Enzymatic Conversion of Odorants in Nasal Mucus Affects Olfactory Glomerular Activation Patterns and Odor Perception

Nagashima, Ayumi; Touhara, Kazushige

doi:10.1523/jneurosci.2527-10.2010

Cited by 128 publications

(115 citation statements)

References 36 publications

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“…Because the Baeyer-Villager (B-V) reaction is known to be mediated (62) by oxidative enzymes (e.g., cytochrome P450), which are present in the nasopharyngeal mucus layer (2,32,63,64), and the B-V reaction of deuterated cyclic ketones forming deuterated lactones is known to show an isotope effect (62), such a reaction might affect odor perception of pairs such as 1 and 1-d 28 . Indeed, we have confirmed that 1-d 28 undergoes peracid-mediated B-V oxidation faster than nondeuterated 1, in accord with literature results (62), although a full kinetic analysis in the case of 1/1-d 28 was not possible due to partial overlap of ketone and lactone peaks under GC-MS conditions.…”

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

confidence: 99%

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: Response Of a Human Musk Or To Deuterated And Nondeuteratedmentioning

confidence: 99%

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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“…It has been proposed that odorants are degraded and therefore removed by the mucosal enzymes (Thiebaud et al 2013). However, some of the enzymatic reactions in the mucus appear to be fast and to occur before odorants reach the receptor site, resulting in affecting the perception (Nagashima and Touhara 2010). Thus, it remains to be shown (1) how exactly odorants travel from the air space into a receptor-binding site to achieve a concentration high enough to activate the receptor and (2) what is the fate of an odorant after the mission of activating an OR is completed in the mucous layer.…”

Section: Odorant Dynamics and Kineticsmentioning

confidence: 99%

Odor and Pheromone Molecules, Receptors, and Behavioral Responses

Touhara

2014

The Olfactory System

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Knowledge about chemosensory signals, receptors, olfactory neural network, and behavioral outputs has grown rapidly. Thus, the molecular logic that mediates recognition and discrimination of chemosensory signals has been revealed. Here, I first summarize the current understanding of mammalian olfaction, from the odorant or pheromone, to the receptor, and finally to the behavioral output. I then discuss important questions to be solved in the future and give some insights. Specifically, how should we categorize volatile compounds that are received by olfactory systems in animals? What should be the next focus of research in the field of olfactory receptors? How can we connect a receptor response to a cognate, biologically meaningful odorant or pheromone with the respective behavioral or physiological output at the level of neural circuitry?

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“…Thus, from sequence and functional perspectives, OAT6 belongs to a large family of facilitative solute carriers of the SLC22 family of multispecific organic anion "drug" transporters, the best studied of which are OAT1 and OAT3. Nevertheless, the unique and rather restricted expression pattern of OAT6 in olfactory mucosa raises the interesting possibility of a role for this transporter in delivery of small-molecule xenobiotics across the nasal-epithelial barrier and potential access to the central nervous system (Genter et al, 2009;Nagashima and Touhara, 2010;Thiebaud et al, 2011;Heydel et al, 2013;Nigam et al, 2015). Moreover, in light of common odorant ligands, and because OAT1 is highly expressed in the kidney (whereas OAT6 is highly expressed in olfactory epithelium), it is possible that volatile odorants excreted via OAT1 into the urine interact with olfactory OAT6 in the nasal epithelium (Kaler et al, 2006(Kaler et al, , 2007Wu et al, 2011;Nigam et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Shared Ligands Between Organic Anion Transporters (OAT1 and OAT6) and Odorant Receptors

Bush

Liu

et al. 2015

Drug Metab Dispos

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The multispecific organic anion drug transporters OAT6 (SLC22A20) and OAT1 (SLC22A6) are expressed in nasal epithelial cells and both can bind odorants. Sequence analysis of OAT6 revealed an evolutionarily conserved 79-amino acid (AA) fragment present not only in OAT6 but also in other SLC22 transporters, such as the organic anion transporter (OAT), organic carnitine transporter (OCTN), and organic cation transporter (OCT) subfamilies. A similar fragment is also conserved in some odorant receptors (ORs) in both humans and rodents. This fragment is located in regions believed to be important for ligand/substrate preference and recognition in both classes of proteins, raising the possibility that it may be part of a potential common ligand/substrate recognition site in certain ORs and SLC22 transporters. In silico screening of an odorant database containing known OR ligands with a pharmacophore hypothesis (generated from a set of odorants known to bind OAT6 and/or OAT1), followed by in vitro uptake assays in transfected cells, identified OR ligands capable of inhibiting OAT6-and/or OAT1-mediated transport, albeit with different affinities. The conservation of the AA fragments between these two different classes of proteins, together with their coexpression in olfactory as well as other tissues, suggests the possibility that ORs and SLC22 transporters function in concert, and raises the question as to whether these transporters function in remote sensing and signaling and/or as transceptors.

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Enzymatic Conversion of Odorants in Nasal Mucus Affects Olfactory Glomerular Activation Patterns and Odor Perception

Cited by 128 publications

References 36 publications

Implausibility of the vibrational theory of olfaction

Implausibility of the vibrational theory of olfaction

Odor and Pheromone Molecules, Receptors, and Behavioral Responses

Shared Ligands Between Organic Anion Transporters (OAT1 and OAT6) and Odorant Receptors

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