Skip to main content
SpringerLink
Log in

Voltage-independent KCNQ4 currents induced by (±)BMS-204352

  • Ion Cannels, Transporters
  • Published:
Pflügers Archiv Aims and scope Submit manuscript

Abstract

The compound BMS-204352 has been targeted for use against acute ischemic stroke, due to its activation of the large-conductance Ca2+-activated K-channel (BK). We have previously described that the racemate (±)BMS-204352 reversibly modulates KCNQ4 voltage dependency. Here we show that (±)BMS-204352 also induces a voltage-independent KCNQ4 current. The channels were stably expressed in human embryonic kidney cells (HEK293), and investigated by use of the whole-cell mode of the patch-clamp technique. (±)BMS-204352 was applied extracellularly (10 μM) in order to precipitate the robust appearance of the voltage-independent current. The voltage-independent KCNQ4 currents were recorded as instantaneous increases in currents upon hyperpolarizing or depolarizing voltage steps elicited from holding potentials of –90 or −110 mV. The voltage-independent current reversed at the equilibrium potential for potassium (E K), hence was carried by a K+ conductance, and was blocked by the selective KCNQ channel blockers XE991 and linopirdine. Similar results were obtained with KCNQ4 channels transiently transfected into Chinese hamster ovary cells (CHO). When (±)BMS-204352 was applied to stably expressed BK channels, only the voltage dependency was modulated. Retigabine, the classic activator of KCNQ channels, did not induce voltage-independent currents. Our data indicate that KCNQ4 channels may conduct voltage-dependent and voltage-independent currents in the presence of (±)BMS-204352.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1.
Fig. 2.
Fig. 3.
Fig. 4.
Fig. 5.
Fig. 6.

Similar content being viewed by others

References

  1. Abbott GW, Sesti F, Splawski I, Buck ME, Lehman MH, Timothy KW, Keating MT, Goldstein SA (1999) MiRP1 forms IKr potassium channels with HERG and is associated with cardiac arrythmia. Cell 97:175–187

    CAS  PubMed  Google Scholar 

  2. Adams PR, Brown DA, Constanti A (1982) Pharmacological inhibition of the M-current. J Physiol (Lond) 332:223–262

  3. Ahring PK, Strøbaek D, Christophersen P, Olesen S-P, Johansen TE (1997) Stable expression of the human large-conductance Ca2+-activated K+ channel α- and β-subunits in HEK293 cells. FEBS Lett 415:67–70

    CAS  PubMed  Google Scholar 

  4. Barhanin J, Lesage F, Guillemare E, Fink M, Lazdunski M, Romey G (1996) KvLQT1 and IsK (minK) proteins associate to form the Iks cardiac potassium current. Nature 384:78–80

    Google Scholar 

  5. Bievert C, Schroeder BC, Kubisch C, Berkovic SF, Propping P, Jentsch TJ, Steinlein OK (1998) A potassium channel mutation in neonatal human epilepsy. Science 279:403–406

    CAS  PubMed  Google Scholar 

  6. Bockenhauer D, Zilberberg N, Goldstein SAN (2001) KCNK2: reversible conversion of a hippocampal potassium leak into a voltage-dependent channel. Nat Neurosci 4:486–491

    CAS  PubMed  Google Scholar 

  7. Brown BS, Yu SP (2000) Modulation and genetic identification of the M channel. Prog Biophys Mol Biol 73:135–166

    CAS  PubMed  Google Scholar 

  8. Brown DA, Adams P (1980) Muscarinic suppression of a novel voltage-sensitive K+ current in a vertebrate neurons. Nature 283:673–676

    Google Scholar 

  9. Catacuzzeno L, Trequattrini C, Petris A, Franciolini F (1999) Bimodal kinetics of a chloride channel form human fibroblasts. J Membr Biol 170:165–172

    CAS  PubMed  Google Scholar 

  10. Charlier C, Singh NA, Ryan SG, Lewis TB, Reus BE, Leach RJ, Leppert M (1998) A pore mutation in a novel KQT-like potassium channel gene in an idiopathic epilepsy family. Nat Genet 18:53–55

    CAS  PubMed  Google Scholar 

  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 80:795–803

    CAS  PubMed  Google Scholar 

  12. Dedek K, Kunath B, Kananura C, Reuner U, Jentsch TJ, Steinlein OK (2001) Myokymia and neonatal epilepsy caused by a mutation in the voltage sensor of the KCNQ2 K+ channel. Proc Natl Acad Sci USA 98:12272–12277

    CAS  PubMed  Google Scholar 

  13. Dreyer I, Michard E, Lacombe B, Thibaud JB (2001) A plant Shaker-like K+ channel switches between two distinct gating modes resulting in either inward-rectifying or "leak" current. FEBS Lett 505:233–239

    CAS  PubMed  Google Scholar 

  14. Dupuis DS, Schrøder RL, Jespersen T, Christensen JK, Christophersen P, Jensen BS, Olesen S-P (2002) Activation of KCNQ5 channels stably expressed in HEK293 cells by BMS-204352. Eur J Pharmacol 437:129–137

    Article  CAS  PubMed  Google Scholar 

  15. Gribkoff VK (2002) Neuroprotection and Maxi-K potassium channels. Presented at the "I-th International Conference on ion channels in drug discovery and development, 20–21 May 2000, New Jersey. Strategic Research Institutehttp://www.srinstitute.com/part_iter_site_page.cfm?pg=agenda/detailed_agenda.cfm&iteration_id=369

  16. Gribkoff VK, Starrett JE Jr, Hewawasam P, Kinney GG, Dworetzkey SI, Boissard CG, Post-Munson DJ, Trojnacki TJ, Huston K, Signor LJ, Lombardo LA, Hibbard JR, Reid SA, Myers RA, Ortiz A, Moon SL, Taber M, Krihnan BS, Yeola SW (2001) Targeting acute focal stroke with an opener of maxi-K potassium channels: BMS-204352. Nat Med 7:471–477

    CAS  PubMed  Google Scholar 

  17. Kharkovets T, Hardelin J-P, Safieddine S, Schweizer M, El-Amraoui A, Petit C, Jentsch TJ (1999) KCNQ4, a K+ channel mutated in a form of dominant deafness, is expressed in the inner ear and the central auditory pathway. Proc Natl Acad Sci USA 97:4333–4338

    Article  Google Scholar 

  18. Knaus H-G, McManus OB, Lee SH, Schmalhofer WA, Garcia-Calvo M, Helms LMH, Sanchez M, Giangiacomo K, Reuben JP, Smith AB, Kaczororowski GJ, Garcia ML (1994) Tremorgenic indole alkaloids potently inhibit smooth muscle high-conductance calcium activated potassium channels. Biochemistry 33:5819–5828

    CAS  PubMed  Google Scholar 

  19. Kubisch C, Schroeder BC, Friedrich T, Lütjohann B, El-Amraoui A, Marlin S, Petit C, Jentsch TJ (1999) KCNQ4, a novel potassium channel expressed in sensory outer hair cells, is mutated in dominant deafness. Cell 96:437–446

    CAS  PubMed  Google Scholar 

  20. Lerche C, Scherer CR, Seebohm G, Derst C, Wei AD, Busch AE, Steinmeyer K (2000) Molecular cloning and functional expression of KCNQ5, a potassium channel subunit that may contribute to neuronal M-current diversity. J Biol Chem 275:22395–22400

    CAS  PubMed  Google Scholar 

  21. Reference deleted

  22. Main MJ, Cryan JE, Dupere JRB, Cox B, Clare JJ, Burbridge SA (2000) Modulation of KCNQ2/3 potassium channels by the novel anticonvulsant retigabine. Mol Pharmacol 58:253–262

    CAS  PubMed  Google Scholar 

  23. Marcotti M, Kros CJ (1999) Developmental expression of the potassium current IK,n contributes to maturation of mouse outer hair cells. J Physiol (Lond) 520:653–660

  24. Marrion NV (1997) Control of M-current. Annu Rev Physiol 59:483–504

    CAS  PubMed  Google Scholar 

  25. Neyroud N, Tesson F, Denjoy I, Leibovici M, Donger C, Barhanin J, Faure S, Gary F, Coumel P, Petit C, Schwartz K, Guicheney P (1997) A novel mutation in the potassium channel gene KVLQT1 causes the Jervell and Lange-Nielsen cardioauditory syndrome. Nat Genet 15:186–189

    CAS  PubMed  Google Scholar 

  26. Proenza C, Angoli D, Agronaovich E, Macri V, Accili EA (2002) Pacemaker channels produce an instantaneous current. J Biol Chem 277:5101–5109

    CAS  PubMed  Google Scholar 

  27. Sakagami M, Fukazawa K, Matsunaga T, Fujita H, Mori N, Takumi T, Ohkubo H, Nakanishi S (1991) Cellular localization of rat Isk protein in the stria vascularis by immunohistochemical observation. Hear Res 56:168–72

    CAS  PubMed  Google Scholar 

  28. Sanguinetti MC, Curran ME, Zou A, Shen J, Spector PS, Atkinson DL, Keating MT (1996) Coassembly of KVLQT1 and mink (IsK) proteins to form cardiac IKs potassium channel. Nature 384:80–83

    Google Scholar 

  29. Schmitt N, Schwarz M, Peretz A, Abitbol I, Attali B, Pongs O (2000) A recessive C-terminal Jervell and Lange-Nielsen mutation of the KCNQ1 channel impairs subunit assembly. EMBO J 19:332–340

    Google Scholar 

  30. Schrøder RL, Jespersen T, Christophersen P, Strøbaek D, Jensen BS, Olesen S-P (2001) KCNQ4 channel activation by BMS-204352 and retigabine. Neuropharmacology 40:888–898

    Google Scholar 

  31. Schroeder BC, Hechenberger M, Weinreich F, Kubisch C, Jentsch T (2000) KCNQ5, a novel potassium channel broadly expressed in brain mediates M-type currents. J Biol Chem 275:24089–24095

    CAS  PubMed  Google Scholar 

  32. Schroeder BC, Waldegger S, Fehr S, Bleich M, Warth R, Greger R, Jentsch TJ (2000) A constitutively open potassium channel formed by KCNQ1 and KCNE3. Nature 403:196–199

    CAS  PubMed  Google Scholar 

  33. Selyanko AA, Hadley JK, Wood IC, Abogadie FC, Delmas P, Buckley NJ, London B, Brown DA (1999) Two types of K+ channel subunits, Erg1 and KCNQ2/3, contribute to the M-like current in a mammalian neuronal cell. J Neurosci 19:7742–7756

    Google Scholar 

  34. Singh NA, Charlier C, Stauffer D, DuPont BR, Leach RJ, Melis R, Ronen GM, Bjerre I, Quattlebaum T, Murphy JV, McHarg ML, Gagnon D, Rosales TO, Peiffer A, Anderson VE, Leppert M. (1998) A novel potassium channel gene, KCNQ2, is mutated in an inherited epilepsy of newborns. Nat Genet 18:25–29

    CAS  PubMed  Google Scholar 

  35. Søgaard R, Ljungstrøm T, Pedersen KA, Olesen S-P, Jensen BS (2000) KCNQ4 channels expressed in mammalian cells: Functional characteristics and pharmacology. Am J Physiol 280:C859–C866

    Google Scholar 

  36. Tatulian L, Delmas P, Abogadie FC, Brown DA (2001) Activation of expressed KCNQ potassium currents and native neuronal M-type potassium currents by the anti-convulsant drug retigabine. J Neurosci 21:5535–5545

    CAS  PubMed  Google Scholar 

  37. Tinel N, Lauritzen I, Chouabe C, Lazdunski M, Borsotto M (1998) The KCNQ2 potassium channel: splice variants, functional and developmental expression. Brain localization and comparison with KCNQ3. FEBS Lett 438:171–176

    CAS  PubMed  Google Scholar 

  38. Tinel N, Diochot S, Borsotto M, Lazdunski M, Barhanin J (2000) KCNE2 confers background current characteristics to the cardiac KCNQ1 potassium channel. EMBO J 19:6326–6330

    Google Scholar 

  39. Wang H-S, Pan Z, Shi W, Brown BS, Wymore RS, Cohen IS, Dixon JE, McKinnon D (1998) KCNQ2 and KCNQ3 potassium channel subunits: Molecular correlates of the M-channel. Science 282:390–393

    Article  Google Scholar 

  40. Wang Q, Shen J, Splawski I, Atkinson D, Li Z, Robinson JL, Moss AJ, Towbin JA, Keating MT (1995) SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome. Cell 80:805–811

    CAS  PubMed  Google Scholar 

  41. Wang Q, Curran ME, Splawski I, Burns TC, Millholland JM, VanRaay TJ, Shen J, Timothy KW, Vincent GM, Jager TD, Schwartz PJ, Towbin JA, Moss AJ, Atkinson DL, Landes GM, Conners TD, Keating MT (1996) Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias. Nat Genet 12:17–23

    PubMed  Google Scholar 

  42. Wickenden AD, Yu W, Zou A, Jegla T, Wagoner PK (2000) Retigabine, a novel anti-convulsant, enhances activation of KCNQ2/Q3 potassium channel. Mol Pharmacol 58:591–600

    CAS  PubMed  Google Scholar 

  43. Wickenden AD, Zou A, Wagoner PK, Jegla T (2001) Characterization of KCNQ5/Q3 potassium channels expressed in mammalian cells. Br J Pharmacol 132:381–384

    CAS  PubMed  Google Scholar 

Download references

Acknowledgement

The Danish Heart Association supported the work.

Author information

Authors and Affiliations

  1. NeuroSearch A/S, 93 Pederstrupvej, DK 2750 , Ballerup, Denmark

    Rikke Louise Schrøder, Dorte Strøbaek, Søren-Peter Olesen & Palle Christophersen

  2. Ålborg University, 7 Frederik Bajers Vej, DK 9220, Ålborg East, Denmark

    Rikke Louise Schrøder

Authors
  1. Rikke Louise Schrøder
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dorte Strøbaek
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Søren-Peter Olesen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Palle Christophersen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Palle Christophersen.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Schrøder, R.L., Strøbaek, D., Olesen, SP. et al. Voltage-independent KCNQ4 currents induced by (±)BMS-204352. Pflugers Arch - Eur J Physiol 446, 607–616 (2003). https://doi.org/10.1007/s00424-003-1116-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00424-003-1116-x

Keywords

Search

Navigation