"We are looking under the hood of these machines for the firsttime," he says. "Many neurological diseases are considered to arisefrom pathologies of synaptic function. The synapse is so complex;at least a few thousand genes control how they work. Repairing themthrough 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 synapticfunction, and use ultra sensitive microscopy technology to watchthese molecules up close and in real-time. The researchers used the same toolkit to examine the function ofcalcium channels, which triggers neurotransmission. "At allsynapses, the secretion of a neurotransmitter is driven by thearrival of an electric impulse, initiated by another neuron," Dr.Ryan says. When this impulse arrives at the nerve terminal ittriggers the opening of calcium channels. The calcium that rushesin is the key trigger that drives a synapse to secrete itsneurotransmitter.
"We have known for the past half century that calcium is a keycontroller of neurotransmission," he says. "Any small change incalcium 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, theybuild the channels in the neuron's cell body and then package themup and ship them to the nerve terminal. In some cases, that is avery long journey - as much as a few feet, such as the distancebetween the brain and the base of the spinal cord or the length ofa leg. In the study, researchers tagged fluorescent proteins onto a genethat encodes protein that makes a calcium channel and delivered itto neurons.
They then watched the progress of the newly formedchannels as they made their way, from day four to day seven, fromthe bodies of neurons to the synapse. They also manipulated the levels of alpha 2 delta, a suspectedcalcium channel partner, and discovered that when the protein wasincreased, more calcium channels were moved to the synapse. Lessalpha 2 delta reduced the flow. "We discovered that alpha 2 deltamade the decision of how many calcium channels should be shippedthe length of the neuron to the synapse," Dr. Ryan says.
"It's likethe channels couldn't be transported without an alpha 2 deltashipping label." The research team found however that alpha 2 delta must work in atleast two steps. When they impaired a piece of alpha 2 delta thatresembles proteins that are involved in how cells bind to eachother, they found that this broken alpha 2 delta could still helpget calcium channels shipped down to synapses. But once there, theyno longer helped drive neurotransmitter release. "This means thatnot only does alpha 2 delta help to get calcium channels shippedout, but it also implies that something at the synapse has tosign-off on receiving the calcium channels, putting them in theright place for them to do their job," Dr. Ryan says.
The researchers suggest that Lyrica might work by interfering withthis final step since the piece of alpha 2 delta they "broke" thatprevents the signing-off resembles parts of proteins that allowsthem to stick to each other in a kind of handshake. These findings suggest that future therapies designed to manipulateneurotransmission could try to target this handshaking process, Dr.Ryan says. To do this will require that researchers identify themissing partner in the handshake. "We hope these exciting findings are providing a new direction inhow to make better drugs to control communication between braincells," Dr.
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