Research Areas

Membrane Targeting of Cardiac Ion Channels

The basic function of the heart is to work as a pump, circulating blood throughout the body. For each successful heartbeat, billions of individual heart cells must contract successfully and in coordinated fashion. A biological electrical system based on ion channels exists to regulate contraction and synchronization. In a diseased heart, damage from blocked arteries and infection leads to improper subcellular localization of these ion channels, contributing to both dangerous heart rhythms and congestive heart failure. Because arrhythmias and heart failure are the primary causes of death and disability in the United States, we are very interested in the regulation of ion channel movements in normal and damaged heart cells.

 

Studying and Rescuing Cell-Cell Communication

The primary protein responsible for cell-cell communication in the heart’s main pumping chambers and for cell-cell communication in most organ systems is connexin 43, which forms gap junctions at cell borders. The Shaw Laboratory is focused on understanding the Cx43 life cycle, from transcription regulation (DNA to RNA) to translational regulation (RNA to protein) to forward trafficking and then internalization for degradation. We have learned that Cx43 transcription can be repressed, that Cx43 undergoes alternative translation forming multiple smaller C-terminal truncation isoforms, that Cx43 can be targeted directly to cell-cell borders using the microtubule and actin cytoskeleton, and that internalization follows a complex dynamic cascade of events. We are learning that the pathways involved in these processes are amenable to pharmaceutical manipulation, and the lab is developing therapies that rescue cell-cell communication in diseased hearts.

 

Calcium Channels and Biomarkers that Prognosticate Heart Failure Outcomes

Using connexin 43 as a model of intracellular channel movement, we also found that a reason the L-type calcium channels traffic to cardiomyocyte T-tubules is that the microtubule cytoskeleton delivers the channels to BIN1-enriched membrane at T-tubules. Further we found that BIN1, which is a membrane scaffolding protein, helps determine the strength of each heartbeat, is decreased in diseased and failing hearts, and is blood available. Thus BIN1 is a blood available quantification of the biochemical reserve of failing hearts. In a clinical study, we found that the blood levels of BIN1 in patients with heart failure correlate with cardiac reserve and that a
low blood level of BIN1 also predicts the occurrence of future ventricular arrhythmias. We are in the process of developing BIN1 as a novel blood test is both a diagnostic and prognostic biomarker of chronic heart failure.