A major interest of this laboratory is understanding how our cells manage to precisely target ion channels and other membrane-spanning proteins to the physiological sites that optimize their physiological efficiency.

Our research began with discovery of the ankyrin family of membrane-adapter proteins, which interact with structurally diverse membrane proteins (Na/K ATPase, Na/Ca exchanger, anion exchanger, voltage-gated Na channels, IP3 R, L1 cell adhesion molecules) and couple these proteins to the spectrin-based membrane skeleton. Ankyrins interact with these diverse proteins through a motif known as ANK repeats, which are found in many different proteins and operate in protein recognition for multiple, structurally unrelated ligands.

We have recently identified a new cardiac arrhythmia syndrome associated with sudden cardiac death that is caused by loss-of-function mutations in ankyrin-B. We have a mouse model for this syndrome. We also have discovered that ankyrin-B mutation results in reduced levels of Na/Ca exchanger, Na/K ATPase, and IP3 R at T-tubule sites in cardiomyocytes and leads to altered Ca2+ signaling and extrasystoles that provide a rationale for the arrhythmia. This work has identified a new mechanism for cardiac arrhythmia due to abnormal coordination of multiple, functionally related ion channels and transporters.

We have also found that conditional knockout of ankyrin-G in the mouse cerebellum results in severe ataxia accompanied by coordinate loss of the sodium channel Nav1.6, KCNQ2/3 channels responsible for M-current, neurofascin (a member of the L1CAM family), and beta IV spectrin from axon initial segments. We have recently identified a human mutation in the ankyrin-binding site of the cardiac sodium channel that causes Brugada syndrome and results in loss of sodium channel localization at T-tubules and intercalated discs. These studies establish a physiological requirement for ankyrins in localization of a variety of ion channels in excitable membranes in the heart and nervous system, and suggest a new class of functional channelopathies due to abnormal cellular localization.

Laboratory personnel currently include one undergraduate student, two graduate students, three post-doctoral fellows, and four permanent staff.