title: Implausibility of the vibrational theory of olfaction.
abstract: The vibrational theory of olfaction assumes that electron transfer occurs across odorants at the active sites of odorant receptors (ORs), serving as a sensitive measure of odorant vibrational frequencies, ultimately leading to olfactory perception. A previous study reported that human subjects differentiated hydrogen/deuterium isotopomers (isomers with isotopic atoms) of the musk compound cyclopentadecanone as evidence supporting the theory. Here, we find no evidence for such differentiation at the molecular level. In fact, we find that the human musk-recognizing receptor, OR5AN1, identified using a heterologous OR expression system and robustly responding to cyclopentadecanone and muscone, fails to distinguish isotopomers of these compounds in vitro. Furthermore, the mouse (methylthio)methanethiol-recognizing receptor, MOR244-3, as well as other selected human and mouse ORs, responded similarly to normal, deuterated, and (13)C isotopomers of their respective ligands, paralleling our results with the musk receptor OR5AN1. These findings suggest that the proposed vibration theory does not apply to the human musk receptor OR5AN1, mouse thiol receptor MOR244-3, or other ORs examined. Also, contrary to the vibration theory predictions, muscone-d30 lacks the 1,380- to 1,550-cm(-1) IR bands claimed to be essential for musk odor. Furthermore, our theoretical analysis shows that the proposed electron transfer mechanism of the vibrational frequencies of odorants could be easily suppressed by quantum effects of nonodorant molecular vibrational modes. These and other concerns about electron transfer at ORs, together with our extensive experimental data, argue against the plausibility of the vibration theory.
authors.affiliation: Department of Chemistry, University at Albany, State University of New York, Albany, NY 12222; eblock@albany.edu seogjoo.jang@qc.cuny.edu hiroaki.matsunami@duke.edu hanyizhuang@sjtu.edu.cn.
authors.forename: Eric
authors.initials: E
authors.lastname: Block
authors.affiliation: Department of Chemistry and Biochemistry, Queens College, and Graduate Center, City University of New York, Flushing, NY 11367; eblock@albany.edu seogjoo.jang@qc.cuny.edu hiroaki.matsunami@duke.edu hanyizhuang@sjtu.edu.cn.
authors.forename: Seogjoo
authors.initials: S
authors.lastname: Jang
authors.affiliation: Department of Molecular Genetics and Microbiology and Department of Neurobiology, Duke Institute for Brain Sciences, Duke University Medical Center, Durham, NC 27710; eblock@albany.edu seogjoo.jang@qc.cuny.edu hiroaki.matsunami@duke.edu hanyizhuang@sjtu.edu.cn.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Matsunami
authors.affiliation: Department of Chemistry, Yale University, New Haven, CT 06520;
authors.forename: Sivakumar
authors.initials: S
authors.lastname: Sekharan
authors.affiliation: Department of Chemistry, University at Albany, State University of New York, Albany, NY 12222;
authors.forename: Bérénice
authors.initials: B
authors.lastname: Dethier
authors.affiliation: Department of Chemistry, Yale University, New Haven, CT 06520; Chemistry Department, Brookhaven National Laboratory, Upton, NY 11973;
authors.forename: Mehmed Z
authors.initials: MZ
authors.lastname: Ertem
authors.affiliation: Department of Chemistry, University at Albany, State University of New York, Albany, NY 12222;
authors.forename: Sivaji
authors.initials: S
authors.lastname: Gundala
authors.affiliation: Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China; and.
authors.forename: Yi
authors.initials: Y
authors.lastname: Pan
authors.affiliation: Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China; and.
authors.forename: Shengju
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China; and.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Chemistry, University at Albany, State University of New York, Albany, NY 12222;
authors.forename: Stephene N
authors.initials: SN
authors.lastname: Lodge
authors.affiliation: Department of Chemistry, Yale University, New Haven, CT 06520;
authors.forename: Mehmet
authors.initials: M
authors.lastname: Ozbil
authors.affiliation: Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China; and.
authors.forename: Huihong
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Department of Chemistry, University at Albany, State University of New York, Albany, NY 12222;
authors.forename: Sonia F
authors.initials: SF
authors.lastname: Penalba
authors.affiliation: Department of Chemistry, Yale University, New Haven, CT 06520;
authors.forename: Victor S
authors.initials: VS
authors.lastname: Batista
authors.affiliation: Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China; and Institute of Health Sciences, Shanghai Jiao tong University School of Medicine/Shanghai Institutes for Biological Sciences of Chinese Academy of Sciences, Shanghai 200031, China eblock@albany.edu seogjoo.jang@qc.cuny.edu hiroaki.matsunami@duke.edu hanyizhuang@sjtu.edu.cn.
authors.forename: Hanyi
authors.initials: H
authors.lastname: Zhuang
mesh_terms: D000818:Animals; D002247:Carbon Isotopes; D003516:Cycloparaffins / Q000737:chemistry; D003903:Deuterium; D004579:Electron Transport; D005229:Fatty Acids, Monounsaturated / Q000737:chemistry; D057809:HEK293 Cells; D006801:Humans; D007536:Isomerism; D051379:Mice; D008954:Models, Biological; D009812:Odorants; D018035:Receptors, Odorant / Q000378:metabolism*; D012903:Smell / Q000502:physiology*; D014732:Vibration
chemical_list: D002247:Carbon Isotopes; D003516:Cycloparaffins; D005229:Fatty Acids, Monounsaturated; D018035:Receptors, Odorant; C008563:musk; D003903:Deuterium; C031021:muscone
keywords: cyclopentadecanone; electron transfer; isotopomers; muscone; olfaction