The expression of ion channels that underlie the rhythmic beating of the heart must be precisely coordinated to fulfill their physiological roles and protect the heart from arrythmias. Repolarization is a particularly vulnerable phase of the cardiac action potential, where even slight imbalance of inward and outward currents can prolong action potential duration and trigger arrhythmias. But mechanisms of how cells maintain the proper expression ratios of different ion channels is unknown. Our lab has identified a physical association of transcripts encoding hERG1a and 1b subunits, which assemble to form cardiac IKr channels, and SCN5A, which encodes the alpha subunit of the predominant depolarizing cardiac Na+ channel (Nav1.5) responsible for native INa and the late Na+ (INa,late) current. These transcripts are physically associated while undergoing translation, or co-translationally associated, and are co-regulated as seen by targeted hERG transcript degradation via short hairpin RNA (shRNA). We find a coordinated reduction of SCN5A transcript levels following hERG shRNA targeting, as well as a reduction in native IKr, INa, and INa,late currents recorded from cardiomyocytes. We recently have found that other ion channel transcripts important for the balance of repolarization, such as CACNA1C, encoding the L-type calcium channel, and KCNQ1, encoding another repolarizing potassium channel, are also associated. I hypothesize that co-translational association and regulation of transcripts is a novel mechanism to establish a balance of opposing conductances in the heart. This proposal looks to discern the components of these complexes and to test if they predict stable protein macromolecular assembles of ion channels at the cell membrane. Successful outcome of this proposal will shift the thinking of how excitable cells maintain the proper ratios of ion channels and may have implications on how translational mechanisms govern macromolecular protein assemblies.
|Program type||Predoctoral Fellowship|
|Effective start/end date||01/01/2020 → 12/31/2021|