All day, every day, brain cells process and release neurotransmitters, hormones, and other compounds to their neighboring cells. This traffic begins inside the neuron, where the cell neatly packages molecules into vesicles, which travel to the cell's surface membrane and spill out into the synapse. For decades, scientists have known that these are the fundamental steps in nerve cell communication. Now, they're using molecular tools to zoom in for a closer look—and discovering neural dynamics in unprecedented detail.
Edwin Chapman is focusing, in particular, on the fusion pore, a watery channel that opens in the neuron. Scientists have known for some time that this pore connects synaptic vesicles to the cell membrane and thus allows outgoing molecules to exit the cell, but their view of how this pore operates is shifting. They now suspect that, in some cases, the fusion pore can release chemicals from the neuron without the vesicle ever fusing with the cell membrane.
Chapman is determining precisely how fusion pores function and how they are structured. Using a broad toolkit, from stopped-flow techniques—methods used to measure the kinetics of chemical reactions—to genetic manipulations, he and his colleagues have developed an experimental system that mimics membrane fusion at the lab bench. With this assay, Chapman's lab has begun isolating and quantifying the molecular mechanisms behind exocytosis. They're using fluorescent probes, for instance, to capture protein-protein interactions in real time. With sophisticated biophysical techniques, the lab not only studies fusion pores in vitro but is at the cutting edge of the study of these structures in their cellular environment, using cultured cell lines and neurons.
One critical component of these experiments is synaptotagmin (SYT), a vesicle protein that appears to help open and close fusion pores. SYT also appears in a darker corner of Chapman's lab. He and his colleagues have found that SYT, together with a ganglioside lipid, serves as a receptor for botulinum neurotoxin B. The deadliest of all substances, botulinum toxin is considered a bioterrorist threat. The researchers have developed decoys that effectively neutralize the toxin and have built two rapid-fire tests to detect it.
Dr. Chapman is also Professor of Physiology at the University of Wisconsin–Madison.
RESEARCH ABSTRACT SUMMARY:
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Edwin Chapman's research is focused on understanding the molecular basis by which Ca2+ triggers the exocytosis of neurotransmitters from neurons, and how changes in this process underlie aspects of synaptic plasticity. The lab is also focused on the cell biology of the clostridial neurotoxins, which cause botulism and tetanus.
Photo: Brian Ebner/AP, © HHMI