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Biological Chemistry

Switching G Protein-Coupled Receptors On And Off With Light

Technique teases out function of an individual receptor, an approach that might aid schizophrenia research

by Carmen Drahl
March 11, 2013 | A version of this story appeared in Volume 91, Issue 10

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Tethered glutamates (blue) move into the glutamate receptor’s (red) binding site in response to light, triggering signaling.
In this reaction scheme, a pair of squiggly lines are sown across two parrallel lines. At one end of the squiggly line is a big C shape with a blue dangling bit. A reversible reaction arrow has violet light on top and green light on the bottom. On the righthand side, the blue dangly bits are captured in the C's they're attached to, and one of the squiggles in each line has changed its angle.
Tethered glutamates (blue) move into the glutamate receptor’s (red) binding site in response to light, triggering signaling.

G protein-coupled receptors (GPCRs) are ubiquitous signaling proteins that wind seven times across cell membranes. They are targets for as many as half of the medications on the market, even though many of their functions are not understood. By engineering a GPCR, a glutamate receptor, so it is controllable by light, Dirk Trauner of the University of Munich; Ehud Y. Isacoff of the University of California, Berkeley; and coworkers have figured out one function of a particular GPCR (Nat. Neurosci., DOI: 10.1038/nn.3346). Some GPCRs already respond to light. But it’s easier to study engineered GPCRs because they can be switched on and off multiple times with precise time control, Trauner says. The new GPCRs feature a tether that switches on or off with light, placing a glutamate trigger either in the GPCR’s binding site or out of reach. The team placed their tethers with help from X-ray structures of the GPCR’s clamshell-like binding site. After generating zebrafish harboring their engineered GPCR, they learned that this particular glutamate receptor controls how the fish escape vibration or sound. Peter Gmeiner, who engineers GPCRs at Germany’s Friedrich Alexander University, thinks this approach might enhance scientists’ understanding of diseases where several GPCRs are implicated, such as schizophrenia.

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