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

Contact Information
361 Carl Building
(PH) 919-684-3538
(FX) 919-684-3590
benne012@mc.duke.edu

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Education

	MD	Johns Hopkins School of Medicine, 1976
	PhD	Adenylate Cyclase and the Mechanism of Action of Cholera Toxin, Department of Pharmacology, Johns Hopkins School of Medicine, 1974
	AB	Chemistry and Biology, Stanford University, 1970

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Experience

	2003-present	James B. Duke Professor, Duke University Medical Center, Durham, NC
	2002-present	Department of Neuroscience, Vice-chair, Department of Cell Biology
	1994-present	Professor, Department of Cell Biology
	1987-present	Professor, Department of Biochemistry and Investigator, Howard Hughes Medical Institute, Duke University Medical Center
	1987	Professor, Department of Cell Biology and Anatomy, The Johns Hopkins School of Medicine, Baltimore, Maryland
	1983-1987	Associate Professor, Department of Cell Biology and Anatomy, The Johns Hopkins School of Medicine, Baltimore, Maryland
	1981-1983	Assistant Professor, Department of Cell Biology and Anatomy, The Johns Hopkins School of Medicine, Baltimore, Maryland
	1977-1980	Staff Scientist in the Department of Molecular Biology, Wellcome Research Laboratories, Research Triangle Park, North Carolina, 1977-1980
	1976	Post-doctoral fellow with Dr. Daniel Branton at the Biological Laboratories, Harvard University, Cambridge, Massachusetts
	1975	Post-doctoral fellow with Dr. Pedro Cuatrecasas, Department of Pharmacology, Johns Hopkins School of Medicine, Baltimore, Maryland

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Selected Publications

1. Bennett, V. and P. Stenbuck. 1979. "The membrane attachment site for spectrin is associated with band 3 in human erythrocyte membranes. Nature, 280(5722), 468-473.
2. Bennett, V. 1979. "Immunoreactive forms of human erythrocyte ankyrin are present in diverse cells and tissues," Nature, 281(5732), 597-598.
3. Lux, S.E., John, K.M. and Bennett, V. 1990. "Analysis of cDNA for human erythrocyte ankyrin indicates a repeated structure with homology to tissue- differentiation and cell-cycle control proteins," Nature, 344(6261), 36-42.
4. Otto, E., Kunimoto, M., McLaughlin, T. and Bennett, V. 1991. "Isolation and characterization of cDNAs encoding human brain ankyrins reveal a family of alternatively-spliced genes. Journal of Cell Biology, 114(2), 241-253.
5. Davis, J.Q., McLaughlin, T., and Bennett, V. 1993. "Ankyrin-binding proteins related to nervous system cell adhesion molecules: candidates to provide transmembrane and intercellular connections in adult brain," Journal of Cell Biology, 232(1), 121-133.
6. Kordeli, E., Lambert, S. and Bennett, V. 1995. "AnkyrinG: a new ankyrin gene with neural-specific isoforms localized at the axonal initial segment and node of Ranvier," Journal of Biological Chemistry, 270(5), 2352-2359.
7. Zhou, D., Lambert, S., Malen, P.L., Carpenter, S., Boland, L.M., and Bennett, V. 1998. "AnkyrinG is required for clustering of voltage-gated Na channels at axon initial segments and for normal action potential firing," Journal of Cell Biology, 143(5), 1295-1304.
8. Jenkins, S.M., and V. Bennett. 2001. "Ankyrin-G coordinates assembly of the spectrin-based membrane skeleton, voltage-gated sodium channels, and L1 CAMs at Purkinje neuron initial segments," Journal of Cell Biology, 155(5), 739-46.
9. Mohler, P.J., Gramolini, A.O. and Bennett, V. 2002. "The ankyrin-B C-terminal domain determines activity of ankyrin-B/G chimeras in rescue of abnormal inositol 1,4,5, triphosphate and Ryanodine receptor distribution in ankyrin-B(-/-) neonatal cardiomyocytes," Journal of Biological Chemistry, 277(12), 10599-10607.
10. Mohler, P.J., Schott, J.-J., Gramolini, A.O., Dilly, K.W., Guatimosim, S., duBell, W.H., Song, L.-S., Haurogne, K., Kyndt, F., Ali, M.E., Rogers, T.B., Lederer, W.J., Escande, D., Le Marec, H., and Bennett, V. 2003. "Ankyrin-B mutation causes type 4 long-QT cardiac arrythmia and sudden cardiac death," Nature, 421(6923), 634-639.

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Patents

1. Methods of Modulating Localization and Physiological Function of IP3 Receptors; filed on January 3, 2003; Serial No. 10/336,031

 

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Short Research Interest Descriptor

Cellular mechanisms for targeting ion channels and other signaling molecules to sites of physiological action.

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Research Interest

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 and couple these proteins to the spectrin-based membrane skeleton. Currently identified ankyrin partners are anion exchangers, the Na/K ATPase, the voltage-dependent sodium channel, and the Na/Ca exchanger. Ankyrin(s) also associate with calcium-release channels including both IP3 and ryanodine receptors. Finally, ankyrins also bind to cell adhesion molecules of the L1 CAM family (L1/neurofascin/ NrCAM/ NgCAM in vertebrates; neuroglian in Drosophila; LAD-1 in C. elegans). 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 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 Directions: 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).

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