New Paradigms for Human Excitable Cell Disease
Peter Mohler (Davis Heart and Lung Institute, The Ohio State University)
(November 19, 2012 3:00 PM - 3:50 PM)
Our research focuses on the molecular mechanisms underlying ion channel and transporter targeting in cardiac and other excitable cells. In particular, we are interested in the role of membrane-associated ankyrin family of polypeptides in the targeting and function of ion channels and transporters. Our work establishes that loss-of-function mutation in ankyrin-B is the basis for a human cardiac arrhythmia syndrome associated with sinus node dysfunction, repolarization defects, and polymorphic tachyarrhythmia in response to stress and/or exercise ("ankyrin-B syndrome"). Additionally, our work revealed that reduction of ankyrin-B in mice results in reduced levels and abnormal localization of Na/Ca exchanger, Na/K ATPase, and InsP3 receptor at T-tubule/SR sites in cardiomyocytes and leads to altered Ca2+ signaling and extrasystoles that provide a rationale for the arrhythmia. A second line of work in the lab is focused on the role of ankyrin-G for targeting voltage-g ated Na channels in heart. These studies establish a physiological requirement for ankyrins in localization of a variety of ion channels in excitable membranes in the heart and demonstrate a new class of functional 'channelopathies' due to abnormal cellular localization of functionally-related ion channels and transporters.