Grant: Travel Awards - Institute Community Support

The hyperpolarization-activated cyclic nucleotide-gated isoform 4 (HCN4) ion channel is a protein located in the heart that regulates the cardiac pacemaker current. Mutations within this channel often result in cardiac arrhythmias and in severe cases can cause cardiac arrest. This focus of this research was on one particular mutation, S672R, which causes bradycardia (slow heart rate). Bradycardia can be particularly serious as it impairs the delivery of oxygen to parts of the body, which can result in symptoms of tiredness and dizziness and in complicated cases, frequent fainting spells, heart failures or sudden death. The aim of our research is to determine the molecular mechanism by which the S672R mutation causes this disease. We believe that through elucidating the mechanism of this mutation's pathology, we could identify compensatory means for the disease phenotype. For instance, our research revealed that the S672R mutation impacted the binding of a small molecule that helps activate HCN4. We believe that by using a variant of that small molecule that binds stronger than the original, we will be able to offset the impaired activation of the HCN4 channel and increase the heart rate of individuals with bradycardia.