Every heartbeat requires a large change in the level of calcium ions within cardiac cells (cardiomyocytes). This involves release of internal calcium stores caused by the opening of a channel structure known as the cardiac ryanodine receptor (RyR2), which is a large protein composed of four equal subunits. Abnormal RyR2 opening-closing is caused by genetic defects or environmental factors that can produce an irregular heartbeat (arrhythmias) and sudden death.

Research in my laboratory is focused on understanding the structure-function relationship of the RyR2 calcium release channel, as well as its regulation by accessory proteins including calsequestrin and the FK506-binding proteins. Our specific aims are twofold:  first, to elucidate the molecular mechanism(s) underlying RyR2 channel dysfunction and abnormal cardiomyocyte calcium handling in arrhythmogenic disorders. Second, to identify drug(s) that restore RyR2 protein-protein interactions and normal channel properties in order to improve intracellular calcium handling and cardiac function. We use various computational, molecular, cellular and physiological approaches, which are available in my group or provided through collaborators with established expertise. My group is supported by the British Heart Foundation (past Intermediate Fellowship and current Senior Research Fellowship).

Areas of Expertise

  • Calcium signalling
  • Excitation-contraction coupling
  • Arrhythmogenic cardiac disease

Publications

  1. & Calsequestrin interacts directly with the cardiac ryanodine receptor luminal domain. Journal of Cell Science, jcs.191643
  2. & Genetic and Biochemical Approaches for In Vivo and In Vitro Assessment of Protein Oligomerization: The Ryanodine Receptor Case Study. Journal of Visualized Experiments(113)
  3. & Structural and functional interactions within ryanodine receptor: Figure 1. Biochemical Society Transactions 43(3), 377-383.
  4. & Non-ventricular, Clinical, and Functional Features of the RyR2R420Q Mutation Causing Catecholaminergic Polymorphic Ventricular Tachycardia. Revista Española de Cardiología (English Edition) 68(5), 398-407.
  5. & Dantrolene rescues aberrant N-terminus intersubunit interactions in mutant pro-arrhythmic cardiac ryanodine receptors. Cardiovascular Research 105(1), 118-128.

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