Brain Cell Communication Mechanism Visualized for First Time

The classic image of communication between brain cells shows a neurotransmitter crossing the synapse and binding to receptors on the surface of a neighboring neuron. Yet scientists have had only a murky picture of the events within the secreting neuron that trigger the release of neurotransmitters.

Now, a group of researchers led by Axel T. Brunger, a Howard Hughes Medical Institute (HHMI) investigator at Yale University, has produced the first glimpses of molecular machinery that propels neurotransmitters into the synapse. The key players are a family of proteins called SNAREs (Soluble NSF Attachment protein REceptor). These proteins haven’t changed much through evolution; SNAREs play a similar role in the secretions of even primitive life forms like yeast.

Within the neuron, vesicles fill up with neurotransmitters, such as dopamine or serotonin. Then they travel out into the neuron’s extensions (axons), where they dock at the membrane and await an electrochemical signal to merge. At this moment, the SNARE proteins form a complex, thereby triggering synaptic fusion.

“It’s sort of like merging two soap bubbles into one, but hardly that simple,” explained R. Bryan Sutton, an HHMI associate in Brunger’s laboratory. They and researchers at the Max-Planck Institute in Gottingen, Germany, report the three-dimensional molecular structure of the synaptic fusion complex in the Sept. 24 issue of Nature.

Formation of the SNARE complex leads to fusion of the cell membrane with vesicles, which are tiny sacs carrying the neurotransmitter inside the neuron. Such vesicle fusion, which occurs millions of times daily in each of the human brain’s 100 billion neurons, causes the neurotransmitter to spew into the synapse, the space between communicating neurons. When this process functions correctly, a signal can jump from neuron to neuron with little or no loss of signal strength over a long distance.

Understanding vesicle fusion promises to shed light on processes like learning and memory, and could be useful in designing new medications for brain disorders, Brunger said.

Like other known fusion mechanisms, such as those used by viruses to infect cells, synaptic fusion employs a protein agent to meld two membranes. In viruses, the fusion protein simply changes its shape. In brain cells, assembly of the SNARE protein complex is necessary to trigger the union of vesicle and cell membrane.

This assembly likely begins by the joining of two SNARE proteins, SNAP-25 and syntaxin, which are found in the cell’s membrane, Brunger said. This two-part complex is then joined by a third protein, called synaptobrevin, from the vesicle. The three proteins assemble into a configuration that sets up electrical and chemical forces that could promote membrane fusion.

In addition, highly flexible helical structures in the complex that are prone to twisting and bending could cause strains that physically deform fatty layers within the two membranes, allowing them to mix. The complex’s highly grooved surface, with distinct electrically and chemically polarized regions, could also be important for fusion and for the binding of regulatory factors affecting neurotransmission, the researchers reported.

“The complex may act like a winch to drive the vesicle down into the neuron’s membrane,” said Brunger. “Diseases such as tetanus and botulism take advantage of the fusion machinery by attacking these ties between neurotransmitter-filled vesicles and the neuron’s membrane, effectively cutting the winch cable and causing neurological symptoms.”

Through a process called X-ray crystallography, the researchers used ultra-bright X-ray radiation from a synchrotron facility to illuminate the tiny protein crystals and determine the shape of the SNARE complex, atom-by-atom. Then they created three-dimensional computer reconstructions that provide clues about how this pivotal protein complex may accomplish its mission.

This research was funded by the U.S. Department of Energy.