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James Fraser BM, BCh, PhD


University Lecturer

Fellow and Director of Studies in Medicine, Gonville and Caius College.

Tel: +44 (0)1223 333815(office), 333891(lab), Fax: +44 (0)1223 333840, E-mail:

Research Interests:  I am interested in cardiac and skeletal muscle electrophysiology. My group uses a combination of computer modelling and experimental work to fully understand the mechanisms underlying both the normal and the pathological behaviours of these tissues. As described below, the use of computer modelling allows us to exploit interesting and helpful synergies between skeletal and cardiac muscle research, accelerating our progress considerably.

Cardiac electrophysiology: Our recent work has focused on the consequences of abnormal Ca2+ homeostasis for cardiac function. We have shown that increased diastolic Ca2+ produces a significant decrease in action potential conduction velocity in both atria (1) and ventricles (2), and that there is a significant correlation between slowed conduction and arrhythmogenicity. This finding directly suggests novel strategies for research, diagnosis and treatment of catecholaminergic polymorphic ventricular tachycardia (CPVT) (see e.g. here), as described in two recent editorials on our papers (here and here).

Skeletal muscle electrophysiology: My work with skeletal muscle forms two broad streams. The first aims to feed findings into my group's cardiac research, while the second is aimed at understanding skeletal muscle electrophysiology with direct relevance to human diseases. The recent focus of the first stream has been on understanding the determinants of conduction velocity in muscle. We have been able to show precisely how conduction velocity is determined and how it is influenced by changes in structure and electrophysiology in health and disease (4, 5). This has informed our work exploring the mechanisms linking abnormal cardiac Ca2+ homeostasis and conduction slowing. Our work in the second stream has recently provided insight into the phenotypic variation in myotonia congenita.

Please see the Research, Teaching and Contact tabs above for further details.

Research Team:

Samantha Salvage (postdoc)

James King (PhD student)

Feifei Ning (visiting postdoctoral scholar)

Luo Ling (visiting doctoral scholar)

Principal Collaborators:

Prof Chris Huang, Department of Physiology, Development and Neuroscience, University of Cambridge.

Dr Andrew Grace, Department of Biochemisty, University of Cambridge.

Assoc Prof Thomas Pedersen, Institute of Physiology and Biophysics, University of Aarhus, Denmark.

Prof Aiqun Ma, Department of Cardiovascular Medicine, Xi'an Jiaotong University, China.

Prof Ron Horgan, Department of Applied Mathematics and Theoretical Physics, University of Cambridge.

Dr Ming Lee, Institute of Cardiovascular Science, University of Manchester.

Dr Yanmin Zhang, Institute of Cardiovascular Science, University of Manchester.

Funding: I am very grateful for the following generous funding:

The Isaac Newton Trust

David Phillips Fellowship from the BBSRC.

Royal Society / National Science Foundation of China International Collaboration Grant

Selected Recent Publications:
To see a full and automatically updated list of my publications please click here)
  1. Lu L, Fraser JA. Functional consequences of NKCC2 splice isoforms: insights from a Xenopus oocyte model. Am J Physiol Renal Physiol. 2014;
  2. Zhang Y, Wang J, Chang S, Zhou N, Xing H, Wang L, Huang C, Ma A, Huang CL-H, Lei M, Fraser JA. The SCN5A Mutation A1180V is Associated With Electrocardiographic Features of LQT3. Pediatr Cardiol. 2014;35:295–300.
  3. King JH, Huang CL-H, Fraser JA. Determinants of myocardial conduction velocity: implications for arrhythmogenesis. Front Physiol. 2013;4:154.
  4. Skov M, Riisager A, Fraser JA, Nielsen OB, Pedersen TH. Extracellular magnesium and calcium reduce myotonia in ClC-1 inhibited rat muscle. Neuromuscul Disord. 2013;23:489–502.
  5. King, J.H., C. Wickramarachchi,  K. Kua, Y. Du, K. Jeevaratnam, H.R. Matthews, A.A Grace, C.L-H.Huang, and J.A. Fraser. 2013. Loss of Nav1.5 Expression and Function in Murine Atria Containing the RyR2-P2328S Gain-of-Function Mutation. Cardiovascular Research 99: 751–9.
  6. King, J.H., Y. Zhang, M. Lei, A.A. Grace, C.L.-H. Huang, and J.A. Fraser. 2013. Atrial arrhythmia, triggering events and conduction abnormalities in isolated murine RyR2-P2328S hearts. Acta physiologica. 207:308-23.
  7. Zhang, Y., J. Wu, K. Jeevaratnam, J.H. King, L. Guzadhur, X. Ren, A.A. Grace, M. Lei, C.L.-H. Huang, and J.A. Fraser. 2013. Conduction Slowing Contributes to Spontaneous Ventricular Arrhythmias in Intrinsically Active Murine RyR2-P2328S Hearts. Journal of Cardiovascular Electrophysiology. 24:210-8.
  8. Wu, J., Y. Zhang, X. Zhang, L. Cheng, W.J. Lammers, A.A. Grace, J.A. Fraser, H. Zhang, C.L.-H. Huang, and M. Lei. 2012. Altered sinoatrial node function and intra-atrial conduction in murine gain-of-function Scn5a+/ΔKPQ hearts suggest an overlap syndrome. American journal of physiology. Heart and circulatory physiology. 302:H1510–23.
  9. Fraser, J.A., C.L.-H. Huang, and T.H. Pedersen. 2011. Relationships between resting conductances, excitability, and t-system ionic homeostasis in skeletal muscle. The Journal of general physiology. 138:95–116.
  10. Pedersen, T.H., C. L-H Huang, and J.A. Fraser. 2011. An analysis of the relationships between subthreshold electrical properties and excitability in skeletal muscle. The Journal of general physiology. 138:73–93.
  11. Fraser, J.A. 2011. Dimethyl sulphoxide addition or withdrawal causes biphasic volume changes and its withdrawal causes t-system vacuolation in skeletal muscle. The Journal of physiology. 589:5555–6.
  12. Huang, C.L.-H., T.H. Pedersen, and J.A. Fraser. 2011. Reciprocal dihydropyridine and ryanodine receptor interactions in skeletal muscle activation. Journal of muscle research and cell motility. 32:171–202.
  13. Zhang, Y., J.A. Fraser, K. Jeevaratnam, X. Hao, S.S. Hothi, A. a Grace, M. Lei, and C.L.-H. Huang. 2011. Acute atrial arrhythmogenicity and altered Ca(2+) homeostasis in murine RyR2-P2328S hearts. Cardiovascular research. 89:794–804.
  14. Zhang, Y., J.A. Fraser, C. Schwiening, M.J. Killeen, A.A. Grace, and C.L.-H. Huang. 2010. Acute atrial arrhythmogenesis in murine hearts following enhanced extracellular Ca(2+) entry depends on intracellular Ca(2+) stores. Acta physiologica (Oxford, England). 198:143–58.
Key Earlier Publications:

(To see a full and automatically updated list of my publications please click here)


I am interested in the electrophysiology of cardiac and skeletal muscle. My aim is to advance understanding of the normal and pathological behaviours of these tissues in order to improve the diagnosis and treatment of cardiac arrhythmias and skeletal muscle pathologies.

My group's strategy is built on a foundation of novel quantitative and experimental techniques that allow continuous cycles of computational analysis, experimental testing and translational assessment. The key theoretical advance has been the development of charge-difference modelling. This allows history-independent modelling (see Figure 1); that is to say, the eventual steady state of the model is independent of the initial value of its variables.


Recent work

My group's recent work has focused on Ca2+ homeostasis in muscle.

In cardiac muscle, abnormalities of intracellular Ca2+ homeostasis are found in common and medically-important conditions as diverse as cardiac failure, atrial fibrillation and cardiac ischaemia. We have employed a model of catecholaminergic polymorphic ventricular tachycardia (CPVT), the RyR2-P2328S mouse, in order to study abnormal Ca2+ homeostasis in isolation. We then aim to apply what we learn in this important, though rare condition to understand the influence of abnormal Ca2+ homeostasis within the more complex multifactorial abnormalities that occur in more common conditions such as atrial fibrillation.

We have found that increased diastolic Ca2+ increases the incidence of both atrial and ventricular arrhythmias (King et al, 2012; Zhang et al, 2012). This is true whether the increased diastolic Ca2+ is brought about acutely, for example with caffeine, or chronically, as a result of a gain-of-function mutation in the cardiac ryanodine receptor (RyR2-P2328S). Using a multielectrode array (click to see image) we demonstrated a reduction in myocardial conduction velocity in RyR2-P2328S hearts. We further showed that this increased the risk that an ectopic stimulus would produce a sustained arrhythmia. This work, and its implications, is well summarized in two recent editorials (here and here).

In skeletal muscle, we have studied the influence of the transverse tubular system on excitability, conduction velocity and ionic homeostasis. We first developed models of skeletal muscle (Pedersen et al, 2011; Fraser et al, 2011) that allowed us to describe the complex interactions between surface and transverse-tubular electrical activity and changes in ion concentrations during repetitive activity. The models allowed us to use experimental work to indirectly measure some important variables that are otherwise impossible to directly measure, including the rapid changes in K+ concentration in the transverse tubular system during exercise.

This strong theoretical framework has allowed us to understand pathologies in which there are severe abnormalities of skeletal muscle electrophysiological homeostasis, including myotonia congenita and myasthenia gravis, and thereby begin in vitro testing of possible therapies for these diseases. The first outputs of this work-stream will be published imminently, so watch this space...

Previous landmark findings from my research include:

A full quantitative description of the determinants of cell volume and the resting potential (Fraser & Huang, 2004.) We highlighted the importance of the osmolality and the mean charge of membrane impermeant anions in determining cell volume and the membrane potential.

Further modelling suggested that intracellular acidification would cause cellular shrinkage due to titration of the charges carried by membrane-impermeant intracellular anions. We confirmed this by demonstrating that intracellular acidification causes cell volume reduction and K+ loss: see Figure 2, (from Fraser, Middlebrook et al, 2005.)

The discovery that skeletal muscle regulates its membrane potential at the expense of its cell volume during osmotic stress (Ferenczi, Fraser et al, 2005; Fraser, Rang et al, 2005.)

Website under construction




Office:     A4, Physiological Laboratory.

                Tel: +44 (0)1223 333815

                Fax: +44 (0)1223 333840

Lab:        A2, A1: Tel: 33891

College:  K12, St. Mary's Court, Gonville & Caius College

                Tel: 01223 701328

Online:   ResearchGate


I will be pleased to consider applications from prospective PhD students by email.