This news should drive every stroke researcher wild with ideas of how to create uses for stroke rehab.
Research findings may lead to new drugs designed to
improve communication between brain cells and effectively treat
neurological disorders
NEW YORK (May 13, 2012) -- Scientists at Weill Cornell Medical
College have discovered that the single protein -- alpha 2 delta --
exerts a spigot-like function, controlling the volume of
neurotransmitters and other chemicals that flow between the synapses of
brain neurons. The study, published online in
Nature, shows how
brain cells talk to each other through these signals, relaying thoughts,
feelings and action, and this powerful molecule plays a crucial role in
regulating effective communication.
In the study, the investigators also suggest how the widely used
pain drug Lyrica might work. The alpha 2 delta protein is the target of
this drug and the new work suggests an approach to how other drugs could
be developed that effectively twist particular neurotransmitter spigots
on and off to treat neurological disorders. The research findings
surprised the research team, which includes scientists from University
College London.
"We are amazed that any single protein has such power," says the
study's lead investigator Dr. Timothy A. Ryan, professor of Biochemistry
and associate professor of Biochemistry in Anesthesiology at Weill
Cornell Medical College. "It is indeed rare to identify a biological
molecule's function that is so potent, that seems to be controlling the
effectiveness of neurotransmission."
The researchers found that alpha 2 delta determines how many calcium
channels will be present at the synaptic junction between neurons. The
transmission of chemical signals is triggered at the synapse by the
entry of calcium into these channels, so the volume and speed of
neurotransmission depends on the availability of these channels.
Researchers discovered that taking away alpha 2 delta from brain
cells prevented calcium channels from getting to the synapse. "But if
you add more alpha 2 delta, you can triple the number of channels at
synapses," Dr. Ryan says. "This change in abundance was tightly linked
to how well synapses carry out their function, which is to release
neurotransmitters."
Before this study, it was known that Lyrica, which is used for
neuropathic pain, seizures and fibromyalgia, binds to alpha 2 delta, but
little was understood about how this protein works to control synapses.
Lifting up the Hood
Dr. Ryan is building what he calls a "shop manual" of neurological
function, much of which centers on synaptic neurotransmission. In 2007
and 2008, he discovered crucial clues to how neurons repackage the
chemicals used to signal across synapses. In 2011, Dr. Ryan discovered
that distinct neurons differently tune the speed by which they package
these chemicals. And in a recent study published April 29 in
Nature Neuroscience,
he described, for the first time, the molecular mechanisms at the
synapse that control the release of dopamine, a crucial
neurotransmitter.
"We are looking under the hood of these machines for the first
time," he says. "Many neurological diseases are considered to arise from
pathologies of synaptic function. The synapse is so complex; at least a
few thousand genes control how they work. Repairing them through
treatment requires that we understand how they work."
Dr. Ryan and his team often use two tools to conduct these studies
-- they pin fluorescent tags on to molecules involved in synaptic
function, and use ultra sensitive microscopy technology to watch these
molecules up close and in real-time.
The researchers used the same toolkit to examine the function of
calcium channels, which triggers neurotransmission. "At all synapses,
the secretion of a neurotransmitter is driven by the arrival of an
electric impulse, initiated by another neuron," Dr. Ryan says. When this
impulse arrives at the nerve terminal it triggers the opening of
calcium channels. The calcium that rushes in is the key trigger that
drives a synapse to secrete its neurotransmitter.
"We have known for the past half century that calcium is a key
controller of neurotransmission," he says. "Any small change in calcium
influx has a big impact on neurotransmission."
Protein Acts like a Shipping Label
But the number of calcium channels at the synapse is not static.
Neurons constantly replace worn out channels, and to do this, they build
the channels in the neuron's cell body and then package them up and
ship them to the nerve terminal. In some cases, that is a very long
journey -- as much as a few feet, such as the distance between the brain
and the base of the spinal cord or the length of a leg.
In the study, researchers tagged fluorescent proteins onto a gene
that encodes protein that makes a calcium channel and delivered it to
neurons.
They then watched the progress of the newly formed channels as
they made their way, from day four to day seven, from the bodies of
neurons to the synapse.
They also manipulated the levels of alpha 2 delta, a suspected
calcium channel partner, and discovered that when the protein was
increased, more calcium channels were moved to the synapse. Less alpha 2
delta reduced the flow. "We discovered that alpha 2 delta made the
decision of how many calcium channels should be shipped the length of
the neuron to the synapse," Dr. Ryan says. "It's like the channels
couldn't be transported without an alpha 2 delta shipping label."
The research team found however that alpha 2 delta must work in at
least two steps. When they impaired a piece of alpha 2 delta that
resembles proteins that are involved in how cells bind to each other,
they found that this broken alpha 2 delta could still help get calcium
channels shipped down to synapses. But once there, they no longer helped
drive neurotransmitter release. "This means that not only does alpha 2
delta help to get calcium channels shipped out, but it also implies that
something at the synapse has to sign-off on receiving the calcium
channels, putting them in the right place for them to do their job," Dr.
Ryan says.
The researchers suggest that Lyrica might work by interfering with
this final step since the piece of alpha 2 delta they "broke" that
prevents the signing-off resembles parts of proteins that allows them to
stick to each other in a kind of handshake.
These findings suggest that future therapies designed to manipulate
neurotransmission could try to target this handshaking process, Dr. Ryan
says. To do this will require that researchers identify the missing
partner in the handshake.
"We hope these exciting findings are providing a new direction in
how to make better drugs to control communication between brain cells,"
Dr. Ryan says.
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The study was funded by the National Institutes of Mental Health and
the Welcome Trust. Co-authors of the study include Dr. Michael B. Hoppa
from Weill Cornell Medical College, and Dr. Beatrice Lana, Dr. Wojciech
Margas, and Dr. Annette C. Dolphin from University College London.
