BME Seminar Series: Dr. Isabelle Deschenes, The Ohio State University
"Cardiac Sodium Channels: Lessons Learned from Bedside to Bench"
Modification in Na+ current (INa) is known to contribute to both cardiac arrhythmias from acquired heart diseases and inherited cardiac arrhythmias. Since the original cloning of the genes encoding for voltage-gated sodium channels and the recording of its function by patch-clamping, the a-subunit of the sodium channel was thought to be a monomer. However, our studies of mutations found in SCN5A linked to different arrhythmic syndromes led us to question the traditional idea of the sodium channel forming a monomer. In fact, we and others have shown that several Brugada Syndrome (BrS) mutations display dominant-negative effects (DN-effect), which could only be attributed to interaction between a-subunits within multimeric complexes. Similarly, we have shown that the defects of several BrS or LQT3 SCN5A mutations could be rescued by different SCN5A polymorphisms expressed on a separate construct, again supporting the idea of an a-a subunit interaction. We demonstrated using different experimental approaches that sodium channels form functional dimers. We also identified the region modulating the dimerization and found that this physical dimerization results in coupled gating of the sodium channels and involves 14-3-3. We further demonstrated that the biophysical coupling is dynamically modulated. Understanding of the mechanisms involved in channel dimerization and functional biophysical coupling could open the door to new approaches and targets to treat and/or prevent sodium channelopathies and dysregulation of INa in heart failure.
Isabelle Deschênes, Ph.D. is Professor and Chair of the Department of Physiology and Cell Biology at The Ohio State University. She came to OSU in August of 2019 from Case Western Reserve University where she was Director of the Heart and Vascular Research Center at The MetroHealth System Dr. Deschênes’ research focuses on the molecular basis of cardiac arrhythmias. Her work provides key insights into the fundamental basis of our understanding of the electrical function of the heart, which is critical for the much-needed design of novel cardiac therapies for cardiac arrhythmias. Her work combines the use of molecular and electrophysiological techniques to study several inherited arrhythmias caused by defects in ion channels such as Long QT and Brudada Syndrome and more commons forms of arrhythmias dues to acquired disease states such as heart failure. Recently her work has focused on the study of the genotype-phenotype discordance observed in several inherited arrhythmias. Results obtained from her translational research focus on incomplete penetrance in inherited arrhythmias have also been applied to a more basic focus allowing her to make fundamental findings on ion channels structure, assembly, trafficking and transcriptional regulation all of which contribute to the development of arrhythmias. Her lab also has extensive experience studying the regulation of ion channels by miRNAs and transcriptional regulation of ion channels. Dr. Deschênes has authored or co-authored more than 100 original scientific manuscripts, chapters, reviews and abstracts. She serves on the review panels of numerous national and international study sections and is the past Chair of the NIH Electrical Signaling, Ion Transport, and Arrhythmias Study Section.