Sato-Akuhara Narumi, Horio Nao, Kato-Namba Aya, Yoshikawa Keiichi, Niimura Yoshihito, Ihara Sayoko, Shirasu Mika, Touhara Kazushige
Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-8657, Japan.
Kansei Science Research, Kao Corporation, Ichikai-machi, Haga-gun, Tochigi 321-3497, Japan.
J Neurosci. 2016 Apr 20;36(16):4482-91. doi: 10.1523/JNEUROSCI.3259-15.2016.
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.
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.
麝香气味因其迷人的香气和生理效应，在香料和医药领域已被广泛使用了两千多年。因此，香料制造商一直渴望开发出安全且易于合成的高品质麝香化合物。我们最近分别在小鼠和人类中鉴定出了对麝香酮有反应的嗅觉受体（ORs）MOR215 - 1和OR5AN1（白须等，2014年）。在本研究中，我们在各种灵长类动物中鉴定出了与MOR215 - 1或OR5AN1在进化上密切相关的麝香ORs，并研究了各种麝香气味剂及相关化合物的构效关系。我们发现每个物种都有一个或两个功能性麝香ORs，它们对麝香化合物表现出特定的配体谱。其中一些，包括人类的OR5AN1，对具有与麝香酮不同化学性质的硝基麝香有反应。OR5AN1的配体特异性反映了人类对麝香气味的感知。小鼠中MOR215 - 1的基因缺失导致对麝香酮的敏感性大幅降低，这表明MOR215 - 1在麝香酮感知中起关键作用。因此，当前的研究揭示了所鉴定的OR与麝香酮感知之间的明确联系。此外，为筛选麝香酮OR的配体而建立的策略可能会促进新型且具有商业用途的麝香气味的开发。
在哺乳动物中长期寻找的麝香气味受体家族被发现，且发现其高度保守并对麝香气味有狭窄的调谐。在小鼠中，删除最敏感的麝香受体导致对麝香酮的敏感性大幅降低，证明了受体与气味感知之间的紧密联系。在人类中，我们发现了一种能识别具有不同化学结构的大环麝香和硝基麝香的麝香受体。构效关系与人类感官感知高度一致，因此可用于在香料领域开发新型麝香香气。最后，鉴定除麝鹿外的哺乳动物中麝香受体的天然配体，将在未来揭示每个物种在进化中的关键作用。
