Building a Better Chemical Trap

You might expect that a stronger cage is always better. But the power of a new chemical cage announced this week lies in its weakness: It's about 100 times more efficient at releasing its prisoner than its widely used counterparts. The flimsy molecular pen may help map the brain's chemical circuitry and decipher the signals that control the beating heart.

One way to study how cells function is to control the availability of a particular biomolecule by encapsulating it in a chemical box until a flash of light sets it free. Researchers have used this strategy to probe how cells react to the sudden release of signalling molecules, such as the neurotransmitter glutamate and calcium ions. But currently available cages do not absorb light very well, and the light needed to bust them open is so intense that it damages the surrounding tissue.

To avoid this problem, biochemist Graham Ellis-Davies of Drexel University in Philadelphia, Pennsylvania, and colleagues synthesized a new compound called nitrodibenzofuran (NDBF), which is similar in chemical make-up to previous cages but disintegrates with a light flash only 1% as bright. The team trapped calcium ions in NDBF and inserted the mixture into heart muscle cells isolated from a guinea pig. Normally, the calcium would stimulate muscle contraction, but the NDBF prevented this from happening. When the researchers shined a short, relatively-weak pulse of UV laser-light on the cells, the cages broke and the freed calcium caused the muscle cells to contract fully, the team reports in the January issue of Nature Methods. Under the same light conditions, standard chemical cages did not break down as well and the cells contracted only partially.

NDBF also can be unlocked with infrared light, which penetrates tissue better than the more commonly used UV light. By focusing the light, researchers can target the release of their caged molecule in a very small volume--roughly a cubic micron. Ellis-Davies and his team plan to use this technique with NDBF-caged neurotransmitters to chemically control the firing of a single neuron in the brain of a living mouse, allowing them to track how neural traffic moves.

Pharmacologist Stephen Adams of the University of California, San Diego, is impressed by how NDBF "catches a lot more light than other cages." But biochemist Wen-Hong Li of the University of Texas Southwestern Medical Center in Dallas cautions that it remains to be seen whether NDBF will absorb light as efficiently when it locks up molecules other than calcium.

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