OSU BME Seminar Series: Dr. Steven Poelzing, Fralin Biomedical Research Institute at Virginia Tech Carilion

Steven Poelzing, PhD
Professor
Translational Biology, Medicine, and Health 
Fralin Biomedical Research Institute at Virginia Tech Carilion

Abstract:

"Sodium Channel Autoregulation as a Mechanism of Concealed Monogenic Disease."

A number of well-studied monogenic cardiovascular diseases are concealed or intermittent in many patients. Despite decades of basic science investigations demonstrating severe protein loss- or gain-of-function, manifest disease is sometimes found in isolated whole-heart preparations or in vivo measurements. In short, the phenotypic manifestation of severe monogenic diseases are intermittently reported in basic science studies. Dr. Poelzing’s lecture will explore voltage-gated sodium channel loss and gain-of function as exemplars that connect the translational spectrum of isolated cell measurements to in vivo electrophysiology. He will make the case that controversial findings in the basic science literature offer insights into why it is often difficult for physicians to detect a disease or offer a prognosis based on genetic testing alone. He will present data on how subcellular nanodomain voltage-gated sodium channel localization autoregulates sodium currents. By disrupting sodium channel autoregulation, he and his collaborators demonstrate how sometimes concealed and intermittent diseases like the Brugada Syndrome and the Long-QT Syndrome Type 3 can present on an ECG during one office visit and be concealed in another.

Bio:

My laboratory focuses on the electrophysiologic substrates leading to abnormal ventricular conduction. With respect to the current proposal, I am interested in the mechanisms that can mask and unmask a relationship between intercalated disc proteins and myocardial repolarization. We have been elucidating the role of ephaptic, or non-gap junction/ non-synaptic, mediated communication between myocytes. We have discovered that sodium and potassium channel localization in specialized sarcolemmal nano-domains next to the gap junction plaque, termed the perinexus, could mediate electrical transmission from cell to cell.  We further demonstrated that our experimental data is incompatible with cable theory, and well explained by models incorporating detailed cellular distribution of sodium channels leading to ephaptic coupling. During the course of the studies, we demonstrated that cell size, sodium channel localization to the intercalated disc, and volume of the intercalated disc modulate voltage-gated sodium channel gain of function associated with acquired and monogenic diseases like the Long-QT Syndrome Type 3. The work is critically important as a model of understanding voltage gated sodium channel gain of function that occurs in more complicated pathologies like heart failure. The mechanism for concealing sodium channel gain of function occurs via depletion of extracellular sodium in intercalated disc nanodomains like the perinexus, such that channels can still conduct, but the driving force for ionic movement into the cell is reduced. In this upcoming proposal, we focus on the localization of potassium channels in the intercalated disc and the role of clinically relevant hypokalemia in modulating sodium channel gain-of-function diseases. The ultimate goal of this proposal is to develop a point-of-care biomarker of enhanced arrhythmogenesis, and so we employ a strategy incorporating structural biology, computational modeling, isolated whole-heart electrophysiology, and in vivo, non-sedated assessment of plasma ionic composition and surface ECG.