Ligand Specificity and Evolution of Mammalian Musk Odor Receptors: Effect of Single Receptor Deletion on Odor Detection.
Musk odors have been used widely for fragrance and medicine for >2000 years because of their fascinating scent and physiological effects. Therefore, fragrance manufacturers have been eager to develop high-quality musk compounds that are safe and easily synthesized. We recently identified muscone-responsive olfactory receptors (ORs) MOR215-1 and OR5AN1 in mice and humans, respectively (Shirasu et al., 2014). In this study, we identified musk ORs that are evolutionarily closely related to MOR215-1 or OR5AN1 in various primates and investigated structure-activity relationships for various musk odorants and related compounds. We found that each species has one or two functional musk ORs that exhibit specific ligand spectra to musk compounds. Some of them, including the human OR5AN1, responded to nitro musks with chemical properties distinct from muscone. The ligand specificity of OR5AN1 reflects the perception of musk odors in humans. Genetic deletion of MOR215-1 in mice resulted in drastic reduction of sensitivity to muscone, suggesting that MOR215-1 plays a critical role in muscone perception. Therefore, the current study reveals a clear link between the identified OR and muscone perception. Moreover, the strategy established for screening ligands for the muscone OR may facilitate the development of novel and commercially useful musk odors.


CONCLUSIONS
The long-sought musk odor receptor family in mammals was discovered and found to be well conserved and narrowly tuned to musk odors. In mice, deletion of the most sensitive musk receptor resulted in drastic reduction in sensitivity to muscone, demonstrating a strong link between receptor and odor perception. In humans, we found one musk receptor that recognized both macrocyclic and nitro musks that had distinct chemical structures. The structure-activity relationships were in a good agreement with human sensory perception and therefore may be used to develop novel musk aroma in fragrance fields. Finally, identification of a natural ligand(s) for musk receptors in mammals other than musk deer would reveal an evolutionarily pivotal role in each species in the future.
Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-8657, Japan.
Narumi
N
Sato-Akuhara
Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-8657, Japan.
Nao
N
Horio
Kansei Science Research, Kao Corporation, Ichikai-machi, Haga-gun, Tochigi 321-3497, Japan.
Aya
A
Kato-Namba
Kansei Science Research, Kao Corporation, Ichikai-machi, Haga-gun, Tochigi 321-3497, Japan.
Keiichi
K
Yoshikawa
Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-8657, Japan, ERATO Touhara Chemosensory Signal Project, the Japan Science and Technology Agency, The University of Tokyo, Tokyo 113-8657, Japan, and.
Yoshihito
Y
Niimura
Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-8657, Japan, ERATO Touhara Chemosensory Signal Project, the Japan Science and Technology Agency, The University of Tokyo, Tokyo 113-8657, Japan, and.
Sayoko
S
Ihara
Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-8657, Japan, ERATO Touhara Chemosensory Signal Project, the Japan Science and Technology Agency, The University of Tokyo, Tokyo 113-8657, Japan, and ktouhara@mail.ecc.u-tokyo.ac.jp ashirasu@mail.ecc.u-tokyo.ac.jp.
Mika
M
Shirasu
Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-8657, Japan, ERATO Touhara Chemosensory Signal Project, the Japan Science and Technology Agency, The University of Tokyo, Tokyo 113-8657, Japan, and ktouhara@mail.ecc.u-tokyo.ac.jp ashirasu@mail.ecc.u-tokyo.ac.jp.
Kazushige
K
Touhara
D000818:Animals; D004305:Dose-Response Relationship, Drug; D019143:Evolution, Molecular; D005229:Fatty Acids, Monounsaturated / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009812:Odorants; D010802:Phylogeny; D018035:Receptors, Odorant / Q000235:genetics* / Q000378:metabolism*; D017384:Sequence Deletion / Q000502:physiology*; D012903:Smell / Q000502:physiology*; D013329:Structure-Activity Relationship
D005229:Fatty Acids, Monounsaturated; D008024:Ligands; D018035:Receptors, Odorant; C008563:musk
evolution; human; mouse; musk; olfactory; receptor