Neurons communicate with each other via chemical signals called neurotransmitters. When a neuron fires, synaptic vesicles filled with neurotransmitters fuse with a nerve cell’s plasma membrane to release their contents into the synaptic cleft. The neurotransmitters then bind to receptors on postsynaptic cells. Edwin Chapman and his team study proteins and molecular triggers that mediate this chemical release. In parallel, his team also investigates the mechanisms that mediate the release of hormones from neurons and neuroendocrine cells.
Chapman’s lab was the first to reconstitute calcium-triggered membrane fusion in vitro, and his team has pioneered studies to look at how the calcium-binding protein synaptotagmin 1 (syt1) triggers membrane fusion. They discovered that syt1 and a set of proteins that mediate vesicle-membrane fusion, called SNAREs, are the minimum complement of proteins essential for calcium triggered fusion. More recently, his laboratory showed that the exocytotic fusion pore is a hybrid structure, composed of both lipids and the transmembrane domains of SNARE proteins. The team is now focused on discerning the functions of a number of additional synaptic and membrane trafficking proteins, which have already been cloned. For example, they recently discovered that a protein named Doc2 drives the slow, asynchronous phase of synaptic transmission.
Chapman is also interested in the botulinum neurotoxins (BoNTs), which block exocytosis. BoNTs inhibit vesicle-membrane fusion by cleaving SNARE proteins, which halts fusion and neurotransmitter release. Chapman’s team discovered the receptors for most of the BoNTs, and showed that they sneak into an open vesicle when it’s exposed during exocytosis. Now, they are looking at what happens once the toxin has infiltrated the neuron, investigating the possibility of “distal effects,” or the toxin’s ability to jump from neuron to neuron in a circuit, doing damage along the way.
In recent years, Chapman has also started to explore organelle trafficking in neurons, looking at how mitochondria and lysosomes move through cells to regulate synaptic function, and to understand how neurons become so highly polarized.