Edwin R. Chapman

Investigator, Howard Hughes Medical Institute,
Professor, Department of Physiology
Ph.D., University of Washington

Contact Information
Email: chapman@physiology.wisc.edu
(608) 263-1762 Phone
(608) 265-5512 Fax

Research Interests
Molecular mechanisms that underlie neuronal exocytosis

Visit the Chapman Lab

Our research is focused on understanding the structure, function and dynamics of the exocytotic membrane "fusion machine" that mediates the release of neurotransmitters from neurons. These studies have begun to reveal insights into how the release machinery is regulated and thereby contributes to neuronal plasticity. Neuronal exocytosis is triggered by Ca²⁺ and occurs via the abrupt opening of a pre-assembled fusion pore. Subsequent dilation of the pore results in the complete fusion of the vesicle membrane with the plasma membrane.

We are currently identifying and reconstituting the sequential protein-protein and protein-lipid interactions that underlie excitation-secretion coupling. To delineate this pathway, we have primarily focused on the Ca²⁺-binding synaptic-vesicle protein, synaptotagmin, which appears to function as the Ca²⁺-sensor that regulates release.

Our work is also focused on components of the "SNARE-complex", which is thought to form the core of the fusion apparatus. The rapid kinetics of exocytosis (<1 ms) indicate that only a handful of molecular rearrangements occur to couple Ca²⁺-synaptotagmin to the opening of the fusion pore. We are using a combination of biochemical, biophysical, imaging, spectroscopic and genetic approaches to delineate the interactions/conformational changes that occur during this window of time.

Current experiments include the reconstitution of Ca²⁺-triggered membrane fusion in vitro, visualization of protein rearrangements and vesicle dynamics inside living cells, genetic manipulations to modulate the efficiency of synaptic transmission, time resolved electrophysiological studies to dissect individual steps in the release pathway and to manipulate the properties of the exocytotic fusion pore, and imaging approaches to monitor 'sub-quantal' exocytosis.

Click on figure at left to play movie (caution: 2 MB file, not recommended for slow Internet connection)

Other major interests are focused on the mechanism by which clostridial neurotoxins bind to and enter presynaptic nerve terminals, the selective sorting of proteins in neurons, and membrane*protein interactions.

Click on the figure at right for a larger view.

Selected Publications

• *Chai, Q., *Arndt, J.W., *Dong, M., Tepp, W.H., Johnson, E.A., #Chapman, E.R. and Stevens, R.C.. Structural basis of receptor recognition by botulinum neurotoxin B. Nature 444: 1096-1100.(*equal contribution.)(# corresponding author)
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• Czibener, C., Sherer, N.M., Becker, S.M., Pypaert, M., Hui, E., Chapman, E.R., Mothes, W., and Andrews, N.W.. (2006). Ca2+and synaptotagmin VII-dependent regulation of lysosomal membrane delivery to nascent phagosomes J. Cell Biol. 174(7):997-1007.
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• Hui, E., Bai, J. and Chapman, E.R. (2006). Ca2+ triggers simultaneous penetration of both C2 domains of synaptotagmin I into membranes. Biophysical J. 91: 1767-1777.
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• Liu, W., Montana, V., Bai, J., Chapman, E.R., Mohideen, U. and Parpura,V. (2006). Single Molecule Mechanical Probing of the SNARE Protein Interactions. Biophysical J. 91: 744-758
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• Dong, M., Yeh, Y., Tepp, W.H., Dean, C., Johnson, E.A., Janz, R. and Chapman, E.R.. (2006). SV2 is the protein receptor for botulinum neurotoxin A. Science 312: 592-596.
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• *Bhalla, A., *Chicka, M.C., Tucker, W.C. and Chapman, E.R. (2006) Ca2+*synaptotagmin directly regulates t-SNARE function during reconstituted membrane fusion Nature Struct. Mol. Biol. 13(4): 323-330. *equal contribution.
  Abstract | Full Text | PDF
   
• Jackson, M.B. and Chapman, E.R. (2006). Fusion pores and fusion machines in Ca2+-triggered exocytosis. Annual Review of Biophysics and Biomolecular Structure. 35: 135-160.
   
• Wang, C.T., Bai, J., Chang, P.Y., Chapman, E.R. and Jackson, M.B. (2006). Synaptotagmin*Ca2+ triggers two sequential steps in regulated exocytosis in rat PC12 cells: fusion pore opening and fusion pore dilation. Journal of Physiology 570: 295-307.
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• Wang, P., Chicka, M.C., Richards, D. and Chapman, E.R.. (2005). Synaptotagmin VII is targeted to secretory organelles in PC12 cells where it functions as a high affinity calcium sensor. Mol. Cell. Biol. 25(19): 8693-702.
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• Bhalla, A., Tucker, W. and Chapman, E.R. (2005) Synaptotagmin isoforms couple distinct ranges of Ca2+, Ba2+ and Sr2+ concentration to SNARE-mediated membrane fusion. Mol. Biol. Cell. 16(10): 4755-64.
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• Liu, T., Tucker, W., Bhalla, A., Chapman, E..R. and Weisshaar, J.C. (2005). SNARE-driven, 25-millisecond vesicle fusion in vitro. Biophysical J. 89(4): 2458-72.
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• Hui, E., Bai, J., Sugimori, M., Llinas, R. and Chapman, E.R.. (2005). Three distinct kinetic groupings of the synaptotagmin family - candidate sensors for rapid and delayed exocytosis. Proc. Natl. Acad. Sci. USA 102(14): 5210-5214.
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• Maher, B., MacKinnon II, R.L., Bai, J., Chapman, E.R. and Kelly, P.T. (2005). Activation of intracellular Ca2+ stores modulates glutamate receptor cycling in hippocampal neurons. J. Neurophysiol. 93: 178-188.
  Abstract | Full Text | PDF
   
• Richards, D., Bai, J. and Chapman, E.R. (2005). Two modes of exocytosis revealed by the rate of FM1-43 efflux in hippocampal boutons. J. Cell Biology 168(6): 929-939
  Abstract | Full Text | PDF
   
• Shen S.S., Tucker, W.C., Chapman, E.R. and Steinhardt, R.A. (2005) Molecular regulation of membrane resealing in 3T3 fibroblasts. J. Biol. Chem. 280:1652-60
  Abstract | Full Text | PDF
   

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