Smart Trap: Nanosensor tracks major brain chemical

The study of neurological diseases and brain functions could become much more precise with the invention of an optical sensor that can closely monitor a specific chemical amidst the brain’s complex neurochemical brew.

GOTCHA! An incoming molecule of the neurotransmitter glutamate (red) makes the lobes (green) snap shut (right) in this depiction of a nanosensor anchored to the surface of a nerve cell. The change in configuration alters the distance between the two fluorescent protein segments (blue and yellow cylinders), resulting in an optical signal. S. Okumoto

Called glutamate, this neurotransmitter is secreted by nerve cells and influences processes ranging from sensory perception to learning and memory. It also plays a role in Alzheimer’s and Parkinson’s disease.

Until recently, it has been almost impossible to study this transient chemical in action. However, Wolf Frommer of the Carnegie Institution at Stanford University and his colleagues recently designed a nanosensor with which they can track the release of glutamate by nerve cells.

Described in an upcoming Proceedings of the National Academy of Sciences, the nanosensor consists of several protein segments stitched together. The sensing part of the construct is derived from the bacterium Escherichia coli. The protein segment changes shape when glutamate binds to it. The protein’s two lobes, which are connected by a hinge, snap together like the jaws of a Venus flytrap.

To their sensing mechanism, the researchers attached two fluorescent jellyfish proteins, one that glows blue and one that glows yellow. In a process known as fluorescence resonance energy transfer, when one protein becomes excited by light, it both emits blue light and transfers energy to the other protein, causing it to produce yellow light.

“It’s like having two musical tuning forks,” says Frommer. “If you hit one fork and you bring the second one close enough to it without touching, the second fork will start to vibrate as well.”

When the sensor binds to glutamate, a change in the nanosensor’s configuration increases the distance between the two fluorescent proteins, Frommer suspects, reducing the amount of energy transferred from the blue to the yellow one.

In a display of finesse, Frommer and his colleagues genetically programmed rat brain cells to produce the nanosensors and anchor the constructs to the surfaces of their cell membranes. When the researchers gave the cells an electrical shock, the cells produced a spurt of glutamate that indeed tripped the nanosensors.

The scientists then observed a dimming of the yellow light. The more glutamate the cells released, the lower the ratio of that yellow light to the blue light.

“This is a major advance,” says Robert Edwards, a neuroscientist at the University of California, San Francisco. “I think a lot of people will jump on this.”

The nanosensor’s location on the cell membranes currently prevents it from tracking glutamate inside the cells. Scientists next may program cells to place the sensor on internal structures to shed light on how they manufacture and deploy the neurotransmitter.

To observe glutamate in whole organisms, rather than only in individual cells, the Stanford group is genetically programming the tiny worm Caenorhabditis elegans to produce the sensors. Eventually, the researchers plan to incorporate the sensors into mice and to use an optical-imaging system to detect changes in fluorescence that would correlate with neural activity.

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