Erg K+ currents modulate excitability in mouse mitral/tufted neurons

  • Wiebke Hirdes
  • Nora Napp
  • Iris Wulfsen
  • Michaela Schweizer
  • Jürgen R. Schwarz
  • Christiane K. BauerEmail author
Ion Channels, Receptors and Transporters


Different erg (ether-à-go-go-related gene; Kv11) K+ channel subunits are expressed throughout the brain. Especially mitral cells of the olfactory bulb are stained intensely by erg1a, erg1b, erg2, and erg3 antibodies. This led us to study the erg current in mitral/tufted (M/T) neurons from mouse olfactory bulb in primary culture. M/T neurons were identified by their morphology and presence of mGluR1 receptors, and RT-PCR demonstrated the expression of all erg subunits in cultured M/T neurons. Using an elevated external K+ concentration, a relatively uniform erg current was recorded in the majority of M/T cells and isolated with the erg channel blocker E-4031. With 4-s depolarizations, the erg current started to activate at −65 mV and exhibited half maximal activation at −51 mV. An increase in the external K+ concentration resulted in an increase in erg whole-cell conductance. The specific group 1 mGluR agonist, DHPG, which depolarizes mitral cells, reduced erg channel availability. DHPG accelerated erg current deactivation, reduced the maximum current amplitude, and shifted availability and activation curves to more depolarized potentials. A pharmacological block of erg channels depolarized the resting potential of M/T cells and clearly demonstrated the involvement of erg channels in the control of mitral cell excitability.


Olfactory bulb Mitral cells HERG Kv11 mGluR1 



We thank Saskia Siegel, Barbara Merz, Telse Kock, Annett Hasse and Dr. Susanne Fehr for their help. This work was supported by the Deutsche Forschungsgemeinschaft (SFB 444, A3; SCHW 292/14-1).


  1. 1.
    Arcangeli A, Becchetti A, Mannini A, Mugnai G, De Filippi P, Tarone G, Del Bene MR, Barletta E, Wanke E, Olivotto M (1993) Integrin-mediated neurite outgrowth in neuroblastoma cells depends on the activation of potassium channels. J Cell Biol 122:1131–1143CrossRefPubMedGoogle Scholar
  2. 2.
    Barros F, Delgado LM, del Camino D, de la Peña P (1992) Characteristics and modulation by thyrotropin-releasing hormone of an inwardly rectifying K+ current in patch-perforated GH3 anterior pituitary cells. Pflugers Arch 422:31–39CrossRefPubMedGoogle Scholar
  3. 3.
    Bauer CK (1998) The erg inwardly rectifying K+ current and its modulation by thyrotrophin-releasing hormone in giant clonal rat anterior pituitary cells. J Physiol 510:63–70CrossRefPubMedGoogle Scholar
  4. 4.
    Bauer CK, Schwarz JR (2001) Physiology of EAG K+ channels. J Membr Biol 182:1–15PubMedGoogle Scholar
  5. 5.
    Bauer CK, Meyerhof W, Schwarz JR (1990) An inward-rectifying K+ current in clonal rat pituitary cells and its modulation by thyrotrophin-releasing hormone. J Physiol 429:169–189PubMedGoogle Scholar
  6. 6.
    Bauer CK, Schäfer R, Schiemann D, Reid G, Hanganu I, Schwarz JR (1999) A functional role of the erg-like inward-rectifying K+ current in prolactin secretion from rat lactotrophs. Mol Cell Endocrinol 148:37–45CrossRefPubMedGoogle Scholar
  7. 7.
    Bian JS, McDonald TV (2007) Phosphatidylinositol 4, 5-bisphosphate interactions with the HERG K+ channel. Pflugers Arch 455:105–113CrossRefPubMedGoogle Scholar
  8. 8.
    Bovolin P, Bovetti S, Fasolo A, Katarova Z, Szabo G, Shipley MT, Margolis FL, Puche AC (2009) Developmental regulation of metabotropic glutamate receptor 1 splice variants in olfactory bulb mitral cells. J Neurosci Res 87:369–379CrossRefPubMedGoogle Scholar
  9. 9.
    Chiesa N, Rosati B, Arcangeli A, Olivotto M, Wanke E (1997) A novel role for HERG K+ channels: spike-frequency adaptation. J Physiol 501:313–318CrossRefPubMedGoogle Scholar
  10. 10.
    Christie JM, Bark C, Hormuzdi SG, Helbig I, Monyer H, Westbrook GL (2005) Connexin36 mediates spike synchrony in olfactory bulb glomeruli. Neuron 46:761–772CrossRefPubMedGoogle Scholar
  11. 11.
    Curran ME, Splawski I, Timothy KW, Vincent GM, Green ED, Keating MT (1995) A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome. Cell 80:795–803CrossRefPubMedGoogle Scholar
  12. 12.
    Esclapez M, Tillakaratne NJ, Tobin AJ, Houser CR (1993) Comparative localization of mRNAs encoding two forms of glutamic acid decarboxylase with nonradioactive in situ hybridization methods. J Comp Neurol 331:339–362CrossRefPubMedGoogle Scholar
  13. 13.
    Furlan F, Guasti L, Avossa D, Becchetti A, Cilia E, Ballerini L, Arcangeli A (2005) Interneurons transiently express the ERG K+ channels during development of mouse spinal networks in vitro. Neuroscience 135:1179–1192CrossRefPubMedGoogle Scholar
  14. 14.
    Furlan F, Taccola G, Grandolfo M, Guasti L, Arcangeli A, Nistri A, Ballerini L (2007) ERG conductance expression modulates the excitability of ventral horn GABAergic interneurons that control rhythmic oscillations in the developing mouse spinal cord. J Neurosci 27:919–928CrossRefPubMedGoogle Scholar
  15. 15.
    Ganetzky B, Robertson GA, Wilson GF, Trudeau MC, Titus SA (1999) The eag family of K+ channels in Drosophila and mammals. Ann NY Acad Sci 868:356–369CrossRefPubMedGoogle Scholar
  16. 16.
    Guasti L, Cilia E, Crociani O, Hofmann G, Polvani S, Becchetti A, Wanke E, Tempia F, Arcangeli A (2005) Expression pattern of the ether-a-go-go-related (ERG) family proteins in the adult mouse central nervous system: evidence for coassembly of different subunits. J Comp Neurol 491:157–174CrossRefPubMedGoogle Scholar
  17. 17.
    Hagendorf S, Fluegge D, Engelhardt C, Spehr M (2009) Homeostatic control of sensory output in basal vomeronasal neurons: activity-dependent expression of ether-à-go-go-related gene potassium channels. J Neurosci 29:206–221CrossRefPubMedGoogle Scholar
  18. 18.
    Hayar A, Heyward PM, Heinbockel T, Shipley MT, Ennis M (2001) Direct excitation of mitral cells via activation of alpha1-noradrenergic receptors in rat olfactory bulb slices. J Neurophysiol 86:2173–2182PubMedGoogle Scholar
  19. 19.
    Heinbockel T, Heyward P, Conquet F, Ennis M (2004) Regulation of main olfactory bulb mitral cell excitability by metabotropic glutamate receptor mGluR1. J Neurophysiol 92:3085–3096CrossRefPubMedGoogle Scholar
  20. 20.
    Hirdes W, Horowitz LF, Hille B (2004) Muscarinic modulation of erg potassium current. J Physiol 559:67–84CrossRefPubMedGoogle Scholar
  21. 21.
    Hirdes W, Schweizer M, Schuricht KS, Guddat SS, Wulfsen I, Bauer CK, Schwarz JR (2005) Fast erg K+ currents in rat embryonic serotonergic neurones. J Physiol 564:33–49CrossRefPubMedGoogle Scholar
  22. 22.
    Hurley KM, Gaboyard S, Zhong M, Price SD, Wooltorton JR, Lysakowski A, Eatock RA (2006) M-like K+ currents in type I hair cells and calyx afferent endings of the developing rat utricle. J Neurosci 26:10253–10269CrossRefPubMedGoogle Scholar
  23. 23.
    Khayari A, Math F, Davrainville JL (1988) Electrical stimulation of primary olfactory nerve induces two types of variations in the extracellular potassium activity within the glomerulus of the rat olfactory bulb in vivo. Brain Res 457:188–191CrossRefPubMedGoogle Scholar
  24. 24.
    Kiehn J, Lacerda AE, Wible B, Brown AM (1996) Molecular physiology and pharmacology of HERG. Single-channel currents and block by dofetilide. Circulation 94:2572–2579PubMedGoogle Scholar
  25. 25.
    Kirchberger NM, Wulfsen I, Schwarz JR, Bauer CK (2006) Effects of TRH on heteromeric rat erg1a/erg1b K+ channels are dominated by the erg1b subunit. J Physiol 571:27–42CrossRefPubMedGoogle Scholar
  26. 26.
    Lecchi M, Redaelli E, Rosati B, Gurrola G, Florio T, Crociani O et al (2002) Isolation of a long-lasting eag-related gene-type K+ current in MMQ lactotrophs and its accommodating role during slow firing and prolactin release. J Neurosci 22:3414–3425PubMedGoogle Scholar
  27. 27.
    Monyer H, Jonas P (1995) Polymerase chain reaction analysis of ion channel expression in single neurons of brain slices. In: Sakmann B, Neher E (eds) Single-channel recording, 2nd edn. Plenum, New York, pp 357–373Google Scholar
  28. 28.
    Mugnaini E, Wouterlood FG, Dahl AL, Oertel WH (1984) Immunocytochemical identification of GABAergic neurons in the main olfactory bulb of the rat. Arch Ital Biol 122:83–113PubMedGoogle Scholar
  29. 29.
    Muramoto K, Kato M, Matsuoka M, Kuroda Y, Ichikawa M (2001) A primary culture system of rat olfactory bulb forming many synapses similar to intact ones and spontaneously generating synchronous intracellular calcium oscillations. Anat Embryol 203:9–21CrossRefPubMedGoogle Scholar
  30. 30.
    Nie L, Gratton MA, Mu KJ, Dinglasan JN, Feng W, Yamoah EN (2005) Expression and functional phenotype of mouse ERG K+ channels in the inner ear: potential role in K+ regulation in the inner ear. J Neurosci 25:8671–8679CrossRefPubMedGoogle Scholar
  31. 31.
    Ohya S, Horowitz B, Greenwood IA (2002) Functional and molecular identification of ERG channels in murine portal vein myocytes. Am J Physiol 283:C866–C877Google Scholar
  32. 32.
    Papa M, Boscia F, Canitano A, Castaldo P, Sellitti S, Annunziato L, Taglialatela M (2003) Expression pattern of the ether-a-gogo-related (ERG) K + channel-encoding genes ERG1, ERG2, and ERG3 in the adult rat central nervous system. J Comp Neurol 466:119–135CrossRefPubMedGoogle Scholar
  33. 33.
    Pessia M, Servettini I, Panichi R, Guasti L, Grassi S, Arcangeli A, Wanke E, Pettorossi VE (2008) ERG voltage-gated K+ channels regulate excitability and discharge dynamics of the medial vestibular nucleus neurones. J Physiol 586:4877–4890CrossRefPubMedGoogle Scholar
  34. 34.
    Sacco T, Bruno A, Wanke E, Tempia F (2003) Functional roles of an ERG current isolated in cerebellar Purkinje neurons. J Neurophysiol 90:1817–1828CrossRefPubMedGoogle Scholar
  35. 35.
    Saganich MJ, Machado E, Rudy B (2001) Differential expression of genes encoding subthreshold-operating voltage-gated K+ channels in brain. J Neurosci 21:4609–4624PubMedGoogle Scholar
  36. 36.
    Sahara Y, Kobuta T, Ichikawa M (2001) Cellular localization of metabotropic glutamate receptors mGluR1, 2/3, 5 and 7 in the main and accessory olfactory bulb of the rat. Neurosci Lett 312:59–62CrossRefPubMedGoogle Scholar
  37. 37.
    Sanguinetti MC, Jiang C, Curran ME, Keating MT (1995) A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the IKr potassium channel. Cell 81:299–307CrossRefPubMedGoogle Scholar
  38. 38.
    Schäfer R, Wulfsen I, Behrens S, Weinsberg F, Bauer CK, Schwarz JR (1999) The erg-like potassium current in rat lactotrophs. J Physiol 518:401–416CrossRefPubMedGoogle Scholar
  39. 39.
    Schledermann W, Wulfsen I, Schwarz JR, Bauer CK (2001) Modulation of rat erg1, erg2, erg3 and HERG K+ currents by thyrotropin-releasing hormone in anterior pituitary cells via the native signal cascade. J Physiol 532:143–163CrossRefPubMedGoogle Scholar
  40. 40.
    Schönherr R, Rosati B, Hehl S, Rao VG, Arcangeli A, Olivotto M, Heinemann SH, Wanke E (1999) Functional role of the slow activation property of ERG K+ channels. Eur J Neurosci 11:753–760CrossRefPubMedGoogle Scholar
  41. 41.
    Shi W, Wymore RS, Wang HS, Pan Z, Cohen IS, McKinnon D, Dixon JE (1997) Identification of two nervous system-specific members of the erg potassium channel gene family. Neurosci 17:9423–9432Google Scholar
  42. 42.
    Shibasaki T (1987) Conductance and kinetics of delayed rectifier potassium channels in nodal cells of the rabbit heart. J Physiol 387:227–250PubMedGoogle Scholar
  43. 43.
    Shigemoto R, Nakanishi S, Mizuno N (1992) Distribution of the mRNA for a metabotropic glutamate receptor (mGluR1) in the central nervous system: an in situ hybridization study in adult and developing rat. J Comp Neurol 322:121–135CrossRefPubMedGoogle Scholar
  44. 44.
    Spector PS, Curran ME, Keating MT, Sanguinetti MC (1996) Class III antiarrhythmic drugs block HERG, a human cardiac delayed rectifier K+ channel. Open-channel block by methanesulfonanilides. Circ Res 78:499–503PubMedGoogle Scholar
  45. 45.
    Sturm P, Wimmers S, Schwarz JR, Bauer CK (2005) Extracellular potassium effects are conserved within the rat erg K+ channel family. J Physiol 564:329–345CrossRefPubMedGoogle Scholar
  46. 46.
    Titus SA, Warmke JW, Ganetzky B (1997) The Drosophila erg K + channel polypeptide is encoded by the seizure locus. J Neurosci 17:2906–2918Google Scholar
  47. 47.
    Trombley PQ, Westbrook GL (1990) Excitatory synaptic transmission in cultures of rat olfactory bulb. J Neurophysiol 64:598–606PubMedGoogle Scholar
  48. 48.
    Van den Pol AN (1995) Presynaptic metabotropic glutamate receptors in adult and developing neurons: autoexcitation in the olfactory bulb. J Comp Neurol 359:253–271CrossRefPubMedGoogle Scholar
  49. 49.
    Walz W (2000) Role of astrocytes in the clearance of excess extracellular potassium. Neurochem Int 36:291–300CrossRefPubMedGoogle Scholar
  50. 50.
    Wang S, Liu S, Morales MJ, Strauss HC, Rasmusson RL (1997) A quantitative analysis of the activation and inactivation kinetics of HERG expressed in Xenopus oocytes. J Physiol 502:45–60CrossRefPubMedGoogle Scholar
  51. 51.
    Warmke JW, Ganetzky B (1994) A family of potassium channel genes related to eag in Drosophila and mammals. Proc Natl Acad Sci U S A 91:3438–3442CrossRefPubMedGoogle Scholar
  52. 52.
    Weinsberg F, Bauer CK, Schwarz JR (1997) The class III antiarrhythmic agent E-4031 selectively blocks the inactivating inward-rectifying potassium current in rat anterior pituitary tumor cells (GH3/B6 cells). Pflugers Arch 434:1–10CrossRefPubMedGoogle Scholar
  53. 53.
    Wimmers S, Bauer CK, Schwarz JR (2002) Biophysical properties of heteromultimeric erg K+ channels. Pflugers Arch 445:423–430CrossRefPubMedGoogle Scholar
  54. 54.
    Wimmers S, Wulfsen I, Bauer CK, Schwarz JR (2001) Erg1, erg2 and erg3 K channel subunits are able to form heteromultimers. Pflugers Arch 441:450–455CrossRefPubMedGoogle Scholar
  55. 55.
    Zhou Z, Gong Q, Ye B, Fan Z, Makielski JC, Robertson GA, January CT (1998) Properties of HERG channels stably expressed in HEK 293 cells studied at physiological temperature. Biophys J 74:230–241CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Wiebke Hirdes
    • 1
  • Nora Napp
    • 2
  • Iris Wulfsen
    • 3
  • Michaela Schweizer
    • 1
  • Jürgen R. Schwarz
    • 1
  • Christiane K. Bauer
    • 2
    Email author
  1. 1.Institut für Neurale Signalverarbeitung, ZMNHUniversitätsklinikum Hamburg-Eppendorf, Universität HamburgHamburgGermany
  2. 2.Institut für Vegetative Physiologie und Pathophysiologie, Zentrum für Experimentelle MedizinUniversitätsklinikum Hamburg-Eppendorf, Universität HamburgHamburgGermany
  3. 3.Institut für Pharmakologie für PharmazeutenUniversitätsklinikum Hamburg-Eppendorf, Universität HamburgHamburgGermany

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