Olfactory Receptor and Neural Pathway Responsible for Highly Selective Sensing of Musk Odors

Shirasu, Mika; Yoshikawa, Keiichi; Tokura, Y.; Nakashima, Ai; Takeuchi, Haruki; Sakano, Hitoshi; Touhara, Kazushige

doi:10.1016/j.neuron.2013.10.021

Cited by 101 publications

(100 citation statements)

References 53 publications

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“…Our experimental results are consistent with the ability of mice (and other mammals) to discriminate between a large array of nonpheromonal chiral odorant enantiomeric pairs, as well as with the ability of mouse receptor MOR215-1 to discriminate (R)-and (S)-muscone (27). Although it is known that the muscone enantiomers "differ from each other with regard to odor quality and the odor detection threshold in humans" (27), data are not yet available on the response of OR5AN1 to muscone enantiomers.…”

Section: Resultssupporting

confidence: 84%

“…S3.3). This response is consistent with a recent report (27), in which OR5AN1 was identified as a human muscone OR, based on homology to the mouse OR MOR215-1, functionally cloned from muscone-responsive glomeruli; a second report on OR5AN1 as the only functional human homolog of mouse muscone ORs in vivo (54); and a third report that only a small number of receptors are thought to be involved in sensing musk odor (55). Our screening and the following confirmation experiments did not reveal any human OR that responded to only one, two, or three of the four isotopomers of 1.…”

Section: Response Of a Human Musk Or To Deuterated And Nondeuteratedsupporting

confidence: 94%

“…A recent study (27) using heterologous cell assays and a c-fos induction assay in the olfactory bulb identified MOR215-1 as a strong musk-responding mouse OR. This study observes that "6% of humans are muscone anosmic.…”

Section: Discussionmentioning

confidence: 99%

“…. ; therefore, muscone may be recognized by only a small set of ORs, including OR5AN1 in humans, and genetic variation in these receptors may cause muscone anosmia" (27). McClintock et al (54) identified five highly related ORs, including MOR215-1, that are likely to be activated by muscone in freely behaving mice, supporting multiple muscone receptors.…”

Section: Discussionmentioning

confidence: 99%

“…This is emphatically not the case." However, these assertions are clearly at odds with the highly developed ability of mice and other mammals to discriminate an array of nonpheromonal chiral odorant enantiomeric pairs (23)(24)(25), with the divergent in vitro responses to enantiomers by different combinations of ORs (26) and, in particular, with the highly selective response of the musk-sensitive mouse receptor, MOR215-1, to (R)-muscone ("l-muscone") compared with (S)-muscone ("d-muscone") (27).…”

Section: Significancementioning

confidence: 99%

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Implausibility of the vibrational theory of olfaction

Block

Jang

Matsunami

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

115

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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...

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Section: Resultssupporting

confidence: 84%

Section: Response Of a Human Musk Or To Deuterated And Nondeuteratedsupporting

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Significancementioning

confidence: 99%

See 3 more Smart Citations

Implausibility of the vibrational theory of olfaction

Block

Jang

Matsunami

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

115

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Olfactory Receptor Genes: Evolution

Niimura

2014

Encyclopedia of Life Sciences

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Many mammal genomes have approximately 1000 genes encoding olfactory receptors (ORs), and OR genes constitute the largest multigene family in mammals. Comparisons among the OR gene repertoires in a broad range of species demonstrates that gene duplication and pseudogenization cause frequent gene gain and loss in this family, causing drastic evolutionary changes in the number of genes depending on species' ecological niches and other sensory modalities. For example, higher primates are equipped with a well‐developed visual system, and they have a reduced OR gene repertoires relative to mammals with lesser visual systems. Additionally, aquatic and terrestrial vertebrates retain different sets of OR genes, and these sets reflect the capacity to detect water‐soluble and airborne odorants, respectively. The origin of vertebrate OR genes can be traced back to the common ancestor of chordates, but insects and nematodes each use a distinct family of genes to encode chemoreceptors; therefore, multiple distinct chemoreceptor gene families emerged independently during animal evolution. Key Concepts: Olfactory receptor (OR) genes are the largest multigene family in mammals. OR gene repertoires changed dynamically during mammalian evolution and these changes depended on each species' ecological niches and other sensory modalities. Distinct chemoreceptor gene families have emerged independently multiple times during animal evolution. Comparative evolutionary analysis of OR genes provides insights into the interactions between genomes and environments.

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Olfactory Receptor Function

Yoshikawa

Touhara

2015

Handbook of Olfaction and Gustation

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Olfactory Receptor and Neural Pathway Responsible for Highly Selective Sensing of Musk Odors

Cited by 101 publications

References 53 publications

Implausibility of the vibrational theory of olfaction

Implausibility of the vibrational theory of olfaction

Olfactory Receptor Genes: Evolution

Olfactory Receptor Function

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