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.