiol 39(4):337–388PubMedCrossRefGoogle Scholar
  35. 35.
    McCormick D, Huguenard J (1992) A model of the electrophysiological properties of thalamocortical relay neurons. J Neurophysiol 68(4):1384–1400PubMedGoogle Scholar
  36. 36.
    McCormick D, Pape H (1990) Properties of a hyperpolarization-activated cation current and its role in rhythmic oscillation in thalamic relay neurones. J Physiol 431:291–318PubMedGoogle Scholar
  37. 37.
    McCrea K, Hill S (1993) Salmeterol, a long-acting beta 2-adrenoceptor agonist mediating cyclic AMP accumulation in a neuronal cell line. Br J Pharmacol 110(2):619–626PubMedCrossRefGoogle Scholar
  38. 38.
    Meuth S, Budde T, Kanyshkova T, Broicher T, Munsch T, Pape H-C (2003) Contribution of TWIK-related acid-sensitive K+ channel 1 (TASK1) and TASK3 channels to the control of activity modes in thalamocortical neurons. J Neurosc Off J Soc Neurosci 23(16):6460–6469Google Scholar
  39. 39.
    Meuth S, Kanyshkova T, Meuth P, Landgraf P, Munsch T, Ludwig A, Hofmann F, Pape H-C, Budde T (2006) Membrane resting potential of thalamocortical relay neurons is shaped by the interaction among TASK3 and HCN2 channels. J Neurophysiol 96(3):1517–1529. doi: 10.1152/jn.01212.2005 PubMedCrossRefGoogle Scholar
  40. 40.
    Meuth S, Pape H-C, Budde T (2002) Modulation of Ca2+ currents in rat thalamocortical relay neurons by activity and phosphorylation. Eur J Neurosci 15(10):1603–1614. doi: 10.1046/j.1460-9568.2002.01999.x PubMedCrossRefGoogle Scholar
  41. 41.
    Pape H (1996) Queer current and pacemaker: the hyperpolarization-activated cation current in neurons. Annu Rev Physiol 58:299–327PubMedCrossRefGoogle Scholar
  42. 42.
    Rankovic V, Landgraf P, Kanyshkova T, Ehling P, Meuth S, Kreutz M, Budde T, Munsch T (2011) Modulation of calcium-dependent inactivation of L-type Ca2+ channels via β-adrenergic signaling in thalamocortical relay neurons. PLoS One 6(12). doi: 10.1371/journal.pone.0027474
  43. 43.
    Rogawski M, Löscher W (2004) The neurobiology of antiepileptic drugs. Nat Rev Neurosci 5(7):553–564PubMedCrossRefGoogle Scholar
  44. 44.
    Sanchez M, McManus O (1996) Paxilline inhibition of the alpha-subunit of the high-conductance calcium-activated potassium channel. Neuropharmacology 35(7):963–968PubMedCrossRefGoogle Scholar
  45. 45.
    Saucerman J, McCulloch A (2006) Cardiac beta-adrenergic signaling: from subcellular microdomains to heart failure. Ann N Y Acad Sci 1080:348–361. doi: 10.1196/annals.1380.026 PubMedCrossRefGoogle Scholar
  46. 46.
    Schridde U, Strauss U, Bräuer A, van Luijtelaar G (2006) Environmental manipulations early in development alter seizure activity, Ih and HCN1 protein expression later in life. Eur J Neurosci 23(12):3346–3358PubMedCrossRefGoogle Scholar
  47. 47.
    Schubert R, Nelson M (2001) Protein kinases: tuners of the BKCa channel in smooth muscle. Trends Pharmacol Sci 22(10):505–512PubMedCrossRefGoogle Scholar
  48. 48.
    Shao L, Halvorsrud R, Borg-Graham L, Storm J (1999) The role of BK-type Ca2+-dependent K+ channels in spike broadening during repetitive firing in rat hippocampal pyramidal cells. J Physiol 521(Pt 1):135–146PubMedCrossRefGoogle Scholar
  49. 49.
    Sherman S, Guillery R (2006) Exploring the thalamus and its role in cortical function, 2nd edn. MIT, CambridgeGoogle Scholar
  50. 50.
    Shipston M, Armstrong D (1996) Activation of protein kinase C inhibits calcium-activated potassium channels in rat pituitary tumour cells. J Physiol 493(Pt 3):665–672PubMedGoogle Scholar
  51. 51.
    Staak R, Pape H (2001) Contribution of GABA(A) and GABA(B) receptors to thalamic neuronal activity during spontaneous absence seizures in rats. J Neurosci Off J Soc Neurosci 21(4):1378–1384Google Scholar
  52. 52.
    Steriade M (1997) Synchronized activities of coupled oscillators in the cerebral cortex and thalamus at different levels of vigilance. Cereb Cortex (NY 1991) 7(6):583–604CrossRefGoogle Scholar
  53. 53.
    Steriade M, Llinás R (1988) The functional states of the thalamus and the associated neuronal interplay. Physiol Rev 68(3):649–742PubMedGoogle Scholar
  54. 54.
    Tian L, Coghill L, McClafferty H, MacDonald S, Antoni F, Ruth P, Knaus H-G, Shipston M (2004) Distinct stoichiometry of BKCa channel tetramer phosphorylation specifies channel activation and inhibition by cAMP-dependent protein kinase. Proc Natl Acad Sci U S A 101(32):11897–11902PubMedCrossRefGoogle Scholar
  55. 55.
    Tian L, Duncan R, Hammond M, Coghill L, Wen H, Rusinova R, Clark A, Levitan I, Shipston M (2001) Alternative splicing switches potassium channel sensitivity to protein phosphorylation. J Biol Chem 276(11):7717–7720PubMedCrossRefGoogle Scholar
  56. 56.
    Tóth T, Crunelli V (1997) Simulation of intermittent action potential firing in thalamocortical neurons. Neuroreport 8(13):2889–2892PubMedCrossRefGoogle Scholar
  57. 57.
    Tseng-Crank J, Foster C, Krause J, Mertz R, Godinot N, DiChiara T, Reinhart P (1994) Cloning, expression, and distribution of functionally distinct Ca(2+)-activated K+ channel isoforms from human brain. Neuron 13(6):1315–1330PubMedCrossRefGoogle Scholar
  58. 58.
    Yan J, Olsen J, Park K-S, Li W, Bildl W, Schulte U, Aldrich R, Fakler B, Trimmer J (2008) Profiling the phospho-status of the BKCa channel alpha subunit in rat brain reveals unexpected patterns and complexity. Mol Cell Proteomics 7(11):2188–2198PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  • Petra Ehling
    • 1
    • 2
    • 3
    • 4
    Email author
  • Manuela Cerina
    • 1
    • 2
    • 3
    • 4
  • Patrick Meuth
    • 1
    • 3
    • 4
  • Tatyana Kanyshkova
    • 1
  • Pawan Bista
    • 1
    • 2
  • Philippe Coulon
    • 1
  • Sven G. Meuth
    • 3
    • 4
  • Hans-Christian Pape
    • 1
  • Thomas Budde
    • 1
  1. 1.Institute of Physiology IUniversity of MünsterMünsterGermany
  2. 2.Otto Creutzfeldt Center for Cognitive and Behavioral NeuroscienceUniversity of MünsterMünsterGermany
  3. 3.Neurology Clinic—Inflammatory Disorders of the Nervous System and NeurooncologyUniversity of MünsterMünsterGermany
  4. 4.Institute of Physiology I, NeuropathophysiologyWestfälische Wilhelms-UniversityMünsterGermany

Personalised recommendations