Dr John Mitcheson

Tel: +44 (0)116 229 7133

Email: jm109@le.ac.uk

Personal details

  • 1988-1991: BSc. Joint Honours Physiology and Biochemistry, Kings College, London.
  • 1991-1992: Wellcome Trust Research Assistant. Department of Physiology, University of Bristol
  • 1992-1995: MRC Ph.D. Studentship. Department of Physiology, University of Bristol. Thesis: The morphology and ionic currents of cardiac myocytes maintained in cell culture
  • 1995-1998: British Heart Foundation Postdoctoral Research Assistant. Department of Physiology, University of Bristol. Project – regulation of ionic currents in single isolated atrioventricular nodal cells by antiarrhythmic drugs
  • 1998-2000: Wellcome Prize Travelling Research Fellow. University of Utah, USA. Mentor Prof Mike Sanguinetti. Project: a structural basis for hERG channel block and drug induced long QT syndrome
  • 2000-2006: Lecturer, University of Leicester, Department of Cell Physiology and Pharmacology
  • 2006–2015: Reader,  Department of Cell Physiology and Pharmacology, University of Leicester
  • 2015-present: Reader, Department of Molecular Cell Biology, University of Leicester

Publications

Research

  • Nitric oxide signalling and role in cardiac health and disease.
  • Mechanistic basis of cardiac arrhythmias.
  • hERG and hEAG potassium channel structure and function.
  • Cardiac ion channel pharmacology
  • Heme regulation of ion channels.
  • Calcium-calmodulin regulation of ion channels.

HERG potassium channels. Functional roles in cardiac myocytes, tumour and neuronal cells and structural basis for physiological and pharmacological properties

HERG is the pore forming subunit of channels important for cardiac action potential repolarisation. Reduction of HERG channel function causes long QT syndrome, a disorder of cardiac action potential repolarisation that prolongs the cardiac action potential and predisposes individuals to potentially lethal cardiac arrhythmias and sudden death.

HERG channel gating

HERG channels have unusual gating properties that are important for their physiological function. They exhibit unusually slow activation, but very fast inactivation kinetics - the opposite to most channels. These unusual gating kinetics are important for timing the onset of current during action potential repolarisation. One aim of my research is to determine the structural components of HERG that enable it to function in this manner.

HERG channel pharmacology

At least 70 commonly used drugs have been shown to cause LQTS by blocking HERG channels. The question we have been trying to address is why so many therapeutically and structurally diverse drugs preferentially block HERG channels and not a large number of other channels with a role in action potential repolarisation in the heart. We have been able to identify several unique properties of the HERG channel that make it susceptible to block and have localised the primary drug binding site. Future aims are to identify additional drug binding sites and obtain a more detailed model of the primary binding site, which can be used in the early phases of drug development for detecting compounds with the potential for causing LQTS.

It is becoming clear that HERG channels are modulated by a variety of second messenger pathways. In collaboration with G Willars and A Tobin we are investigating mechanisms of G-protein receptor mediated modulation of HERG channel activity.

Oncogenic potential of HERG

HERG channels are expressed in numerous primary tumour cells and tumour derived cell lines. At present it is not clear if the HERG gene itself is oncogenic or whether HERG channel expression is an adaptation of some cancer cells that provides a selective advantage for cancer cells. We are evaluating the oncogenic potential of HERG and investigating molecular mechanisms of HERG effects on cell proliferation, substrate adhesion, morphology and motility.

Techniques

  • Site directed mutagenesis
  • Expression of wild type and mutant HERG channels in Xenopus oocytes and mammalian cell lines.
  • Two electrode voltage clamp recording and single channel patch clamp recording in oocytes.
  • Whole cell and excised macropatch recordings in mammalian cell lines and cardiac myocytes.
  • Protein phosphorylation assays and phospho-peptide mapping.
  • Cell proliferation, morphology and motility assays.

Research group and funding

Present group members

  • Rachel Caves
  • Steve Thomson
  • Eva Loerinczi

Current funding

  • MRC 5 year Career Establishment Award (Feb 2002-2007)
  • Collaborative partnership with Pfizer Global Research and Development (Dec 2001-2004)
  • British Heart Foundation project grant (Oct 2001 - 2004)
  • 2 x MRC/Novartis CASE studentships (Oct 2003 – 2006)
  • BBSRC/GlaxoSmithKline CASE studentship (Oct 2003- 2006)
  • BBSRC/Pfizer CASE studentship (Oct 2004 – 2007)

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Contact Details

Department of Molecular and Cell Biology
Henry Wellcome Building
Lancaster Road
Leicester
LE1 7RH (Postal)

LE1 7HB (Sat Nav/Online maps)

T:  +44(0)116 229 7038
F:  +44(0)116 229 7123
MolCellBiol@le.ac.uk

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Redfearn Lecture 2017

To Be Confirmed