Tadpole Tests Confirm Light-Activated Anesthetic Is Reversible

With a switchable version of a popular anesthetic, researchers can now use light to control another important neurotransmitter receptor, the GABA_A receptor (Angew. Chem. Int. Ed., DOI: 10.1002/anie.201205475). Scientists have already controlled animals’ heartbeat, pain, and visual response with light-activated blockers of ion channels in the nervous system. To command GABA_A, a chloride channel, Dirk Trauner of the University of Munich, Erwin Sigel of Switzerland’s University of Bern, and coworkers made azobenzene derivatives of the anesthetic propofol. GABA_A plays a major role in propofol’s activity, though the molecule’s mode of action is not entirely clear. In the dark, the azo-propofols are in the trans form and increase GABA_A’s chloride current. Upon exposure to blue-violet light, they convert to the cis form, reversing the effect. The team’s best compound so far, AP2, reverts to the trans form on its own, because its amino group makes the cis form unstable. Tadpoles exposed to trans-AP2 are anesthetized, but shining blue-violet light rapidly wakes them. Trauner isn’t sure how applicable AP2 will be in clinical anesthesia, but his team plans to study its activity in retinas, because GABA_A also is involved in the biology of vision.