A number of serious human diseases are associated with abnormal targeting and/or organization of ion channels, transporters, and receptors at specialized cell membrane domains. Our research is focused on identifying the cellular pathways underlying membrane protein targeting in cardiac and other excitable cells. In particular, we are interested in the role of the ankyrin family of polypeptides in ion channel and transporter targeting. Our recent work establishes that loss-of-function mutation in ankyrin-B is the basis for a new human cardiac syndrome associated with bradycardia, abnormal heart rate variability, repolarization defects, and polymorphic ventricular arrhythmia. Additionally, our work has revealed that reduction of ankyrin-B in mice results in abnormal localization of functionally-related ion channels and transporters resulting in aberrant myocyte calcium signaling. Current work is focused on two ankyrin-based areas of research directly related to human disease. We are interested in identifying the molecular components of ankyrin-B-dependent targeting of ion channels and transporters to excitable cell membranes. Additionally, we are actively characterizing the role of ankyrin-G in targeting of voltage-gated sodium channels in ventricular cardiomyocytes. Our ultimate goal is to identify new mechanisms to regulate cell excitability in vivo.