How do faults in the ryanodine receptor lead to abnormal heart rhythms?

Drug-induced stabilisation of RyR2 to improve calcium handling and cardiac function in arrhythmogenic cardiac disease

BHF Senior Basic Science Research Fellow Dr Spyros Zissimopoulos is studying a protein involved in the electrical activity of the heart muscle cells that help the heart beat regularly. Dr Zissimopoulos is looking at how defects in the ryanodine receptor protein, RyR2, lead to abnormal heart rhythms (arrhythmias). RyR2 proteins are channels that allow calcium to flow into heart muscle cells from a large store within the cell – a vital process for the heart to beat properly. Faulty genes (for instance, in the inherited heart condition catecholaminergic polymorphic ventricular tachycardia) can cause abnormal RyR2 opening or closing, resulting in an irregular heartbeat or even sudden death. During his BHF Intermediate Fellowship, Dr Zissimopoulos discovered that communication between the four subunits that make up RyR2 channels is crucial, and this fails when RyR2 is abnormal. He also identified how a drug called dantrolene can partially fix the faults. In this fellowship, Dr Zissimopoulos will find out if the RyR2 defects they discovered are also present in people with inherited heart conditions caused by faults in RyR2 and people with heart failure. They will work out if and how defective RyR2 subunit interactions lead to arrhythmias, and will identify new drugs that could correct faulty RyR2 channels to restore healthy heart function. This research, involving mice, will reveal more about how changes in this channel are involved in irregular heartbeats and other forms of heart disease. It could reveal new ways to treat people with these conditions.