Large bowl-shaped structure of MG23 channel and typical recording of MG23 cation current oscillations.
Acting Group Leader (Sitsapesan Group)
My research is focused on the functional investigation of ion-channels that are present on intracellular Ca2+-stores in cardiac and skeletal muscle. These channels include not only known Ca2+-release channels such as ryanodine receptors (RyRs) but also novel, uncharacterised cation-channels with unknown physiological roles. For example, using single-channel techniques, I have provided evidence for a novel intracellular cation-conducting channel named mitsugumin23 (MG23), which can form large homo-multimeric structures and it is thought to be involved in the regulation of apoptotic signals in cells. I am also interested in understanding how RyR channels are modulated by other nearby proteins (such as MG23) that may be important in heart failure or other diseases that can lead to sudden cardiac death including junctophilin, calsequestrin and FKBP12/12.6. In a new project, I have been studying the actions of a group of drugs called ‘statins’, and researching into their side effects on muscle cells. I have discovered that a commonly used drug, simvastatin, affects the RyR channels in the heart differently to the RyR channels in skeletal muscle. These effects may contribute both to the usefulness of the drugs and to their side effects.
Quantitative RyR1 reduction and loss of calcium sensitivity of RyR1Q1970fsX16+A4329D cause cores and loss of muscle strength.
Elbaz M. et al, (2019), Hum Mol Genet
Enhanced activity of multiple TRIC-B channels: an endoplasmic reticulum/sarcoplasmic reticulum mechanism to boost counterion currents.
O'Brien F. et al, (2019), J Physiol, 597, 2691 - 2705
Promiscuous attraction of ligands within the ATP binding site of RyR2 promotes diverse gating behaviour.
Lindsay C. et al, (2018), Sci Rep, 8
Simvastatin activates single skeletal RyR1 channels but exerts more complex regulation of the cardiac RyR2 isoform.
Venturi E. et al, (2018), Br J Pharmacol, 175, 938 - 952
Atorvastatin Activates Skeletal RyR1 Channels: Towards Reducing Statin Side-Effects
Lindsay C. et al, (2018), BIOPHYSICAL JOURNAL, 114, 470A - 470A