Advertisement

Inhibition of the K+ conductance and Cole-Moore shift of the oncogenic Kv10.1 channel by amiodarone

  • C. Barriga-Montoya
  • A. Huanosta-Gutiérrez
  • A. Reyes-Vaca
  • A. Hernández-Cruz
  • A. Picones
  • F. Gómez-LagunasEmail author
Ion channels, receptors and transporters
Part of the following topical collections:
  1. Ion channels, receptors and transporters

Abstract

The ectopic overexpression of the voltage-dependent Eag1 (Kv10.1) K+ channel is associated with the cancerous phenotype in about 70% of human cancers and tumor cell lines. Recent reports showed that, compared with the canonical Shaker-related Kv family, Kv10.1 presents unique structural and functional properties. Herein, we report the interaction of the class III anti-arrhythmic compound amiodarone with Kv10.1. Using whole-cell patch clamp, we found that amiodarone inhibits Kv10.1 channel conductance with nanomolar affinity. Additionally, and interestingly, we also report that amiodarone inhibits the characteristic Cole-Moore shift of Eag1 channels. Our observations are interpreted considering the structural-functional characteristics of these channels. We conclude that amiodarone possibly binds with high affinity to the voltage sensor module, altering the gating of Kv10.1.

Keywords

Eag channels Kv10.1 Cole-Moore shift Amiodarone Pharmacology Cancer 

Notes

Acknowledgements

The authors thank Dr. Daniel Balleza for his participation in the initial phase of this work and to Mrs. Josefina Bolado of the School of Medicine, UNAM, for reviewing the English language of the manuscript.

Authors’ contributions

CBM, AHG ARV, AHC, and AP made experiments and contributed to the analysis of results; FGL designed the work, made experiments, analyzed results and wrote the article.

Funding information

This research was supported by PAPIIT grants IN22461-RN22461 and IN219918 grants from CONACyT Laboratorios Nacionales Consolidaci461-RN224616, for reviewin05 and 153504, and PAPIIT IN211616 and IN220916. AHG is a DGAPA-UNAM postdoctoral fellow.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.

Supplementary material

424_2017_2092_FIG9_ESM.gif (124 kb)
Supplementary Figure 1

A test for inactivation of control, unmodified, Kv10.1 channels. Non-inactivated current fraction vs. pre-pulse voltage (H616, for revi3 independent experiments carried out with non-modified, control, Kv10.1 channels. I K was evoked by a constant + 50 mV/0.1 s pulse following 1-s pre pulses from −140 to +50 mV, applied in 10 mV increments, as indicated. The non-inactivated fraction was obtained as I K(+50 mV)/I K,max, as a function of pre-pulse potential. See that at any voltage, I K drops less than 10% (for some voltages current drop is even less than 5%). Pair of pulses were applied every 20 sec. (GIF 124 kb)

424_2017_2092_MOESM1_ESM.tif (8.3 mb)
High resolution (TIFF 8498 kb)

References

  1. 1.
    Armstrong CM (1971) Interaction of tetraethylammonium ion derivatives with the potassium channels of giant axons. J Gen Physiol 58(4):413–437.  https://doi.org/10.1085/jgp.58.4.413 CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Balser JR, Bennett PB, Hondeghem LM, Roden DM (1991) Suppression of time-dependent outward current in guinea pig ventricular myocytes. Actions of quinidine amiodarone. Circ Res, 69(2):519–529Google Scholar
  3. 3.
    Bauer CK, Schwarz JR (2001) Physiology of EAG K+ channels. J Membrane Biol 182:1–15Google Scholar
  4. 4.
    Cole KS, Moore JW (1960) Potassium ion current in the squid giant axon: dynamic characteristics. Biophys J 1(1):1–14.  https://doi.org/10.1016/S0006-3495(60)86871-3 CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Cornish-Bowden A (2014) Fundamentals of enzyme kinetics. Fourth edition. Wiley-BlackwellGoogle Scholar
  6. 6.
    Downie BR, Sánchez A, Knötgen H, Contreras-Jurado C, Gymnopoulos M, Weber C, Stühmer W, Pardo LA (2008) Eag1 expression interferes with hypoxia homeostasis and induces angiogenesis in tumors. J Biol Chem 283(52):36234–36240.  https://doi.org/10.1074/jbc.M801830200 CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Doyle DA, Morais Cabral J, Pfuetzner RA, Kuo A, Gulbis JM, Cohen SL, Chait BT, MacKinnon R (1998) The structure of the potassium channel: molecular basis of K+ conduction and selectivity. Science 280(5360):69–77.  https://doi.org/10.1126/science.280.5360.69 CrossRefPubMedGoogle Scholar
  8. 8.
    Gagnon DG, Bezanilla F (2009) A single charged voltage sensor is capable of gating the Shaker K+ channel. J Gen Physiol 133(5):467–483.  https://doi.org/10.1085/jgp.200810082 CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Garg V, Sachse FB, Sanguinetti MC (2012) Tunning of EAG K+ channel inactivation: molecular determinants of amplification by mutations and small molecules. J Gen Physiol 140:307–324CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Gómez-Lagunas F, Carrillo E, Pardo LA, Stühmer W (2017) Gating modulation of the tumor-related Kv10.1 channel by Mibefradil. J Cell Physiol 232(8):2019–2032.  https://doi.org/10.1002/jcp.25448 CrossRefPubMedGoogle Scholar
  11. 11.
    Gómez-Lagunas F, Barriga-Montoya C (2017) Mibefradil inhibition of the Cole-Moore shift and K+-conductance of the tumor-related Kv10.1 channel. Channels (Austin) 26:1–4Google Scholar
  12. 12.
    Hegle AP, Marble DD, Wilson GF (2006) A voltage-driven switch for ion-independent signaling by ether-a-go-go K+ channels. Proc Natl Acad Sci U S A 103(8):2886–2891.  https://doi.org/10.1073/pnas.0505909103 CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Holmgren M, Smith PL, Yellen G (1997) Trapping of organic blockers by closing of voltage-dependent K+ channels. Evidence for a trap door mechanism of activation kinetics. J Gen Physiol 109:527–535CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Hoshi T, Armstrong CM (2015) The Cole-Moore shift still unexplained?. Biophys J 109:1312–1316, 7, DOI:  https://doi.org/10.1016/j.bpj.2015.07.052
  15. 15.
    Ju M, Wray D (2006) Molecular regions responsible for differences in activation between heag channels. Biochem Biophys Res Commun 342(4):1088–1097.  https://doi.org/10.1016/j.bbrc.2006.02.062 CrossRefPubMedGoogle Scholar
  16. 16.
    Kamiya K, Atsushi N, Yasui K, Hojo M, Sanguinetti MC, Kodama I (2001) Short- and long-term effects of amiodarone on the two components of cardiac delayed rectifier K+ current. Circulation 103(9):1317–1324.  https://doi.org/10.1161/01.CIR.103.9.1317 CrossRefPubMedGoogle Scholar
  17. 17.
    Kodama I, Kamiya K, Toyama J (1997) Cellular electropharmacology of amiodarone. Cardiovasc Res 35:13–29, 1, DOI:  https://doi.org/10.1016/S0008-6363(97)00114-4
  18. 18.
    Long SB, Campbell EB, MacKinnon R (2005) Crystal structure of a mammalian voltage-dependent Shaker family K+ channel. Science 309:897–903, 5736, DOI:  https://doi.org/10.1126/science.1116269
  19. 19.
    Loewe A, Lutz Y, Wilhelms M, Sinnecker D, Barthel P, Scholz EP, Dössel O, Schmidt G, Seemann G (2014) In silico assessment of the dynamic effects of amiodarone and dronedarone on human atrial patho-electrophysiology. Europace 16:iv30–iv38CrossRefPubMedGoogle Scholar
  20. 20.
    Lörinczi É, Gómez-Posada JC, de la Peña P, Tomczak AP, Fernández-Trillo J, Leipscher U, Stühmer W, Barros F, Pardo LA (2015) Voltage-dependent gating of KCNH potassium channels lacking a covalent link between voltage-sensing and pore domains. Nat Commun 6:6672.  https://doi.org/10.1038/ncomms7672 CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Morais Cabral JH, Lee A, Cohen SL, Chait BT, Li M, MacKinnon R (1998) Crystal structure and functional analysis of the HERG potassium channel N terminus: a eukaryotic PAS domain. Cell 95(5):649–655.  https://doi.org/10.1016/S0092-8674(00)81635-9 CrossRefPubMedGoogle Scholar
  22. 22.
    Occhiodoro T, Bernheim L, Liu JH, Bijlenga P, Sinnreich M, Bader CR, Fischer-Lougheed J (1998) Cloning of a human ether-à-go-go potassium channel expressed in myoblasts at the onset of fusion. FEBS Lett 434:177–182, 1-2, DOI:  https://doi.org/10.1016/S0014-5793(98)00973-9
  23. 23.
    Ouadid-Ahidouch H, Ahidouch A, Pardo LA (2016) Kv10.1 K+ channel: from physiology to cancer. Pflugers Arch-Eur J Physiol 468:751–762Google Scholar
  24. 24.
    L A Pardo, D del Camino, A Sánchez, F Alves, A Brüggemann, S Beckh, and W Stühmer (1999) Oncogenic potential of EAG channels. EMBO J 18:5540–5547, 20, DOI:  https://doi.org/10.1093/emboj/18.20.5540
  25. 25.
    Pardo L. A., Stühmer W. (2014) The role of K+ channels in cancer. Nat Rev Cancer 14:39–48, 1, DOI:  https://doi.org/10.1038/nrc3635
  26. 26.
    Peña A, Calahorra C, Michel B, Ramírez J, Sánchez NS (2009) Effects of amiodarone on K+, inaternal pH and Ca2+ homeostasis in Saccharomyces cerevisiae. FEMS Yeast Res 9(6):832–848.  https://doi.org/10.1111/j.1567-1364.2009.00538.x CrossRefPubMedGoogle Scholar
  27. 27.
    Sato T, Takizawa T, Saito T, Kobayashi S, Hara Y, Nakaya H (2003) Amiodarone inhibits sarcolemmal but not mitochondrial KATP channels in guinea pig ventricular cells. J Pharmacol Exp Ther 307(3):955–960.  https://doi.org/10.1124/jpet.103.055863 CrossRefPubMedGoogle Scholar
  28. 28.
    Schönherr R, Mannuzzu L, Isacoff EY, Heinemann S (2002) Conformational switch between slow and fast gating modes: allosteric regulation of voltage sensor movility in the eag K+ channel. Neuron 35(935–949):5.  https://doi.org/10.1016/S0896-6273(02)00869-3 Google Scholar
  29. 29.
    Silverman WR, Roux B, Papazian DM (2003) Structural basis of two-stage voltage-dependent activation in K+ channels. Proc Natl Acad Sci U S A 100(5):2935–2940.  https://doi.org/10.1073/pnas.0636603100 CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Tamargo J, Caballero R, Gómez R, Valenzuela C, Delpón E (2004) Pharmacology of cardiac potassium channels. Cardiovasc Res 62:9–33, 1, DOI:  https://doi.org/10.1016/j.cardiores.2003.12.026
  31. 31.
    Tang CY, Bezanilla F, Papazian DM (2000) Extracellular Mg2+ modulates slow gating transitions and the opening of ether-a-go-go potassium channels. J Gen Physiol 115(3):319–337.  https://doi.org/10.1085/jgp.115.3.319 CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Terlau H, Ludwig J, Steffan R, Pongs O, Stngsan W, Heinemann SH (1996) Extracellular Mg2+ regulates activation of rat eag potassium channel. Pflugers Arch 432(2):301–312.  https://doi.org/10.1007/s004240050137 CrossRefPubMedGoogle Scholar
  33. 33.
    Terlau H, Heinemann S, Stuhmer W, Pongs O, Ludwig J (1997) Amino terminal-dependent gating of the potassium channel rat eag is compensated by a mutation in the S4-segment. J Physiol 502(3):537–543.  https://doi.org/10.1111/j.1469-7793.1997.537bj.x CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Ting-Feng L, Guey-Mei J, Hsin-Yu F, Ssu-Ju F, Hao-Han W, Mei-Miao C, Chung-Jiuan J (2014) The Eag domain regulates the voltage-dependent inactivation of rat Eag1 K+ channels. PLoS One 9:e110423CrossRefGoogle Scholar
  35. 35.
    Tomczak A, Fernández-Trillo J, Bharill S, Papp F, Panyi G, Stühmer W, Isacoff EY, Pardo AL (2017) A new mechanism of voltage-dependent gating exposed by Kv10.1 channels interrupted between voltage sensor and pore. J Gen Physiol 30:577–593CrossRefGoogle Scholar
  36. 36.
    Turker I, Yu C-C, Chang P-C, Chen Z, Sohma Y, Lin S-F, Chen PS, Ai T (2013) Amiodarone inhibits apamin-sensitive potassium currents. PLoS One 8(7):e70450.  https://doi.org/10.1371/journal.pone.0070450 CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Waldhauser KM, Brecht K, Hebeisen S, Ha HR, Konrad D, Bur D, Krrradener S (2008) Interaction with the hERG channel and cytotoxicity of amiodarone and amiodarone analogs. Br J Pharmacol 155:585–595CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    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 91:3438–3442, 8, DOI:  https://doi.org/10.1073/pnas.91.8.3438
  39. 39.
    Wei A, Jegla T, Salkoff L (1996) Eight potassium channel families revealed by the C. elegans genome proyect. Neuropharmacology 35(7):805–829.  https://doi.org/10.1016/0028-3908(96)00126-8 CrossRefPubMedGoogle Scholar
  40. 40.
    Whicher J, MacKinnon R (2016) Structure of the voltage-gated K+ channel Eag1 reveals an alternative voltage sensing mechanism. Science 353(6300):664–669.  https://doi.org/10.1126/science.aaf8070 CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Wu L, Rajamani S, Shryock JC, Li H, Ruskin J, Antzelevitch C, Belardinelli L (2008) Augmentation of late sodium current unmasks the proarrythmic effects of amiodarone. Cardiovasc Res. 77:481–488CrossRefPubMedGoogle Scholar
  42. 42.
    Yang M, Brackenbury WJ (2013) Membrane potential and cancer progression. Front Physiol 4,185, DOI:  https://doi.org/10.3389/fphys.2013.00185
  43. 43.
    Zagotta WN, Hoshi T, Aldrich RW (1994) Shaker potassium channel gating III. Evaluation of kinetic models for activation. J Gen Physiol 103:321–362CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2017

Authors and Affiliations

  • C. Barriga-Montoya
    • 1
  • A. Huanosta-Gutiérrez
    • 1
  • A. Reyes-Vaca
    • 1
  • A. Hernández-Cruz
    • 2
  • A. Picones
    • 2
  • F. Gómez-Lagunas
    • 1
    Email author
  1. 1.School of MedicineNational Autonomous University of Mexico (UNAM)MexicoMexico
  2. 2.National Laboratory of Channelopathies, Institute of Cellular PhysiologyUNAMMexicoMexico

Personalised recommendations