EDITOR’S CHOICE IN NEUROSCIENCE

There is very little about membrane vesicle fusion that Yale University biochemist James Rothman doesn’t know—he codiscovered SNAREs, the proteins that orchestrate the process. But one unanswered question in the field of membrane fusion has been what happens during the first milliseconds of synaptic transmission between neurons—when a vesicle full of neurotransmitters inside a neuron fuses to the cell membrane, opening a pore to release its contents into the synapse.

A fusion pore, the opening that occurs when a vesicle binds to a cell membrane, is present for just hundreds of microseconds, a thousand times shorter than the blink of an eye. Immediately after it opens, the pore rapidly expands as the vesicle membrane melts into the surrounding cell membrane. That quick transition has made it extremely difficult to study the pore, says Rothman. “We thought that if we could find a way to artificially stabilize the fusion pore, without interfering with its opening, we might be able to gain some new insights into neurotransmission,” he said.

To do so, Rothman’s group, together with Frédéric Pincet’s team at CNRS in Paris, France, created fusion pores in nanodiscs—circular discs of lipid bilayers, held together by scaffold proteins wrapped around each lipid disc like a belt. Because of the nanodiscs’ small size and rigid structure, a fusion pore can form but does not expand beyond 2 nm, essentially freezing the pore in place for analysis.