This project is designed to query the biological impact and molecular basis of a known proarrhythmic cellular kinase, CaMKII, to regulate a voltage-gated potassium current, IKs. Sustained adrenergic receptor stimulation, a hallmark of heart failure, increases the risk for the development of fatal ventricular arrhythmias. During sustained adrenergic stimulation, CaMKII activity is enhanced while IKs function is decreased. Both mechanisms are known to increase arrhythmogenicity. This study will reveal if sustained adrenergic receptor stimulation decreases IKs through CaMKII signaling. A decrease in IKs function during heart failure could have therapeutic implications since the reduced function of this current prolongs repolarization. The central hypothesis is that CaMKII functionally inhibits IKs to prolong repolarization during sustained adrenergic receptor stimulation by altering the assembly of the pore forming subunit, KCNQ1, with the auxiliary subunit, KCNE1. We propose a systematic series of investigations that will assess the phosphorylation status of endogenous KCNQ1, function of IKs with a biologically relevant background, and KCNQ1-KCNE1 assembly and trafficking during enhanced CaMKII activation.
In Specific Aim 1, we will assess the ability of CaMKII-mediated IKs regulation to contribute to arrhythmia development during sustained adrenergic receptor stimulation.
In Specific Aim 2, we will probe a potential mechanism for IKs functional reductions during post-translational modifications through KCNQ1-KCNE1 complex assembly. Overall, this research sequence has been designed to provide feasibility studies while demonstrating the development of innovative technology to assess the impact of post- translational modifications on protein-protein interactions. Thus, this research will provide a mechanistic framework with informative feasibility data to justify further research to assess and modulate molecular mechanisms whereby heart failure promotes a susceptibility to arrhythmias.
Patients with heart failure are at an increased risk to develop arrhythmias which substantially contributes to their morbidity and mortality. This proposal will guide a better understanding of the molecular mechanisms whereby heart failure promotes a susceptibility to arrhythmias. Ultimately, understanding these mechanisms could inform a therapeutic strategy to prevent sudden cardiac death.
