Gail Robertson

Professor
Ph.D., 1986, Washington University, St. Louis

Contact Information
Email: garobert@wisc.edu
(608) 265-3339 Phone
(608) 265-5512 Fax

Postdoctoral Fellow position available (click here)

 
Research Interests
Molecular mechanisms of ion channel function

Gail Robertson

The electrical signals responsible for neuronal communication and cardiac rhythmicity depend on potassium channels, proteins that regulate the movement of potassium ions across cell membranes. The disruption of these channels by inherited diseases or drugs can lead to neurological defects or cardiac arrhythmias.

Work in our lab focuses on voltage-gated potassium channels encoded by the human Ether-a-go-go-Related Gene, or hERG1. In 1995, we showed that hERG1 expressed in Xenopus oocytes produces currents with the unique biophysical and pharmacological properties of the cardiac repolarizing current known as IKr. This work established hERG1 channels as a potential target for acquired long QT syndrome (LQTS), in which block of IKr by drugs intended for a wide range of therapeutic targets can trigger life-threatening ventricular arrhythmias known as torsades de pointes. In addition, these studies explained the underlying cause of inherited type 2 LQTS (LQT2), which had been linked to the hERG1 gene, as a loss or reduction of cardiac IKr

In subsequent studies we have shown that the hERG gene encodes two closely related subunits that readily assemble to form IKr in native tissues. hERG 1a, the original hERG isolate, and hERG 1b are identical except for their cytoplasmic, amino (N) termini, which are non-homologous domains that interact in the earliest stages of biogenesis to promote subunit oligomerization. hERG 1b subunits expressed alone fail to produce robust currents because of an exposed endoplasmic reticulum (ER) retention signal that is masked by association with 1a. hERG 1a/1b heteromers produce more current than hERG 1a homomeric channels because they open more quickly and because they spend less time in the inactivated state at positive potentials. These differences in gating kinetics can all be attributed to the reduced number of 1a N termini, which modulate channel gating properties. These studies illustrate the importance of the 1b subunit in the oligomeric complex that produces IKr, and establish hERG 1b-specific sequences as potential targets for LQT2.

In this post-genomic era, we are close to knowing the composition and stoichiometry of all ion channels in the heart and other excitable tissues. Yet we know little about the mechanisms that regulate surface expression and relative numbers of different channel types. In the heart, even a minor perturbation of this delicate balance can have catastrophic consequences. Our efforts are currently focused on determining mechanisms of surface expression, understanding the checkpoints of hERG trafficking (each of which represents a potential LQTS target), and therapeutic approaches that can restore normal physiological function to a diseased heart.

Another area of investigation in the lab is acquired LQTS, which affects an estimated 1-8% of the general public. We now know that most compounds that cause this adverse drug reaction are hERG blockers, so early screening for hERG block in the drug discovery process is used to ensure these compounds do not reach the pharmacy shelves. However, a staggering 70% of lead compounds block hERG, so most compounds are dropped from development before their efficacy for therapeutic applications can be realized. We are studying why drugs block hERG but not structurally related channels. We are interested in genetic variations and disease states that reduce the numbers of functional hERG channels to subclinical levels until additional stressors such as hERG-blocking drugs further diminish repolarization and trigger torsades de pointes arrhythmias. One long-range goal of this work is to develop a genetic screen that protects susceptible individuals from harm while removing the barriers that currently impede the development of life-saving therapeutic treatment options in the broader population. Another is to develop therapeutics that promote hERG channel expression and counteract the adverse effects of other drugs and disease states on cardiac repolarization.

We employ a wide array of techniques to address these objectives. We use electrophysiological techniques such as voltage clamp and patch clamp from Xenopus oocytes and HEK-293 cells to monitor gating kinetics and surface channel expression levels. We carry out biophysical analysis of gating in normal and mutant channels together with molecular modeling to identify structural domains of channel function. We also use protein biochemistry to monitor oligomeric assembly of channel subunits, subcellular hERG trafficking and interactions of hERG with proteins in the trafficking pathway. We complement these cellular studies with confocal immunocytochemistry.

Current Lab Members
Phu Tran, Ph.D. Postdoctoral Fellow
Sunita Joshi Graduate Student - Cell and Molecular Biology
Yaxian Zhao Graduate Student - Physiology Graduate Training Program
Abdalla Saad Senior Research Specialist
Fang Liu Research Specialist
 
Past Lab Members
Matthew Trudeau, Ph.D. Assistant Professor, Univ. of Maryland School of Medicine
Ian Herzberg, Ph.D. Regional Sales Manager, Brookhaven Instruments
Janet Branchaw, Ph.D. Undergraduate Education Coordinator for the Center for Biology Education, UW-Madison
Anne Lynn Gillian-Daniel Nuclear Magnetic Resonance Facility at Madison
Ebru Aydar Researcher, Imperial College London
Jinling Wang, Ph.D. Scientific translator
Eugenia Jones, Ph.D. Chief Strategy Consultant, Gist Consulting
Harinath Sale, Ph.D. Biocon, Ltd., Bangalore
Pallavi Phartiyal, Ph.D. Research fellow, AAAS
Jamal Tayyib, M.S., M.D. Resident at Mt. Sinai
Adam Rucker, M.S., J.D. Patent Attorney, North Carolina
Samantha Delfosse, B.S. Wisconsin State Crime Laboratories
Sarah Wynia-Smith, Ph.D. Postdoctoral Fellow at UC-Berkeley
Elon Roti Roti, Ph.D. Postdoctoral Fellow at UW-Madison
Rebecca Uelmen, Ph.D. Scientist, Kimberly Clark Corporation

Selected Publications

  • Trudeau, M.C., Leung, L.M., Roti Roti, E. and ROBERTSON, G.A. (2011). ). hERG1a N-terminal eag domain-containing polypeptides regulate homomeric hERG1b and heteromeric hERG1a/hERG1b channels: A possible mechanism for long QT syndrome J. Gen. Physiol. 138:581-592
     
  • Abi-Gerges, N., Holkham, H., Jones, E.M.C., Pollard, C.E.Valentin, J.-P. and Robertson, G.A. (2011). hERG Subunit Composition Determines Differential Drug Sensitivity. British J. Pharmacol. Mar 30. doi: 10.1111/j.1476-5381.2011.01378.x. [Epub ahead of print]
     
  • Es-Salah-Lamoureux, Z., Fougere, R., Xiong, P. Y., Robertson, G. A., Fedida, D. (2010). Fluorescence-tracking of activation gating in human ERG channels reveals rapid S4 movement and slow pore opening. PLoS ONE 5(5): e10876.
     
  • Fergestad, T., Harinath, S., Bostwick, B., Schaffer, A., Ho, L.L., ROBERTSON, G.A. and Ganetzky, B. (2010). Down and out is an essential regulator of ERG channels in Drosophila. Proc. Natl. Acad. Sci. 107(12):5617-21
     
  • Wynia Smith, S.L., Gillian-Daniel, A.L., Satyshur, K. and ROBERTSON, G.A. (2008). hERG gating microdomains defined by S6 mutagenesis and modeling. J. Gen. Physiol. 132:507-20 (Cover).
     
  • Sridhar, A., Nishijima, Y., Terentyev, D., Terenteyva, R., Uelmen, R., Kukielka, M., ROBERTSON, G.A., Gyorke, S., Billman, G.E., and Carnes, C.A. (2008). Repolarization abnormalities and afterdepolarizations in a canine model of sudden cardiac death. Am J Physiol Regul Integr Comp Physiol, 295(5):R1463-72
     
  • Sale, H., Wang, J., O'Hara, T.J., Tester, D.J., Phartiyal, P., He, J.-Q., Rudy, Y, Ackerman, M.J. and ROBERTSON, G.A. (2008). Physiological properties of heteromeric hERG 1a/1b channels and a hERG 1b-specific mutation associated with Long QT Syndrome. Circulation Res. 103(7):e81-95
    Abstract | PDF
     
  • Sridhar, A., Nishijima, Y., Terentyev, D., Terenteyva, R., Uelmen, R., Kukielka, M., ROBERTSON, G.A., Gyorke, S., Billman, G.E., and Carnes, C.A. (2008). Repolarization abnormalities and afterdepolarizations in a canine model of sudden cardiac death. Am J Physiol Regul Integr Comp Physiol. 295(5):R1463-72
     
  • Wynia Smith, S.L., Gillian-Daniel, A.L., Satyshur, K. and ROBERTSON, G.A. (2008). hERG gating microdomains defined by S6 mutagenesis and modeling. J. Gen. Physiol. 132:507-20.
    Abstract | PDF
     
  • Phartiyal, P., Jones, E.M.C. and Robertson, G.A. (2008). ER retention and rescue by heteromeric assembly regulate hERG 1a/1b surface channel composition. J. Biol. Chem. 283: 3702 - 3707.
    Abstract | Full Text | PDF
     
  • Phartiyal, P., Jones, E.M.C. and Robertson, G.A. (2007). Heteromeric assembly of hERG 1a and 1b subunits occurs cotranslationally via amino terminal interactions. J. Biol. Chem. 282: 9874-9882.
    PDF
     
  • Robertson, G.A. and January, C.T. (2005). hERG Trafficking and Pharmacological Rescue of LQTS-2 Mutant Channels. In: Handbook of Experimental Pharmacology 171:349-355. Basis and Treatment of Arrhythmia. Colleen Clancy and Robert Kass, ed. Springer-Verlag.
    PDF
     
  • Robertson, G.A., Jones, E.M.C. and Wang, J. (2005). Gating and Assembly of Heteromeric hERG1a/1b Channels underlying IKr in the Heart. Novartis Foundation Symposium 266:4-15.
    PDF
     
  • Jones, E.M.C., Roti Roti, E.C., Wang, J., Delfosse, S.A. and Robertson, G.A. Cardiac IKr channels minimally comprise hERG 1a and 1b subunits (2004). J. Biol. Chem. 279:44690-44694.
    PDF
     
  • Roti Roti, E.C., Myers, C.D., Ayers, R.A., Boatman, D.E., Delfosse, S.A., Chan, E.K.L., Ackerman, M.J.,January, C.T. and Robertson, G.A. (2002). Interaction with GM130 during HERG ion channel trafficking Disruption by LQT2 mutations. J. Biol. Chem. 277;47779-47785.
    Abstract | Full Text | PDF
     
  • Robertson, G.A. (2000) LQT2: Amplitude reduction and loss of selectivity in the tail that wags the HERG channel. [Editorial] Circulation Research 86(5):492-493, 2000 Mar 17.
    Full Text | PDF
     
  • Wang, J., Myers, C.D. and Robertson, G.A. (2000). Dynamic Control of Deactivation Gating by a Soluble Amino-Terminal Domain in HERG K+ Channels. J. Gen. Physiol. 115: 749-758.
    Abstract | Full Text | PDF
     
  • Trudeau, M.C., Titus, S.A., Branchaw, J.L., Ganetzky, B. and Robertson, G.A. (1999). Functional analysis of a mouse Elk-type K+ channel. J. Neurosci., 19:2906-2918.
    Abstract | Full Text
     
  • Wang, J., Trudeau, M.C., Zappia, A. and Robertson, G.A. (1998). Regulation of deactivation by an amino terminal domain in HERG potassium channels. J. Gen. Physiol. 112:637-647.
    Abstract | Full Text
     
  • Herzberg*, I.M., Trudeau*, M.C. and Robertson, G.A. (1998). Transfer of rapid inactivation and E-4031 sensitivity from HERG to M-EAG Channels. J. Physiol. 511:3-14. (*Designates co-first authors.)
    Abstract | Full Text
     
  • Robertson, G.A., J.W. Warmke, and B. Ganetzky. (1996). Potassium currents expressed from Drosophila and mouse eag cDNAs in Xenopus oocytes. Neuropharmacology 35: 841-850.
     
  • Trudeau, M. C., J.W. Warmke, B. Ganetzky, and G.A. Robertson. (1995). HERG, a human inward rectifier in the voltage-gated potassium channel family. Science 269: 92-95.
    PDF

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