Switching G Protein-Coupled Receptors On And Off With Light

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.