Overview
We have recently reported that humans heterozygous for a E1425G loss-of-function mutation in ankyrin-B and mice heterozygous for a null mutation in ankyrin-B have type 4 long QT syndrome, a cardiac arrhythmia associated with sudden cardiac death. We also have discovered that ankyri9n-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 co-ordination 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, neurofascin (a member of the L1CAM family), and beta IV spectrin from axon initial segments. These studies, together with the role of ankyrin-B in type 4 long QT syndrome, 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.
Future research will be based on the discovery that ankyrin-B and ankyrin-G have physiological roles as coordinators of multiple functionally related proteins in specialized cell membrane compartments. A major effort will be to understand mechanisms, beginning at a protein level with ankyrin-B structure and function, and including the cellular basis for ankyrin-B-dependent protein sorting in cardiomyocytes. We also plan to study the roles of ankyrins B and G in ion channel organization in the visual system using targeted gene knockouts in rods, retinal ganglion neurons, and retinal pigmented epithelial cells (mice with loss of function may be blind but should be viable).
Current Appointments & Affiliations
George Barth Geller Distinguished Professor of Molecular Biology
·
2012 - Present
Biochemistry,
Basic Science Departments
Professor Emeritus of Biochemistry
·
2023 - Present
Biochemistry,
Basic Science Departments
Member of the Duke Cancer Institute
·
1987 - Present
Duke Cancer Institute,
Institutes and Centers
Education, Training & Certifications
Johns Hopkins University ·
1976
M.D.
Johns Hopkins University ·
1975
Ph.D.