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-d 30 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.olfaction | isotopomers | cyclopentadecanone | muscone | electron transfer I n 1870, the British physician William Ogle wrote: "As in the eye and the ear the sensory impression is known to result not from the contact of material particles given off by the object seen or heard, but from waves or undulations of the ether or the air, one cannot but suspect that the same may be true in the remaining sense, and that the undulatory theory of smell. . . [may be] the true one" (1, 2). Of the 29 different "theories of odour" listed in the 1967 edition of The Chemical Senses (3), nine associate odor with vibrations, particularly those theories championed by Dyson (4, 5) and Wright (6-8). However, the premise that olfaction involves detection of vibrational frequencies of odorants remains highly speculative because neither the structures of the odorant receptors (ORs) nor the binding sites or the activation mechanisms triggered upon odorant binding to ORs have been established. In 1996-1997, Turin (9-12) elaborated on the undulatory theory of smell, as considered in more detail below, and suggested that a mechanism analogous to inelastic electron tunneling spectroscopy (13) may be involved, where tunneling electrons in the receptor probe the vibrational frequencies of odorants. In 2013, Gane et al. (14) In judging the plausibility...

Experimental evaluation of the generalized vibrational theory of G protein-coupled receptor activation

“…Additionally, more modern examinations of this theory with both humans and insect subjects have provided mixed and controversial results. (14,(16)(17)(18)(22)(23)(24).There have been several tests of the previous iterations of the VTO, including odor blending (25,26) and isotope exchange (20,(27)(28)(29)(30); each of these methods-odor blending (11, 18) and isotope exchange (11, 31)-has been used to evaluate the modern VTO. Initial justifications of the VTO correlated characteristics of the vibrational spectra with olfactory perception (12), continued within ORs (32), and expanded into non-OR GPCRs (33-36).…”

“…Additionally, more modern examinations of this theory with both humans and insect subjects have provided mixed and controversial results. (14,(16)(17)(18)(22)(23)(24).…”

“…has arisen and has gained both supporters (13)(14)(15)(16) and detractors (17,18); the novelty of this incarnation of the VTO is ascribable to its nonthermal-and nonphoton-based mechanism. Turin's theory is a contemporary reincarnation of the more classical theory proposed by Dyson (19), Wright (20), and Wright and Serenius (21), where the activation of the olfactory receptor is performed-or sensitive to-the molecular vibrations of the olfactant.…”

Laying a controversial smell theory to rest

“…These early theories of how ORs detect odorants were developed using psychophysical experiments, in which human volunteers sniffed odor molecules and described what they perceived. In PNAS, Block et al (7) shift the "shape vs. vibration" debate from olfactory psychophysics to the biophysics of the ORs themselves. The authors mount a sophisticated multidisciplinary attack on the central tenets of the vibration theory using synthetic organic chemistry, heterologous expression of ORs, and theoretical considerations to find no evidence to support the vibration theory of smell.…”

“…The paper by Block et al (7) brings the field to an interesting juncture. Is this negative evidence sufficiently persuasive to lay the theory to rest, or should the screening of ORs and isotopomers continue until the absence of evidence passes the standard of reasonable doubt that would condemn the spectral theory?…”