Faculty: Edwin R. Chapman, PhD
|Dept:|| Professor, Neuroscience
Investigator, Howard Hughes Medical Institute
|Lab Page:||Click Here|
Figure 1. Model of the molecular mechanism of
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 and kinetics of synaptic transmission, and time resolved optical and electrophysiological studies to dissect individual steps in the release pathway and to manipulate the properties of the exocytotic fusion pore.
More recently, we have expanded our efforts to study how changes in membrane trafficking underlie synaptic plasticity and to elucidate the molecular basis for asynchronous synaptic transmission.
Finally, we study the actions of the clostridial neurotoxins, which cause botulism and tetanus poisoning, with emphasis on identifying the pathways of entry, the receptors that mediate entry, and the translocation of the toxins across membranes.
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
Other Positions & Affiliations
- Investigator, Howard Hughes Medical Institute
Selected Publications: (Find recent publications on PubMed)
- Liu H, Chapman ER, Dean C."Self" versus "non-self" connectivity dictates properties of synaptic transmission and plasticity.PLoS One. 2013 Apr 29;8(4):e62414. doi: 10.1371/journal.pone.0062414. Print 2013. PMID: 23658626 [PubMed - in process]
- Beetz C, Johnson A, Schuh AL, Thakur S, Varga RE, Fothergill T, Hertel N, Bomba-Warczak E, Thiele H, Nürnberg G, Altmüller J, Saxena R, Chapman ER, Dent EW, Nürnberg P, Audhya A. Inhibition of TFG function causes hereditary axon degeneration by impairing endoplasmic reticulum structure.Proc Natl Acad Sci U S A. 2013 Mar 26;110(13):5091-6. doi: 10.1073/pnas.1217197110. Epub 2013 Mar 11. PMID: 23479643 [PubMed - indexed for MEDLINE]
- Kwon SE, Chapman ER. (2012) Glycosylation is dispensable for sorting of synaptotagmin 1 but is critical for targeting of SV2 and synaptophysin to recycling synaptic vesicles. J Biol Chem. 2012 Oct 12;287(42):35658-68. doi: 10.1074/jbc.M112.398883. Epub 2012 Aug 20. PMID: 22908222 [PubMed - indexed for MEDLINE]
- Wu Y, Gu Y, Morphew MK, Yao J, Yeh FL, Dong M, Chapman ER. (2012) All three components of the neuronal SNARE complex contribute to secretory vesicle docking. J Cell Biol. 198(3):323-30. doi: 10.1083/jcb.201106158. PMID: 22869597 [PubMed - indexed for MEDLINE]
- Saludes JP, Morton LA, Ghosh N, Beninson LA,Chapman ER, Fleshner M, Yin H. (2012) Detection of highly curved membrane surfaces using a cyclic peptide derived from synaptotagmin-I.ACS Chem Biol. 7(10):1629-35. Epub 2012 Jul 17. PMID: 22769435 [PubMed - in process]
- Yao J, Gaffaney JD, Kwon SE and Chapman, ER. (2011). Doc2 is a Ca2+-sensor required for asynchronous neurotransmitter release. Cell 147:666-77. PMCID:PMC3220409
- Hui E, Johnson C., Yao J, Dunning M, and Chapman, ER. (2009). Synaptotagmin-mediated bending of the target membrane is a critical step in Ca2+-regulated fusion. Cell 138: 709-721.PMCID: PMC2758036
- Dong, M, Yeh ., Tepp WH, Dean C, Johnson EA, Janz R. and Chapman ER. (2006). SV2 is the protein receptor for botulinum neurotoxin A. Science 312:592-596.