Teasing apart the complex circuitry of the brain might someday proceed with the flip of a switch, now that scientists have invented a light-responsive version of a common class of cell-surface proteins. The design permits precise control over whether channels into neurons are opened or closed to the ions that propagate nerve impulses.
To send information quickly, the brain relies on the neurotransmitter glutamate. This chemical attaches to the inside of a clamshell-shaped part of the glutamate receptor, a protein on the surface of nerve cells. Once that occurs, the clamshell closes and the receptor’s ion channel opens.
Researchers had previously constructed a few examples of light-controlled receptors. But Ehud Y. Isacoff, Dirk Trauner, and their colleagues at the University of California, Berkeley wanted to create a system that was applicable to the many kinds of receptors with clamshell shapes like that in the glutamate receptor.
The researchers assembled a string of compounds with glutamate at one end. In the middle of the string, they put a chemical called azobenzene, which changes its shape when illuminated by certain wavelengths of light. At the other end, the team placed maleimide, a compound that binds tightly to sulfur.
The next step was to tether the string-bound glutamate to its receptor. The group genetically engineered a version of the receptor with the sulfur-containing amino acid cysteine at a strategic spot near the lip of the clamshell. After growing lab cultures of nerve cells bearing the altered receptors, the researchers added their modified glutamate. The maleimide end of the string attached to the cysteine, anchoring the glutamate near the shell.
The string operates as a robotic arm does, says Trauner. In the dark, the arm stretches out, such that the glutamate stays far from the receptor. Upon irradiation with ultraviolet light, the arm bends, bringing the glutamate end to the clamshell site on the receptor.
The glutamate binds inside the clamshell and the ion channel opens, the researchers report. When hit with green light, the arm stretches back out, causing the ion channel to close.
The researchers turned the channel on and off with repeated switching between ultraviolet and green light for more than 30 minutes, they report in the January Nature Chemical Biology.
With the optical switch in place, researchers could use focused light signals to open ion channels in specific areas of brain tissue, a potentially powerful technique for determining how neuronal networks function, Isacoff says. “You could isolate specific cells in a neural circuit … and ask what they do for the operation of the circuit,” he says.
The group plans to test the system in animals such as fruit flies and to extend the design to additional receptors. The researchers are also tweaking their system to tether glutamate to normal receptors without a cysteine mutation, notes Trauner.
Neurobiologist Edward M. Callaway of the Salk Institute for Biological Studies in La Jolla, Calif., calls the new findings “a really exciting development” that researchers could apply to studies of various types of neurons.