Date of this Version
Ketamine elicits various neuropharmacological effects, including sedation, analgesia, general anesthesia, and antidepressant activity. Through an in vitro screen, we identified four mouse olfactory receptors (ORs) that responded to ketamine. In addition to their presence in the olfactory epithelium, these G protein (heterotrimeric guanine nucleotide–binding protein)–coupled receptors (GPCRs) are distributed throughout the central nervous system. To better understand the molecular basis of the interactions between ketamine and ORs, we used sequence comparison and molecular modeling to design mutations that (i) increased, reduced, or abolished ketamine responsiveness in responding receptors, and (ii) rendered non-responding receptors responsive to ketamine. We showed that olfactory sensory neurons (OSNs) that expressed distinct ORs responded to ketamine in vivo, suggesting that ORs may serve as functional targets for ketamine. The ability to both abolish and introduce responsiveness to ketamine in GPCRs enabled us to identify and confirm distinct interaction loci in the binding site, which suggested a signature ketamine-binding pocket that may guide exploration of additional receptors for this general anesthetic drug.
This is the author’s version of the work. It is posted here by permission of the AAAS for personal use, not for redistribution. The definitive version was published in Sci Signal. ; 8(370): ra33. doi:10.1126/scisignal.2005912.
Ho, J., Perez Aguilar, J., Gao, L., Saven, J. G., Matsunami, H., & Eckenhoff, R. G. (2015). Molecular Recognition of Ketamine by a Subset of Olfactory G Protein–coupled Receptors. Science Signaling, 8 (370), http://dx.doi.org/10.1126/scisignal.2005912
Date Posted: 07 December 2016
This document has been peer reviewed.