John Mitcheson

Personal Details

John Mitcheson

Reader in ion channel physiology and pharmacology

John Mitcheson Department: Molecular and Cell Biology
Telephone: +44 (0)116 229 7133
Email: jm109@le.ac.uk

Biography

  • 1992      Wellcome Trust Research Assistant. Department of Physiology, University of Bristol.
  • 1992-1995 MRC PhD Studentship, Department of Physiology, University of Bristol.
  • 1995 - 1998 BHF Postdoctoral Research Assistant, Department of Physiology, University of Bristol
  • 1998 - 2000 Wellcome Prize Travelling Research Fellow, University of Utah, USA.
  • 2000 – 2006  Lecturer, University of Leicester
  • 2006 – present Reader, University of Leicester

Qualifications

  • Departmental Head of Research
  • Senior Fellow of the Higher Education Academy
  • PhD Cardiac myocyte electrophysiology, University of Bristol
  • BSc (Hons) Physiology and Biochemistry, Kings College, London

Teaching

  • Cardiac, skeletal and smooth muscle physiology  

     

     

     

     

  •  Neurophysiology – ionic basis of action potentials, biophysics of action potential conduction, neuronal diseases related to ion channel dysfunction and axon demyelination   

     

     

     

     

  • Exercise physiology – neuromuscular and skeletal adaptations to exercise 

     

     

     

     

  • Ion channel structure, function and modulation by drugs    

     

     

     

     

  • Cardiac physiology – Ion channel biophysics, channel gating properties and their relationship to regulation of ventricular action potentials and pacemaker activity in the sino-atrial node, mechanisms of arrhythmia, long QT syndrome and sudden cardiac death

Publications since 2010

  1. Bate N, Caves RE, Skinner SP, Goult BT, Basran J, Mitcheson JS, & Vuister GW. (2018). A Novel Mechanism for Calmodulin-Dependent Inactivation of Transient Receptor Potential Vanilloid 6.. Biochemistry. doi:10.1021/acs.biochem.7b01286 
  2. Kapetanaki SM, Burton MJ, Basran J, Uragami C, Moody PCE, Mitcheson JS, Schmid R, Davies NW, Dorlet P, Vos MH, Storey NM, Raven, E. (2018). A mechanism for CO regulation of ion channels. NATURE COMMUNICATIONS, 9, 10 pages. doi:10.1038/s41467-018-03291-z 
  3. Mitcheson JS & Hancox JC. (2017). Modulation of hERG potassium channels by a novel small molecule activator. British Journal of Pharmacology, 174(20), 3669-3671. doi:10.1111/bph.13964 
  4. Lörinczi E, Helliwell M, Finch A, Stansfeld PJ, Davies NW, Mahaut-Smith M, Muskett FW, Mitcheson JS. Calmodulin Regulates Human Ether à Go-Go 1 (hEAG1) Potassium Channels through Interactions of the Eag Domain with the Cyclic Nucleotide Binding Homology Domain. J Biol Chem. 2016 Aug 19;291(34):17907-18. doi: 10.1074/jbc.M116.733576.  
  5. Burton MJ, Kapetanaki SM, Chernova T, Jamieson AG, Dorlet P, Santolini J, Moody PC, Mitcheson JS, Davies NW, Schmid R, Raven EL, Storey NM. A heme-binding domain controls regulation of ATP-dependent potassium channels. Proc Natl Acad Sci U S A. 2016 Apr 5;113(14):3785-90. doi: 10.1073/pnas.1600211113 
  6. Hancox JC, Melgari D, Dempsey CE, Brack KE, Mitcheson J, Ng GA. hERG potassium channel inhibition by ivabradine may contribute to QT prolongation and risk of torsades de pointes. Ther Adv Drug Saf. 2015 Aug;6(4):177-9. doi:10.1177/2042098615595546.  
  7. Melgari D, Brack KE, Zhang Y, El Harchi A, Mitcheson JS, Dempsey CE, Ng GA, Hancox JC. hERG potassium channel inhibition by ivabradine requires channel gating. J Mol Cell Cardiol. 2015 Oct;87:126-8. doi: 10.1016/j.yjmcc.2015.08.002.  
  8. Melgari D, Brack KE, Zhang C, Zhang Y, El Harchi A, Mitcheson JS, Dempsey CE, Ng GA, Hancox JC. hERG potassium channel blockade by the HCN channel inhibitor bradycardic agent ivabradine. J Am Heart Assoc. 2015 Apr 24;4(4). pii: e001813. doi: 10.1161/JAHA.115.001813.  
  9. Mitcheson JS, Arcangeli A. The therapeutic potential of hERG1 K+ channels for treating cancer and cardiac arrhythmias. Ion Channel Drug Discovery. Editors Brian Cox and Martin Gosling, Royal Society of Chemistry. 2015, Issue 39, Pages 258-296 
  10. Gasparoli L, D’Amico M, Masselli M, Pillozzi S, Caves R, Khuwaileh R, Tiedke W, Mugridge K, Pratesi A, Mitcheson JS, Basso G, Becchetti A and Arcangeli A. The new pyrimido-indole compound CD-160130 preferentially inhibits the Kv 11.1B isoform and produces antileukemic effects without cardio-toxicity. Mol Pharmacol. 2015 Feb;87(2):183-96. doi: 10.1124/mol.114.094920. 
  11. Pier DM, Shehatou GS, Giblett S, Pullar CE, Tresize DJ, Pritchard CA, Challiss J, Mitcheson JS. Long-term Channel Block is Required to Inhibit Cellular Transformation by Human Ether-a-go-go-related Gene (hERG1) Potassium Channels. Mol Pharmacol. 2014 Aug;86(2):211-21. doi: 10.1124/mol.113.091439. 
  12. Mitcheson JS, Stanfield P. Bioelectricity, Ionic Basis of Membrane Potentials and Propagation of Voltage Signals. Encyclopedia of Biophysics, Editor Roberts, Gordon C.K., Springer Berlin Heidelberg, 2013, pp189-192. http://dx.doi.org/10.1007/978-3-642-16712-6_356 
  13. Varadarajan S, Bampton ET, Smalley JL, Tanaka K, Caves RE, Butterworth M, Wei J, Pellecchia M, Mitcheson JS, Gant TW, Dinsdale D, Cohen GM. A novel cellular stress response characterised by a rapid reorganisation of membranes of the endoplasmic reticulum. Cell Death Differ. 2012 Dec;19(12):1896-907. doi: 10.1038/cdd.2012.108. 
  14. Cavalli A, Buonfiglio R, Ianni C, Masetti M, Ceccarini L, Caves R, Chang MW, Mitcheson JS, Roberti M, Recanatini M. Computational design and discovery of "minimally structured" hERG blockers. J Med Chem. 2012 Apr 26;55(8):4010-4. doi: 10.1021/jm201194q. 
  15. Muskett FW, Thouta S, Thomson SJ, Bowen A, Stansfeld PJ, Mitcheson JS. Mechanistic insight into human ether-à-go-go-related gene (hERG) K+ channel deactivation gating from the solution structure of the EAG domain. J Biol Chem. 2011 Feb 25;286(8):6184-91. doi: 10.1074/jbc.M110.199364. 
  16. Muskett FW, Mitcheson JS. Resonance assignment and secondary structure prediction of the N-terminal domain of hERG (Kv11.1). Biomol NMR Assign. 2011 Apr;5(1):15-7. doi: 10.1007/s12104-010-9256-3. 
  17. Perry M, Sanguinetti M, Mitcheson JS. Revealing the structural basis of action of hERG potassium channel activators and blockers. J Physiol. 2010 Sep 1;588(Pt17):3157-67. doi: 10.1113/jphysiol.2010.194670.

Research

The role of voltage gated potassium channels in healthy and diseased tissues
The overall goal of my research is to understand the role of voltage gated potassium channels in normal health and human disease. I have a long-standing interest in the role of potassium channels, particularly hERG (Kv11), in cardiac repolarization and how dysfunction leads to arrhythmias and sudden cardiac death. More recently, I have also become interested in the role of hEAG (Kv10), a close relative of hERG, in cancer. We use a combination of electrophysiology, molecular biology, protein biochemistry and structure biology techniques to study ion channels in native tissues and cell lines.  

 

 

Molecular and cellular mechanisms of sudden cardiac death. The role of potassium channels.
Sudden cardiac death resulting from malignant arrhythmias such as ventricular fibrillation (VF) is a major unsolved clinical problem. The risks of VF are affected by underlying heart disease and by the activity of the autonomic nerve supply to the heart. We have a well-established collaboration with Prof Andre Ng and have recently been awarded a joint BHF 5 year programme grant to study how intrinsic heterogeneity, autonomic function and disease interact to increase vulnerability to VF. Using a heart failure model established at Leicester by Prof Andre Ng’s group, we investigate at the cellular and molecular level, ion channel remodelling, and heterogeneity of calcium responses, action potentials and responses to β-adrenergic receptor signalling with the onset of heart failure. We are particularly interested in how the activity of hERG and another important delayed rectifier K channel (Kv7.1) become modified with heart failure.  

 

 

hEAG, cancer and cell proliferation
hEAG channels are aberrantly over-expressed in many human cancers and inhibition of hEAG channel function by blockers, antibodies and siRNA decreases the proliferation of tumour cells and the size of tumours. hEAG channels are exquisitely sensitive to intracellular calcium, with a half maximal inhibition of ~100nM. We are interested in whether Ca2+-regulation of hEAG1 channels is functionally important in cell proliferation and cancer progression. Exciting recent evidence from my lab indicates that disruption of hEAG1 channel inhibition by intracellular calcium also reduces cell proliferation rates of hEAG1 expressing cells. On-going studies are working out the molecular mechanisms.  

 

 

hERG channel gating  
hERG (human ether-ago-go related gene) channels are vital for cardiac action potential repolarization. They are the pore-forming subunits of channels that conduct IKr, a potassium current that is vital for terminating cardiac action potentials. Reduction of hERG channel function causes long QT syndrome (LQTS), a cardiac disease that predisposes individuals to potentially lethal cardiac arrhythmias and sudden death.  

 

 

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
Many commonly used drugs have been shown to cause drug-induced LQTS by blocking hERG channels. Work I conducted many years ago identified the drug binding site for high affinity blockers and the features of hERG that make it so pharmacologically promiscuous. I am interesting in understanding the molecular basis for drug interactions with hERG and using insights from new cryo-EM structures of the channel to refine our models of hERG and minimize the risk of drug induced arrhythmias. 

 

 

Techniques 

 

 

  • Molecular biology techniques including site directed mutagenesis, PCR, in-vitro transcription, RT-RT PCR
  • 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.
  • Calcium and nitric oxide single cell imaging

Supervision 

 

 

These are PhD research project areas that are currently active. Please email me for further information or if you have any questions.

 

 

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

 

 

Past PhD students, MRes students, Post-Docs and Technicians

The lab is highly International, with past members of the group coming from many different Asian and European nations

 

 

Rawan Khuwaileh (PhD)

 

 

Rachel Caves (PhD + Post Doc)

 

 

Matthew Helliwell (MRes)

 

 

Eva Loerinczi (Post Doc)

 

 

Kadhr Alatawi

 

 

Sardar Weli (PhD – jointly supervised with Noel Davies)

 

 

Steve Thomson (PhD)

 

 

Samrat Thouta (Technician and MSc student)

 

 

Sarah Dalibalta (PhD)

 

 

George Shehatou (PhD)

 

 

Mike Chang (PhD)

 

 

David Pier (PhD)

 

 

Seung Ho Kang (Technician)

 

 

Rachel Hardman (Post Doc)

 

 

Phill Stansfeld (PhD)

 

 

Sarah Nelson (PhD & Post Doc)

 

 

Jenny Bailey (Technician)

 

 

Matthew Perry (Post Doc)

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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Department of Molecular and Cell Biology

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

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