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,” 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
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, 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.”
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,” 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,” 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,”
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, 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,” Ryan
says.
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.
Source: New York- Presbyterian Hospital/Weill Cornell Medical Center/Weill Cornell Medical College
