Research Summary

The Fedida laboratory is interested in problems of cardiac repolarization and rhythm that mainly involve the study of ion channels that regulate normal electrical activity and contractility in the heart. We also study ion channels in viruses that are important for their infectivity. Ion channels are small proteins that regulate the flow of charged cations and anions across cell membranes, and they are found in all cells throughout the body, and in all species in the Animal Kingdom. Come and have a look at some of the projects we are pursuing that involve the biophysics of potassium ion channels, how they are synthesized and transported to and from the cell surface, and how they open and close. We also investigate late sodium currents and heart failure, and viral ion channels from influenza A.

Technologies & Methods
Projects
  • Gating Currents
  • Single Channel Recordings
  • Voltage Clamp Fluorimetry
  • Late Sodium Currents
  • Viroporins
  • Long QT Syndrome
  • Ion Channel Trafficking
Bio

BSc Hon Class I (Physiology), Leeds University, UK
PhD (Cardiac Electrophysiology), Leeds University, UK
BMBCh (Clinical Medicine), Oxford University, UK

David Fedida obtained his B.Sc. and Ph.D. degrees at the University of Leeds in England in cardiac electrophysiology and his medical Degree (BM, B.Ch.) from Oxford University. After a brief period spent in residency training in General Surgery and Cardiovascular Medicine in the UK, he spent postdoctoral periods at Oxford with Denis Noble, Wayne Giles in Calgary, and Arthur Brown at Baylor College of Medicine in Texas where he first identified Kv1.5 as the molecular basis of the delayed rectifier, IKur, in human atrium.

Presently he is a Professor in the Department of Anesthesiology, Pharmacology & Therapeutics with funding from the Heart and Stroke Foundation of BC and Yukon and The Canadian Institutes for Health Research. This funding is to study molecular mechanisms for the gating of voltage-activated potassium channels, trafficking of potassium channels in the heart and for the discovery of small molecule inhibitors of viral ion channels, viroporins, for treatment of viral infections.

David Fedida is also a consultant for Cardiome Pharma Corp in Vancouver where he has been involved in the design and electrophysiological testing of Cardiome’s agents for the treatment of supraventricular arrhythmias – notably Vernakalant, which has been shown to be successful in the conversion of recent onset atrial fibrillation (AF) in Phase II and III trials and has European approval for the IV treatment of AF.

Publications

 
Comprehensive List

List of publications on PubMed

Selected Publications

  1. Microscopic mechanisms for long QT syndrome type 1 revealed by single-channel analysis of IKs with S3 domain mutations in KCNQ1.
    Eldstrom J, Wang Z, Werry D, Wong N, Fedida D.
    Heart Rhythm. 2014 Oct 29. pii: S1547-5271(14)01246-6. doi: 10.1016/j.hrthm.2014.10.029. [Epub ahead of print]
  2. Aminoadamantanes with persistent in vitro efficacy against H1N1 (2009) influenza A.
    Kolocouris A, Tzitzoglaki C, Johnson FB, Zell R, Wright AK, Cross TA, Tietjen I, Fedida D, Busath DD.
    J Med Chem. 2014 Jun 12;57(11):4629-39. doi: 10.1021/jm500598u.
  3. CrossTalk proposal: The late sodium current is an important player in the development of diastolic heart failure (heart failure with a preserved ejection fraction).
    Pourrier M, Williams S, McAfee D, Belardinelli L, Fedida D.
    J Physiol. 2014 Feb 1;592(Pt 3):411-4. doi: 10.1113/jphysiol.2013.262261.
  4. Rebuttal from Marc Pourrier, Sarah Williams, Donald McAfee, Luiz Belardinelli and David Fedida.
    Pourrier M, Williams S, McAfee D, Belardinelli L, Fedida D.
    J Physiol. 2014 Feb 1;592(Pt 3):419. doi: 10.1113/jphysiol.2013.268896.
  5. Ranolazine improves diastolic function in spontaneously hypertensive rats.
    Williams S, Pourrier M, McAfee D, Lin S, Fedida D.
    Am J Physiol Heart Circ Physiol. 2014 Mar;306(6):H867-81.
  6. Allosteric coupling of the inner activation gate to the outer pore of a potassium channel.
    Peters CJ, Fedida D, Accili EA.
    Sci Rep. 2013 Oct 23;3:3025. doi: 10.1038/srep03025.
  7. Gating charge movement precedes ionic current activation in hERG channels.
    Goodchild SJ, Fedida D.
    Channels (Austin). 2014 Jan-Feb;8(1):84-9.
  8. The neutral, hydrophobic isoleucine at position I521 in the extracellular S4 domain of hERG contributes to channel gating equilibrium.
    Dou Y, Goodchild SJ, Velde RV, Wu Y, Fedida D.
    Am J Physiol Cell Physiol. 2013 Aug 15;305(4):C468-78.
  9. ShakerIR and Kv1.5 mutant channels with enhanced slow inactivation also exhibit K+ o-dependent resting inactivation.
    Cheng YM, Fedida D, Kehl SJ.
    Pflugers Arch. 2013 Nov;465(11):1545-55
  10. Cytoskeletal Roles in Cardiac Ion Channel Expression.
    Steele DF, Fedida D.
    Biochim Biophys Acta. 2014 Feb;1838(2):665-73.
  11. Dual effect of phosphatidylinositol (4,5)-bisphosphate PIP2 on Shaker K+ channels.
    Abderemane-Ali F, Es-Salah-Lamoureux Z, Delemotte L, Kasimova MA, Labro AJ, Snyders DJ, Fedida D, Tarek M, Baró I, Loussouarn G.
    J Biol Chem. 2013 Apr 12;288(15):10951.
  12. Components of gating charge movement and S4 voltage-sensor exposure during activation of hERG channels.
    Wang Z, Dou Y, Goodchild SJ, Es-Salah-Lamoureux Z, Fedida D.
    J Gen Physiol. 2013 Apr;141(4):431-43.
    Comment in: The electric heart of hERG. [J Gen Physiol. 2013]
  13. Single-channel basis for the slow activation of the repolarizing cardiac potassium current, I(Ks).
    Werry D, Eldstrom J, Wang Z, Fedida D.
    Proc Natl Acad Sci U S A. 2013 Mar 12;110(11):E996-1005.
  14. The new antiarrhythmic drug Vernakalant: Ex-vivo study of human atrial tissue from sinus rhythm and chronic atrial fibrillation.
    Wettwer E, Christ T, Endig S, Rozmaritsa N, Matschke K, Lynch JJ, Pourrier M, Gibson JK, Fedida D, Knaut M, Ravens U.
    Cardiovasc Res. 2013 Apr 1;98(1):145-54
  15. External Ba2+ block of Kv4.2 channels is enhanced in the closed-inactivated state.
    Kehl SJ, Fedida D, Wang Z.,
    Am J Physiol Cell Physiol. 2013 Feb 15;304(4):C370-81.
  16. Biolistic transfection of freshly isolated adult ventricular myocytes.
    Steele DF, Dou Y, Fedida D.
    Methods Mol Biol. 2013;940:145-55.
  17. Basis for allosteric open-state stabilization of voltage-gated potassium channels by intracellular cations.
    Goodchild SJ, Xu H, Es-Salah-Lamoureux Z, Ahern CA, Fedida D.
    J Gen Physiol. 2012 Nov;140(5):495-511.
    -Comment in: Open-state stabilization in Kv channels: voltage-sensor relaxation and pore propping by a bound ion. [J Gen Physiol. 2012]
  18. Trafficking of an endogenous potassium channel in adult ventricular myocytes.
    Wang T, Cheng Y, Dou Y, Goonesekara C, David JP, Steele DF, Huang C, Fedida D.
    Am J Physiol Cell Physiol. 2012 Nov 1;303(9):C963-76.
  19. Dynamic of ion channel expression at the plasma membrane of cardiomyocytes.
    Balse E, Steele DF, Abriel H, Coulombe A, Fedida D, Hatem SN.
    Physiol Rev. 2012 Jul;92(3):1317-58. Review.
  20. Contributions of intracellular ions to Kv channel voltage sensor dynamics.
    Goodchild SJ, Fedida D.
    Front Pharmacol. 2012;3:114.
  21. Golgi export signal ties proper folding to AP1 binding.
    Steele DF, Fedida D.
    Circ Res. 2012 Mar 16;110(6):802-4.
  22. The voltage-gated channel accessory protein KCNE2: multiple ion channel partners, multiple ways to long QT syndrome.
    Eldstrom J, Fedida D.
    Expert Rev Mol Med. 2011 Dec 14;13:e38. Review.
  23. Mechanism of accelerated current decay caused by an episodic ataxia type-1-associated mutant in a potassium channel pore.
    Peters CJ, Werry D, Gill HS, Accili EA, Fedida D.
    J Neurosci. 2011 Nov 30;31(48):17449-59.
  24. The Ca(v)1.4 calcium channel is a critical regulator of T cell receptor signaling and naive T cell homeostasis.
    Omilusik K, Priatel JJ, Chen X, Wang YT, Xu H, Choi KB, Gopaul R, McIntyre-Smith A, Teh HS, Tan R, Bech-Hansen NT, Waterfield D, Fedida D, Hunt SV, Jefferies WA.
    Immunity. 2011 Sep 23;35(3):349-60.
  25. Blockade of permeation by potassium but normal gating of the G628S nonconducting hERG channel mutant.
    Es-Salah-Lamoureux Z, Xiong PY, Goodchild SJ, Ahern CA, Fedida D.
    Biophys J. 2011 Aug 3;101(3):662-70.
  26. Functional characterization of the LQT2-causing mutation R582C and the associated voltage-dependent fluorescence signal.
    Fougere RR, Es-Salah-Lamoureux Z, Rezazadeh S, Eldstrom J, Fedida D.
    Heart Rhythm. 2011 Aug;8(8):1273-80.
  27. A novel mechanism for LQT3 with 2:1 block: a pore-lining mutation in Nav1.5 significantly affects voltage-dependence of activation.
    Horne AJ, Eldstrom J, Sanatani S, Fedida D.
    Heart Rhythm. 2011 May;8(5):770-7.
  28. Research into the therapeutic roles of two-pore-domain potassium channels.
    Es-Salah-Lamoureux Z, Steele DF, Fedida D.
    Trends Pharmacol Sci. 2010 Dec;31(12):587-95. Review.
  29. Cholesterol and cardiac arrhythmias.
    Goonasekara CL, Balse E, Hatem S, Steele DF, Fedida D.
    Expert Rev Cardiovasc Ther. 2010 Jul;8(7):965-79. Review.
  30. Fast and slow voltage sensor rearrangements during activation gating in Kv1.2 channels detected using tetramethylrhodamine fluorescence.
    Horne AJ, Peters CJ, Claydon TW, Fedida D.
    J Gen Physiol. 2010 Jul;136(1):83-99
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