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High Throughput Screening pp 187–208Cite as

Recent Advances in Electrophysiology-Based Screening Technology and the Impact upon Ion Channel Discovery Research

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Part of the book series: Methods in Molecular Biology ((MIMB,volume 565))

Abstract

Ion channels are recognised as an increasingly tractable class of targets for the discovery and development of new drugs, with a diverse range of ion channel proteins now implicated across a wide variety of disease states and potential therapeutic applications. Whilst the field now ranks as one of the most dynamic fields for drug discovery research, it has historically been regarded by many researchers as a class of proteins associated with numerous technical challenges. Recent advances in our understanding of molecular biology and the increasing acceptance of electrophysiology-based screening methodology mean that ion channels are rapidly progressing towards universal acceptance as worthy and approachable targets for drug discovery. This chapter will outline the commercially available electrophysiology-based screening technologies and give an overview of the range of options for progressing pharmaceutical research and development against this important target class.

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References

  1. Bernard, G., Shevell, M.I. (2008) Channelopathies: a review. Pediatr. Neurol. 38(2), 73–85.

    Article  Google Scholar 

  2. Hille, B. (2001) Ion Channels of Excitable Membranes. Sinauer Associates, Inc.

    Google Scholar 

  3. Clapham, D. (2006) An introduction to TRP channels. Ann. Rev. Physiol. 68, 619–647.

    Article  Google Scholar 

  4. Gosling, M., Poll, C., Li, S. (2005) TRP channels in airway smooth muscle as therapeutic targets. Nayun-Schmiedebergs Arch. Pharmacol. 371, 277–284.

    Article  CAS  Google Scholar 

  5. Xie, M., Holmqvist, M.H., Hsia, A.Y. (2004, April) Ion channel drug discovery expands into new disease areas. Curr. Drug Discov., 31–33.

    Google Scholar 

  6. Southan, A., James, I.F., Cronk, D. (2005) Ion channels new opportunities for an established target class. Drug Discov. World 6 (3), 17–23.

    Google Scholar 

  7. Hogg, D.S., Boden, P., Lawton, G., Kozlowski, R.Z. (2006) Ion channel drug targets unlocking the potential. Drug Discov. World 7(3), 83–92.

    Google Scholar 

  8. Yang, Y.C., Kuo, C.C. (2005) An inactivation stabilizer of the Na+channel acts as an opportunistic pore blocker modulated by external Na+. J. Gen. Physiol. 125(5), 465–481.

    Article  CAS  Google Scholar 

  9. Koidl, B., Miyawaki, N., Tritthart, H.A. (1997) A novel benzothiazine Ca2+channel antagonist, semotiadil, inhibits cardiac L-type Ca2+currents. Eur. J. Pharmacol. 322(2–3), 243–247.

    Article  CAS  Google Scholar 

  10. Baxter, D.F., Kirk, M., Garcia, A.F., Raimondi, A., Holmqvist, M.H., Flint, K.K., Bojanic, D., Distefano, P.S., Curtis, R., Xie, Y. (2002) A novel membrane potential-sensitive fluorescent dye improves cell-based assays for ion channels. J. Biomol. Screen. 7(1), 79–85.

    Article  CAS  Google Scholar 

  11. Vickery, R., Amagasu, S., Chang, R., Mai, N., Kaufman, E., Martin, J., Hembrado, J., O'Keefe, M., Gee, C., Marquess, D., Smith., J. (2004) Comparison of the Pharmacological properties of rat NaV1.8 with rat NaV1.2a and human NaV1.5 voltage-gated sodium channel subtypes using a membrane potential sensitive dye and FLIPR. Receptors and Channels 10(1), 11–23.

    Article  CAS  Google Scholar 

  12. Minta, A., Kao, J.P., Tsien, R.Y. (1989) Fluorescent indicators for cytosolic calcium based on rhodamine and fluorescein chromophores. J. Biol. Chem. 264, 8171–8178.

    CAS  Google Scholar 

  13. Huang, C.J., Harootunian, A., Maher, M.P., Quan, C., Raj, C.D., McCormack, K., Numann, R., Negulescu, P.A., González, J.E. (2006) Characterization of voltage-gated sodium-channel blockers by electrical stimulation and fluorescence detection of membrane potential. Nat. Biotechnol. 24(4), 415–416.

    Article  Google Scholar 

  14. Gill, R., Lee, S.S, Hesketh, J.C., Fedida, D., Rezazadeh, S., Stankovich, L., Liang D. (2003) Flux assays in high throughput screening of ion channels in drug discovery. Assay Drug Dev. Technol. 1(5), 709–717.

    Article  CAS  Google Scholar 

  15. Liu, C.J., Priest, B.T., Bugianesi, R.M., Dulski, P.M., Felix, J.P., Dick, I.E., Brochu, R.M., Knaus, H.G., Middleton, R.E., Kaczorowski, G.J., Slaughter, R.S., Garcia, M.L., Köhler, M.G. (2006) A high-capacity membrane potential FRET-based assay for NaV1.8 channels. Assay Drug Dev. Technol. 4, 37–48.

    Article  CAS  Google Scholar 

  16. Kolok, S., Nagy, J., Szombathelyi, Z., Tarnawa, I. (2006) Functional characterization of sodium channel blockers by membrane potential measurements in cerebellar neurons: Prediction of compound preference for the open/inactivated state. Neurochem. Int. 49, 593–604.

    Article  CAS  Google Scholar 

  17. Hamill, O.P., Marty, A., Neher, E., Sakmann, B., Sigworth, F.J. (1981) Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches. Pflugers Arch. 391, 85–100.

    Article  CAS  Google Scholar 

  18. Asmild, M., Oswald, N., Krzywkowski, K.M., Friis, S., Jacobsen, R.B., Reuter, D., Taboryski, R., Kutchinsky, J., Vestergaard, R.k., Schrøder, R.l., Sørensen, C.B., Bech, M., Korsgaard, M.P.G., Willumsen, N. (2003) Upscaling and automation of electrophysiology: Toward high throughput screening in ion channel drug discovery. Receptors and Channels 9, 49–58.

    Article  CAS  Google Scholar 

  19. Owen, D., Silverthorne, A. (2002) Channelling drug discovery, current trends in ion channel discovery research. Drug Discov. World 3(2), 48–61.

    Google Scholar 

  20. Schroeder, K., Neagle, B., Trezise, D.J., Worley, J. (2003) Ionworks HT: A new high-throughput electrophysiology measurement platform. J. Biomol. Screen. 8(1), 50–64.

    Article  CAS  Google Scholar 

  21. Finkel, A., Wittel, A., Yang, N., Handran, S., Hughes, J., Costantin, J. (2006) Population patch clamp improves data consistency and success rates in the measurement of ionic currents. J. Biomol. Screen. 11(5), 488–496.

    Article  CAS  Google Scholar 

  22. John, V.H., Dale, T.J., Hollands, E.C., Chen, M.X., Partington, L., Downie, D.L., Meadows, H.J., Trezise, D.J. (2007) Novel 384-well population patch clamp electrophysiology assays for Ca2+-activated K+channels. J. Biomol. Screen. 12(1), 50–60.

    Article  CAS  Google Scholar 

  23. Clark, G.S., Todd, D., Liness, S., Maidment, S.A., Dowler, S., Southan, A.P. (2005) Expression and characterisation of a two pore potassium channel in HEK293 cells using different assay platforms. Proceedings of the British Pharmacological Societyat http://www.pA2online.org/abstracts/Vol3Issue4abst105P.pdf.

  24. Lee, Y.T., Vasilyev, D.V., Shan, Q.J., Dunlop, J., Mayer, S., Bowlby, M.R. (2008) Novel pharmacological activity of loperamide and CP-339,818 on human HCN channels characterized with an automated electrophysiology assay. Eur. J. Pharmacol. 581(1–2), 97–104.

    Article  CAS  Google Scholar 

  25. Tao, H., Santa Ana, D., Guia., A, Huang, M., Ligutti, J., Walker, G., Sithiphong, K., Chan, F., Guoliang, T., Zozulya, Z., Saya, S., Phimmachack, R., Sie, C., Yuan, J., Wu, L., Xu, J., Ghetti, A. (2004) Automated tight seal electrophysiology for assessing the potential hERG liability of pharmaceutical compounds. Assay Drug Dev. Technol. 2(5), 497–506.

    Article  CAS  Google Scholar 

  26. Kutchinsky, J., Friis, S., Asmild, M., Taboryski, R., Pedersen, S., Vestergaard, R.K., Jacobsen, R.B., Krzywkowski, K., Schrøder, R.L., Ljungstrøm, T., Hélix, N., Sørensen, C.B., Bech, M., Willumsen, N.J. (2003) Characterization of potassium channel modulators with QPatch automated patch-clamp technology: system characteristics and performance. Assay Drug Dev. Technol. 1(5), 685–693.

    Article  CAS  Google Scholar 

  27. Farre, C., Stoelzle, S., Haarmann, C., George, M., Brüggemann, A., Fertig, N. (2007) Automated ion channel screening: patch clamping made easy. Ion channel drug discovery expands into new disease areas. Expert Opin. Ther. Targets 11(4), 557–565.

    Article  CAS  Google Scholar 

  28. Lepple-Wienhues, A., Ferlinz, K., Seeger, A., Schäfer, A. (2003) Flip the tip: An automated, high quality, cost-effective patch clamp screen. Receptors Channels 9(1), 13–17.

    Article  CAS  Google Scholar 

  29. Dunlop, J., Roncarati, R., Jow, B., Bothmann, H., Lock, T., Kowal, D., Bowlby, M., Terstappen, G.C. (2007) In vitro screening strategies for nicotinic receptor ligands. Biochem. Pharmacol. 74(8), 1172–1181.

    Article  CAS  Google Scholar 

  30. Papke, R.L. (2006) Estimation of both the potency and efficacy of alpha7 nAChR agonists from single-concentration responses. Life Sci. 78(24), 2812–2819.

    Article  CAS  Google Scholar 

  31. Schnizler, K., Küster, M., Methfessel, C., Fejtl, M. (2003) The robocyte: Automated cDNA/mRNA injection and subsequent TEVC recording on Xenopus oocytes in 96-well microtiter plates. Receptors Channels 9(1), 41–48.

    Article  CAS  Google Scholar 

  32. Xu, S.-Z., Sukumar, P., Zeng, F., Li, J., Jairaman, A., English, A., Naylor, J., Ciurtin, C., Majeed, Y., Milligan, C.J., Bahnasi, Y.M., Al-Shawaf, E., Porter, K.E., Jiang, L.-H., Emery, P., Sivaprasadarao, A., Beech, D.J. (2008) TRPC channel stimulation by extracellular thioredoxin. Nature 451 (7174), 69–73.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Ion Channel Biology BioFocus DPI, Saffron Walden, Essex, UK

    Andrew Southan

  2. BioFocus DPI, Saffron Walden, Essex, UK

    Gary Clark

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  1. Andrew Southan
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  2. Gary Clark
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    © 2009 Humana Press, a part of Springer Science+Business Media, LLC

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    Southan, A., Clark, G. (2009). Recent Advances in Electrophysiology-Based Screening Technology and the Impact upon Ion Channel Discovery Research. In: Janzen, W., Bernasconi, P. (eds) High Throughput Screening. Methods in Molecular Biology, vol 565. Humana Press. https://doi.org/10.1007/978-1-60327-258-2_9

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    • DOI: https://doi.org/10.1007/978-1-60327-258-2_9

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    • Publisher Name: Humana Press

    • Print ISBN: 978-1-60327-257-5

    • Online ISBN: 978-1-60327-258-2

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