Research ArticlesNeuroscience

Molecular recognition of ketamine by a subset of olfactory G protein–coupled receptors

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Sci. Signal.  31 Mar 2015:
Vol. 8, Issue 370, pp. ra33
DOI: 10.1126/scisignal.2005912

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Wake up and smell the ketamine!

Ketamine antagonizes ion channels known as N-methyl-d-aspartate (NMDA) receptors to mediate its effects as an anesthetic; however, ketamine also has other properties, which suggests that it has other targets. Ho et al. found that ketamine activated four mouse olfactory receptors, which are a subfamily of G protein (heterotrimeric guanine nucleotide–binding protein)–coupled receptors (GPCRs). Structural analysis revealed residues that formed a ketamine-binding site in these olfactory receptors, and mutation of nonresponsive olfactory receptors to engineer the ketamine-binding site rendered them responsive to ketamine. Together, these data suggest that members of this family of GPCRs are functional ketamine receptors and provide a means to identify other potential targets of this pleiotropic drug.

Abstract

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 nonresponding 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.

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