This illustration
shows a protein complex at work in brain signaling. It contains two joined protein complexes:
SNARE, shown in blue, red, and green, and synaptotagmin-1, shown in orange. The combined complex is
responsible for the calcium-triggered release of neurotransmitters
from our brain’s nerve cells in a process called
synaptic vesicle fusion. In the background,
electrical signals travel through a neuron. (SLAC National Accelerator Laboratory)
X-ray Laser Experiment Could Help in Designing New Drugs for
Brain Disorders
(August 17, 2015) 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 brain signaling so rapidly.
“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.