June 29, 2005 Proteins are the puzzle-pieces of life, involved in how organisms grow and flourish, but studying their complex biological processes in living systems has been extremely difficult. Now, a team of chemists and neurobiologists led by Timothy Dore at the University of Georgia and Erin M. Schuman at the California Institute of Technology has found a way to use light to regulate protein synthesis in specific locations.
The new method, which uses so-called "caged compounds" that can be turned on with light, could lead to more intricate studies of such important but poorly understood processes, such as protein synthesis in nerve synapses.
The research was published today in the journal Chemistry & Biology. Coauthors on the paper are Schuman, Michael Goard, Girish Aakalu, Carlo Quinonez and Jamii St. Julien, all of the Howard Hughes Medical Institute and Division of Biology at the California Institute of Technology. Lesya Fedoryak from Dore's lab is also an author of the paper, as is Stephen Poteet, now a medical student at the University of Alabama, Birmingham, who participated in UGA's Chemistry Summer Undergraduate Research Program in 2001.
The idea of "caged compounds" has been around for some 30 years. In the current application, the team attached a light-sensitive molecule called a chromophore to a bioactive molecule called an effector through a single covalent bond that inactivates the bioactive molecule. Exposing the caged compound to light releases the effector in its active form.
"It's analogous to placing an animal in a cage to restrict its activity," said Dore, "but the term 'cage' is really a misnomer because we are not actually placing a molecule inside of a molecule."
The team developed a caged anisomycin compound that can be activated by exposure to ultraviolet light or an infrared laser beam. (Anisomycin is an antibiotic that inhibits protein synthesis.) The new chromophore, called Bhc, is the only one sensitive enough to light that it can mediate light-induced protein synthesis inhibition in a living system.
While previous studies have focused on releasing molecules that activate biological events, little has been done in the area of regulating the inhibition of biological processes.
"Ultimately, we want to understand the role local protein synthesis plays in biological systems such as neurons," said Schuman. "When and where in the neuron is protein synthesis used to bring about changes? How does protein synthesis regulate synaptic strength and axonal outgrowth? These are questions we'd like to answer."
Another example of a process the new method can help clarify involves the role of protein synthesis in the development of an organism. Since stem cells in humans, for example, differentiate into skin, brain and muscle cells, among many others, researchers want to know the controlling mechanisms for how these cells are chosen for their specific roles.
"If we had a way to selectively abolish protein synthesis in subcellular compartments and observe the effects, then we could infer the role of local protein synthesis in development," said Dore.
Generally speaking, there are few research tools available that are location-specific, so the new method adds a potentially powerful tool for scientists. Often, manipulations are carried out on all parts of a sample, but researchers have learned that much of biological function is dependent on the specific location of a particular event.
While the new caged compound and its photoreactive properties may never be used for anything as complex as drug delivery, it may well serve a purpose in studying such areas as memory, brain function and even Alzheimer's Disease.
"Our technique will enable scientists to conduct experiments aimed at understanding the mechanisms of learning and memory at the molecular and cellular level," said Dore.
The technique could also be used in drug discovery and development, though it is much more likely to be used in advancing knowledge about biological systems.
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