Vann Bennett, M.D., Ph.D.
(Johns Hopkins School of Medicine)

James B. Duke Professor, Departments of Cell Biology, Biochemistry, and Neuroscience

Investigator, Howard Hughes Medical Institute

Programs: CMB, Molecular Cancer Biology

A major interest of this laboratory is in understanding how cells in metazoan organisms manage to target ion channels to 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. In collaboration with Piotr Marszalek of Mechanical Engineering we have discovered that ank repeats can function as nanosprings. Ankyrin thus may act as a mechanosensor in addition to its role in protein recognition.

Several discoveries have provided insight into the physiological and clinical significance of ankyrins in the nervous system and heart. We have identified a new cardiac arrhythmia syndrome associated with sudden cardiac death that is caused by loss-of function mutations in ankyrin-B, and have a mouse model for this syndrome. We also have discovered 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 KCNQ2/3 channels from axon initial segments. We have recently discovered that a mutation in the principal voltage-gated sodium channel in the heart (Nav1.5) that blocks ankyrin-G binding also causes cardiac arrhythmia and loss of targeting of Nav1.5 to the cell surface of cardiomyocytes. These studies establish a 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.

E-mail
benne012@mc.duke.edu

361 CARL Building
Box 3892 Duke University Medical Center
Durham, NC 27710

Telephone
919-684-3538, 919-684-3105
Fax
919-684-3590

Selected Publications
Abdi KM, Mohler PJ, Davis JQ, Bennett V. (2006) Isoform specificity of ankyrin-B: a site in the divergent C-terminal domain is required for intramolecular association.   J Biol Chem. 281:5741-9. -PDF-

Lee G, Abdi K, Jiang Y, Michaely P, Bennett V, Marszalek PE. (2006) Nanospring behaviour of ankyrin repeats. Nature.440:246-9. -PDF-

Pan Z, Kao T, Horvath Z, Lemos J, Sul JY, Cranstoun SD, Bennett V, Scherer SS, Cooper EC. (2006) A common ankyrin-G-based mechanism retains KCNQ and NaV channels at electrically active domains of the axon. J Neurosci. 26:2599-613. -PDF-

Mohler, PJ, Davis, JQ, Bennett, V. (2005) Ankyrin-B coordinates the Na/K ATPase, Na/Ca exchanger, and InsP3 receptor in a specialized microdomain of cardiac T-tubules. Plos Biology 3:e423. -PDF-

Ango F, di Cristo G, Higashiyama H, Bennett V, Wu P, Huang ZJ. (2004) Ankyrin-based subcellular gradient of neurofascin, an immunoglobulin family protein, directs GABAergic innervation at Purkinje axon initial segment. Cell 119:257-72. -PDF-

Mohler PJ, Rivolta I, Napolitano C, LeMaillet G, Lambert S, Priori SG, Bennett V. (2004) Nav1.5 E1053K mutation causing Brugada syndrome blocks binding to ankyrin-G and expression of Nav1.5 on the surface of cardiomyocytes. Proc Natl Acad Sci USA. 101:17533-8. -PDF-

Mohler PJ, Yoon W, Bennett V. (2004) Ankyrin-B targets beta 2-spectrin to an intracellular compartment in neonatal cardiomyocytes. J Biol Chem. 279:40185-93. -PDF-

Mohler, P.J., Splawski, I., Napolitano, C., Botteli, G., Sharpe, L., Timothy, K., Priori, S.G., Keatiing, M.T., and Bennett, V. (2004) A cardiac arrhythmia syndrome caused by loss of ankyrin-B function. Proc. Nat. Acad. Sci. USA. 101:9137-42. -PDF-

Kizhatil, K. and Bennett, V. (2004) Lateral Membrane Biogenesis in Human Bronchial Epithelial Cells Requires 190 kDa Ankyrin-G. J. Biol. Chem. 279:16706-16714. -PDF-

Mohler, P. J et al. (2003) Ankyrin-B mutation causes type 4 long QT cardiac arrhythmia and sudden cardiac death. Nature 421:634-639. -PDF-

Bennett, V. Baines, A. Spectrin and ankyrin-based pathways: metazoan inventions for integrating cells into tissues. (2001) Phys. Rev. 81:1353-92. -PDF-