Scientists discover atomic-resolution details of brain signaling

August 17, 2015
A protein complex at work in brain signaling. Its structure, which contains joined protein complexes known as SNARE and synaptotagmin-1, is shown in the foreground. This complex is responsible for the calcium-triggered release of neurotransmitters from our brain's nerve cells in a process called synaptic vesicle fusion. The SNARE structure is shown in blue, red, and green, and synaptotagmin-1 is shown in orange. The background image shows electrical signals traveling through a neuron. Credit: SLAC National Accelerator Laboratory

Scientists have revealed never-before-seen details of how our brain sends rapid-fire messages between its cells. They mapped the 3-D atomic structure of a two-part protein complex that controls the release of signaling chemicals, called neurotransmitters, from brain cells. Understanding how cells release those signals in less than one-thousandth of a second could help launch a new wave of research on drugs for treating brain disorders.

The experiments, at the Linac Coherent Light Source (LCLS) X-ray laser at the Department of Energy's SLAC National Accelerator Laboratory, build upon decades of previous research at Stanford University, Stanford School of Medicine and SLAC. Researchers reported their latest findings today in the journal Nature.

"This is a very important, exciting advance that may open up possibilities for targeting new drugs to control neurotransmitter release. Many mental disorders, including depression, schizophrenia and anxiety, affect neurotransmitter systems," said Axel Brunger, the study's principal investigator. He is a professor at Stanford School of Medicine and SLAC and a Howard Hughes Medical Institute investigator.

"Both parts of this protein complex are essential," Brunger said, "but until now it was unclear how its two pieces fit and work together."

Unraveling the Combined Secrets of Two Proteins

The two protein parts are known as neuronal SNAREs and synaptotagmin-1.

Earlier X-ray studies, including experiments at SLAC's Stanford Synchrotron Radiation Lightsource (SSRL) nearly two decades ago, shed light on the structure of the SNARE complex, a helical protein bundle found in yeasts and mammals. SNAREs play a key role in the brain's chemical signaling by joining, or "fusing," little packets of neurotransmitters to the outer edges of neurons, where they are released and then dock with chemical receptors in another neuron to trigger a response.

A 'Smoking Gun' for Neurotransmitter Release

In this latest research, the scientists found that when the SNAREs and synaptotagmin-1 join up, they act as an amplifier for a slight increase in calcium concentration, triggering a gunshot-like release of neurotransmitters from one neuron to another. They also learned that the proteins join together before they arrive at a neuron's membrane, which helps to explain how they trigger signaling so rapidly.

From left, Axel Brunger, Artem Lyubimov, Qiangjun "John" Zhao and Minglei Zhou view images from an experiment at SLAC's Linac Coherent Light Source, an X-ray free-electron laser. Researchers used a robotic setup to zap tiny, frozen crystals (the screen at upper left shows one crystal) with a series of X-ray pulses. They analyzed X-ray images of these crystals to determine the atomic-scale structure of a protein complex that provides clues to how our brains send rapid chemical messages. Credit: SLAC National Accelerator Laboratory

"The neuron is not building the 'gun' as it sits there on the membrane - it's already there," Brunger said.

The team speculates that several of the joined protein complexes may group together and simultaneously interact with the same vesicle to efficiently trigger neurotransmitter release, an exciting area for further studies.

"The structure of the SNARE-synaptotagmin-1 complex is a milestone that the field has awaited for a long time, and it sets the framework for a better understanding of the system," said James Rothman, a professor at Yale University who discovered the SNARE proteins and shared the 2013 Nobel Prize in Physiology or Medicine.

Thomas C. Südhof, a professor at the Stanford School of Medicine and Howard Hughes Medical Institute investigator who shared that 2013 Nobel Prize with Rothman, discovered synaptotagmin-1 and showed that it plays an important role as a calcium sensor and calcium-dependent trigger for neurotransmitter release.

"The new structure has identified unanticipated interfaces between synaptotagmin-1 and the neuronal SNARE complex that change how we think about their interaction by revealing, in atomic detail, exactly where they bind together," Südhof said. "This is a new concept that goes much beyond previous general models of how synaptotagmin-1 functions."

Equipment used in a highly automated, robotic X-ray crystallography system at SLAC's Linac Coherent Light Source X-ray laser. The metal drum at lower left contains liquid nitrogen for cooling crystallized samples studied with LCLS's intense X-ray pulses. This setup was used in an experiment exploring the molecular machinery involved in brain signaling in atomic-scale detail. Credit: SLAC National Accelerator Laboratory

Using Crystals, Robotics and X-rays to Advance Neuroscience

To study the joined protein structure, researchers in Brunger's laboratory at the Stanford School of Medicine found a way to grow crystals of the complex. They used a robotic system developed at SSRL to study the crystals at SLAC's LCLS, an X-ray laser that is one of the brightest sources of X-rays on the planet. SSRL and LCLS are DOE Office of Science User Facilities.

The researchers combined and analyzed hundreds of X-ray images from about 150 protein crystals to reveal the atomic-scale details of the joined structure.

SSRL's Aina Cohen, who oversaw the development of the highly automated platform used for the neuroscience experiment, said, "This experiment was the first to use this robotic platform at LCLS to determine a previously unsolved structure of a large, challenging multi-protein complex." The study was also supported by X-ray experiments at SSRL and at Argonne National Laboratory's Advanced Photon Source.

"This is a good example of how advanced tools, instruments and X-ray methods are providing us new insights into what are truly complex mechanisms," Cohen said.

Brunger said future studies will explore other protein interactions relevant to . "What we studied is only a subset," he said. "There are many other factors interacting with this system and we want to know what these look like. This by no means is the end of the story."

Explore further: Nobel Prize winner reports new model for neurotransmitter release

More information: Architecture of the synaptotagmin-SNARE machinery for neuronal exocytosis, DOI: 10.1038/nature14975

Related Stories

Robotics meet X-ray lasers in cutting-edge biology studies

November 24, 2014

Scientists at the Department of Energy's SLAC National Accelerator Laboratory are combining the speed and precision of robots with one of the brightest X-ray lasers on the planet for pioneering studies of proteins important ...

Protein recycling machine visualized

January 13, 2015

Howard Hughes Medical Institute (HHMI) scientists have new structures of an essential cellular recycling machine that depict its structure with near atomic-level detail. The structures, which show a protein called NSF alone ...

X-ray study may aid in designing better blood pressure drugs

April 23, 2015

An experiment at the Department of Energy's SLAC National Accelerator Laboratory has revealed in atomic detail how a hypertension drug binds to a cellular receptor that plays a key role in regulating blood pressure. The results ...

Recommended for you

Feeling the force between sand grains

August 24, 2016

For the first time, Lawrence Livermore National Laboratory (LLNL) researchers have measured how forces move through 3D granular materials, determining how this important class of materials might pack and behave in processes ...

Spherical tokamak as model for next steps in fusion energy

August 24, 2016

Among the top puzzles in the development of fusion energy is the best shape for the magnetic facility—or "bottle"—that will provide the next steps in the development of fusion reactors. Leading candidates include spherical ...

Funneling fundamental particles

August 24, 2016

Neutrinos are tricky. Although trillions of these harmless, neutral particles pass through us every second, they interact so rarely with matter that, to study them, scientists send a beam of neutrinos to giant detectors. ...

4 comments

Adjust slider to filter visible comments by rank

Display comments: newest first

JVK
1 / 5 (3) Aug 17, 2015
"Both parts of this protein complex are essential... but until now it was unclear how its two pieces fit and work together."

RNA-mediated amino acid substitutions are fixed in the organized genomes of all genera via the experience-dependent de novo creation of receptors. Receptors allow nutrients into the cell types that must be differentiated to be functional. Differentiation occurs via changes in energy that link Schrodinger's claims to quantum biology sans mutations.

Start with the epigenetic effects of the sun's biological energy on the light-induced de novo creation of nucleic acids. They link photosynthesis and nutrient uptake via light as a nutrient source to food sources of nutrients, which link the chemistry of nutrient-dependent RNA-mediated protein folding to cell type differentiation in all cells of all individuals of all living genera via the laws of physics and biophysical constraints on the physiology of reproduction.

Theorists start with mutations.
JVK
1 / 5 (3) Aug 18, 2015
The theorists who do not start with mutations may start with energy. But, starting with energy in cells exemplifies ignorance of top-down causation. First the energy must get inside the cells.

See for example: http://www.scienc...92.short Excerpt: "Energy-releasing chemical reactions are at the core of the living process of all organisms."

It's as if someone convinced them others would believe that starting from energy release / entropy was an acceptable way to answer Schrodinger's question "What is Life?"

Is the answer: Life is entropy, or "Life is physics and chemistry and communication" http://dx.doi.org...as.12570
jimsecor
not rated yet Aug 23, 2015
Please god not more ammunition for big PHRMA to screw around with brains and ruin lives. Anything they are given, they will distort to fit their narrow, simplistic, linear mental gear box. As this is only a small part of the picture, they're ability to screw up anything would be exponentially increased. Think of some other use.
JVK
1 / 5 (1) Aug 23, 2015
Big pharma has never considered any aspect of physics or attempted to link biophysically constrained protein folding to drug development. Their shotgun approach begins with mutations and claims that there is a gene for that! "That" is why billions have been wasted on drug development with severe side effects on the economy and some people who thought the drugs were "safe."

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.