Sniffing Out Ketamine’s Targets In The Brain

Doctors have used general anesthetics in the operating room for more than 150 years, yet neuroscientists don’t know much about how these drugs knock out patients. Roderic G. Eckenhoff of the University of Pennsylvania and colleagues now report that the anesthetic ketamine binds to and activates olfactory receptors in mouse brains, suggesting the receptors may be targets for new anesthetics. The finding also could help researchers uncover other ketamine-binding proteins in the central nervous system, possibly leading to the discovery of additional anesthetic targets. Besides detecting odorant molecules in the nose, olfactory receptors are linked to signaling in other cells. Eckenhoff’s team found three mouse olfactory receptors in the brain that bind ketamine but not other general anesthetics. Using these receptors’ amino acid sequences and structures of related receptors, the researchers built a model of the ketamine binding site (Sci. Signal. 2015, DOI: 10.1126/scisignal.2005912). They confirmed their model by mutating ketamine-binding receptors and nonresponsive receptors to eliminate and introduce, respectively, the ability to bind the drug. With this binding motif in hand, Eckenhoff hopes to search protein structure databases to find novel ketamine receptors.