Faculty: Edwin R. Chapman
|Training Areas:||Molecular & Cellular Pharmacology|
Cellular & Molecular Biology
Figure 1. Model of the molecular mechanism of
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.
Figure 2.Imaging synapses from hippocampal neurons
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.
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.
Honors & Awards
- 2012 Kellett Mid-Career Award
- 2012 Rose Award (to Sam Kwo - outstanding thesis in the neurosciences)
- 2009 Rose Award (to Enfu Hui - outstanding thesis in the neurosciences)
- 2008 Rose Award (to Michael Chicka - outstanding thesis in the neurosciences)
- 2004 Romnes Award
- 2004 Rose Award (to Min Dong - outstanding thesis in the neurosciences)
- 2003 Rose Award (to Jihong Bai - outstanding thesis in the neurosciences)
- 2002 Editorial Board, JBC
- 1999 PEW Award
- 1999 Dave McClain AHA Award
- 1998 Shaw Scientists Award
- 1996 U. of Wisconsin/Howard Hughes Medical Institute Career Development Award
- 1996 U. of Wisconsin/Howard Hughes Medical Institute Infomatics Award
Other Positions & Affiliations
- Investigator, Howard Hughes Medical Institute
Selected Publications: (Find recent publications on PubMed)
- Morton LA, Yang H, Saludes JP, Fiorini Z, Beninson L, Chapman ER, Fleshner M, Xue D, Ying H. MARCKS-ED peptide as a curvature and lipid sensor. ACS Chem Biol. 2013 Jan 18;8(1)218-25. doi: 10.1021/cb300429e. Epub 2012 Oct 29. PMID: 23075500
- Kwon SE, Chapman ER. Glyosylation is dispensable for sorting of synaptotgamin 1 but is critical for targeting of SV2 and synaptophysin to recylcing synaptic vesicles. J Biol Chem. 2012 Oct 12;287(42):35658-68. doi: 10.1074/jbc.M112.398883. Epub 2012 Aug 20. PMID 22908222
- Wu Y, Gu Y, Morphew MK, Yao J, Yeh FL, Dong M, Chapman ER. All three components of the neuronal SNARE complex contribute to secretory vesicle docking. J Cell Biol. 2012 Aug 6;198(3):323-30. doi: 10.1083/jcb.201106158. PMID: 22869597
- Saludes JP, Morton LA, Ghosh N, Beninson LA, Chapman ER, Fleshner M, Yin H. Detection of highly curved membrane surfaces using a cylcic peptide derived from synaptotagmin-I. ACS Chem Biol. 2012 Oct 19;7(10):1629-35. doi: 10.1021/cb3002705. Epub 2012 Jul 17. PMID: 22769435
- Sun S, Tepp WH, Johnson EA and Chapman ER. (2012) Botulinum Neurotoxins B and E Translocate at Different Rates and Exhibit Divergent Responses to GT1b and Low pH. Biochemistry. 2012 Jul 2. [Epub ahead of print] PMCID: PMC3398548
- Dean C, Liu H, Staudt T, Stahlberg MA, Vingill S, Bückers J, Kamin D, Engelhardt J, Jackson MB, Hell SW, and Chapman ER. (2012) Distinct subsets of Syt-IV/BDNF vesicles are sorted to axons versus dendrites and recruited to synapses by activity. J Neurosci. 32:5398-5413. PMID: 22514304
- Dean C, Dunning FM, Liu H, Bomba-Warczak E, Martens H, Bharat V, Ahmed S, and Chapman ER. (2012) Axonal and dendritic synaptotagmin isoforms revealed by a pHluorin-syt functional screen. Mol Biol Cell. 23:1715-1727. PMCID: PMC3338438
- Striegel AR, Biela LM, Evans CS, Wang Z, Delehoy JB, Sutton RB, Chapman ER, and Reist NE. (2012) Calcium binding by synaptotagmin's C2A domain is an essential element of the electrostatic switch that triggers synchronous synaptic transmission. J Neurosci. 32:1253-1260. PMID: 22279210
- Yao, J, Gaffaney, J.D., Kwon, S.E. and Chapman, E.R.. (2011). Doc2 is a Ca2+-sensor required for asynchronous neurotransmitter release. Cell 147(3):666-77. PMID: 22036572 [PMCID - in process]
- Yao J, Kwon SE, Gaffaney JD, Dunning FM, and Chapman, ER. (2011). Uncoupling the roles of synaptotagmin I as a dual Ca2+ sensor during endocytosis and exocytosis of synaptic vesicles. Nature Neuroscience 15:243-249.
- *Kwon, S.E. and Chapman, E.R.. (2011). Synaptophysin regulates the kinetics of synaptic vesicle endocytosis in central neurons. Neuron 70: 847-854. PMID: 21658579 [PMCID - in process]
- Hui E, Gaffaney JC, Wang Z, Johnson C, Evans C. and Chapman ER. (2011). Mechanism and function of synaptotagmin-mediated membrane apposition. Nature Struct. Mol. Biol. 18:813-821. PMID: 21642967 [PMCID - in process]
- Sun S, Suresh S, Liu H, Tep, WH, Johnson EA, Edwardson JM, and Chapman ER. (2011). Probing the assembly of a botulinum neurotoxin translocation channel. Cell Host & Microbe 10:237-247. PMCID: PMC3243646
- Wang Z, Liu H, Gu Y and Chapman, ER. (2011) Reconstituted synaptotagmin I mediates vesicle docking, priming, and fusion. J. Cell Biol. 195:1159-1170. PMCID: PMC3246889
- Yeh F, Zhu Y, Tepp WH, Johnson EA, Bertics PJ, and Chapman ER. (2011) Retargeting clostridial neurotoxins to macrophages reduces TNFα release. Biochemistry 50:10419-10421. PMCID: PMC3226321
- Wu, Y., Ma, L., Cheley, S., Bayley, H., Cui, Q. and Chapman, E.R. (2011) Permeation of styryl dyes through nanometer-scale pores in membranes. Biochemistry (in press). PMID: 21815625 [PMCID - in process]
- Wang D, Zhang Z, Dong M, Sun S, Chapman ER, and Jackson MB. (2011) Syntaxin requirement for Ca2+-triggered exocytosis in neurons and endocrine cells demonstrated with an engineered neurotoxin. Biochemistry 50: 2711-2713. PMID: 21401123 [PMCID - in process]