title: Molecular recognition of ketamine by a subset of olfactory G protein-coupled receptors.
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.
authors.affiliation: Department of Molecular Genetics and Microbiology, and Department of Neurobiology, Duke University, Durham, NC 27710, USA.
authors.forename: Jianghai
authors.initials: J
authors.lastname: Ho
authors.affiliation: Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Jose Manuel
authors.initials: JM
authors.lastname: Perez-Aguilar
authors.affiliation: Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Lu
authors.initials: L
authors.lastname: Gao
authors.affiliation: Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Jeffery G
authors.initials: JG
authors.lastname: Saven
authors.affiliation: Department of Molecular Genetics and Microbiology, and Department of Neurobiology, Duke University, Durham, NC 27710, USA.|Duke Institute for Brain Sciences, Duke University, Durham, NC 27710, USA.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Matsunami
authors.affiliation: Department of Anesthesiology and Critical Care, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Roderic G
authors.initials: RG
authors.lastname: Eckenhoff
mesh_terms: D000778:Anesthetics, Dissociative / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D001921:Brain / Q000378:metabolism*; D007649:Ketamine / Q000378:metabolism*; D008156:Luciferases; D051379:Mice; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D011485:Protein Binding; D011487:Protein Conformation; D018035:Receptors, Odorant / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D017422:Sequence Analysis, DNA
chemical_list: D000778:Anesthetics, Dissociative; D018035:Receptors, Odorant; D007649:Ketamine; D008156:Luciferases
references.citation: J Psychopharmacol. 2013 May;27(5):444-50
references.pmid: 23428794
references.citation: Angew Chem Int Ed Engl. 2013 Oct 11;52(42):11021-4
references.pmid: 24038729
references.citation: Crit Rev Clin Lab Sci. 2005;42(4):311-92
references.pmid: 16281738
references.citation: Invest Ophthalmol Vis Sci. 1988 Mar;29(3):419-28
references.pmid: 3343097
references.citation: Nature. 2009 May 21;459(7245):356-63
references.pmid: 19458711
references.citation: Science. 2008 Nov 21;322(5905):1211-7
references.pmid: 18832607
references.citation: J Mol Biol. 2004 Sep 10;342(2):571-83
references.pmid: 15327956
references.citation: J Neurosci. 2005 Feb 16;25(7):1806-15
references.pmid: 15716417
references.citation: Biochemistry. 2000 Jul 25;39(29):8497-502
references.pmid: 10913255
references.citation: Neuropsychopharmacology. 2011 Nov;36(12):2561-70
references.pmid: 21814187
references.citation: J Comput Chem. 2009 Dec;30(16):2785-91
references.pmid: 19399780
references.citation: BMC Genomics. 2006;7:121
references.pmid: 16716209
references.citation: Science. 2014 Mar 21;343(6177):1370-2
references.pmid: 24653035
references.citation: Nature. 2011 Mar 31;471(7340):651-5
references.pmid: 21389988
references.citation: Nat Protoc. 2008;3(9):1402-13
references.pmid: 18772867
references.citation: Mol Cell Neurosci. 2008 Jul;38(3):312-24
references.pmid: 18468454
references.citation: Science. 2003 Mar 28;299(5615):2054-8
references.pmid: 12663925
references.citation: Nature. 2008 Jul 24;454(7203):486-91
references.pmid: 18594507
references.citation: J Biol Chem. 2007 Jan 12;282(2):1216-24
references.pmid: 17114180
references.citation: Proc Natl Acad Sci U S A. 1992 Nov 15;89(22):10915-9
references.pmid: 1438297
references.citation: Mol Cell Neurosci. 2005 Dec;30(4):506-12
references.pmid: 16185894
references.citation: Science. 2007 Nov 23;318(5854):1258-65
references.pmid: 17962520
references.citation: PLoS One. 2013;8(2):e55368
references.pmid: 23405139
references.citation: Science. 2010 Nov 19;330(6007):1091-5
references.pmid: 21097933
references.citation: Cell. 2012 Nov 21;151(5):1126-37
references.pmid: 23178128
references.citation: BMC Bioinformatics. 2009;10:136
references.pmid: 19426475
references.citation: Nature. 2013 Feb 14;494(7436):185-94
references.pmid: 23407534
references.citation: Biochemistry. 2011 Feb 8;50(5):843-53
references.pmid: 21142015
references.citation: Protein Sci. 2004 Jan;13(1):240-54
references.pmid: 14691239
references.citation: Nat Rev Mol Cell Biol. 2002 Sep;3(9):639-50
references.pmid: 12209124
references.citation: Sci Signal. 2009;2(60):ra9
references.pmid: 19261596
references.citation: J Comput Chem. 2005 Dec;26(16):1781-802
references.pmid: 16222654
references.citation: J Cell Sci. 2004 Nov 15;117(Pt 24):5835-45
references.pmid: 15522887
references.citation: Curr Top Med Chem. 2005;5(3):315-24
references.pmid: 15857314
references.citation: Cell. 1999 Mar 5;96(5):713-23
references.pmid: 10089886
references.citation: Br J Anaesth. 1985 Feb;57(2):197-203
references.pmid: 3970799
references.citation: J Mol Biol. 1990 Oct 5;215(3):403-10
references.pmid: 2231712
references.citation: J Anesth. 2013 Apr;27(2):284-92
references.pmid: 23099434
references.citation: Nat Rev Neurosci. 2008 May;9(5):370-86
references.pmid: 18425091
references.citation: Proc Natl Acad Sci U S A. 2013 Mar 12;110(11):4410-5
references.pmid: 23401498
references.citation: Development. 1999 Oct;126(20):4547-56
references.pmid: 10498689
references.citation: J Phys Chem B. 1998 Apr 30;102(18):3586-616
references.pmid: 24889800
references.citation: Structure. 2009 Jan 14;17(1):8-14
references.pmid: 19141277
references.citation: Neurobiol Dis. 2014 Jan;61:55-71
references.pmid: 24076101
references.citation: J Struct Biol. 2007 Sep;159(3):400-12
references.pmid: 17601748
references.citation: Nature. 2011 Jan 13;469(7329):175-80
references.pmid: 21228869
references.citation: Gene. 1989 Apr 15;77(1):51-9
references.pmid: 2744487
references.citation: Nature. 2011 Sep 29;477(7366):549-55
references.pmid: 21772288
references.citation: Cell. 1991 Apr 5;65(1):175-87
references.pmid: 1840504
references.citation: Structure. 2014 Aug 5;22(8):1120-39
references.pmid: 25066135
references.citation: Biochemistry. 2003 Dec 16;42(49):14507-14
references.pmid: 14661963
references.citation: Nucleic Acids Res. 2006 Jul 1;34(Web Server issue):W116-8
references.pmid: 16844972
references.citation: Curr Opin Cell Biol. 2014 Apr;27:56-62
references.pmid: 24680431
references.citation: J Mol Biol. 1993 Dec 5;234(3):779-815
references.pmid: 8254673
references.citation: Curr Protoc Protein Sci. 2007 Nov;Chapter 2:Unit 2.9
references.pmid: 18429317