The scent of musk plays a unique role in the history of perfumery. Musk odorants comprise six diverse chemical classes and perception difference in strength and quality among human panelists have long puzzled the field of olfaction research. Three odorant receptors (OR) had recently been described for musk odorants: OR5AN1, OR1N2 and OR5A2. High functional expression of the difficult-to-express human OR5A2 was achieved by a modification of the C-terminal domain and the link between sensory perception and receptor activation for the trilogy of these receptors and their key genetic variants was investigated: All three receptors detect only musky smelling compounds among 440 commercial fragrance compounds. OR5A2 is the key receptor for the classes of polycyclic and linear musks and for most macrocylic lactones. A single P172L substitution reduces sensitivity of OR5A2 around 50-fold. In parallel, human panelists homozygous for this mutation have an around 40 – 60-fold higher sensory detection threshold for selective OR5A2 ligands. For macrocyclic lactones, OR5A2 could further be proven as the key OR by a strong correlation between in vitro activation and the sensory detection threshold in vivo. OR5AN1 is the dominant receptor for the perception of macrocyclic ketones such as muscone and some nitromusks, as panelists with a mutant OR5A2 are still equally sensitive to these ligands. Finally, OR1N2 appears to be an additional receptor involved in the perception of the natural (E)-ambrettolide. This study for the first time links OR activation to sensory perception and genetic polymorphisms for this unique class of odorants.

中文翻译：

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人类麝香受体三部曲：将受体激活、基因型和感官知觉联系起来

麝香的香气在香水史上扮演着独特的角色。麝香气味剂由六种不同的化学类别组成，人类小组成员对强度和质量的感知差异长期以来一直困扰着嗅觉研究领域。最近描述了麝香气味剂的三种气味受体（OR）：OR5AN1、OR1N2 和 OR5A2。通过修饰 C 端结构域实现了难以表达的人 OR5A2 的高功能表达，并研究了这些受体三部曲及其关键遗传变异的感觉感知和受体激活之间的联系：所有三种受体均检测到440 种商用香料化合物中唯一具有麝香气味的化合物。 OR5A2 是多环和线性麝香类别以及大多数大环内酯的关键受体。单个 P172L 取代可将 OR5A2 的敏感性降低约 50 倍。与此同时，该突变纯合的人类小组成员对选择性 OR5A2 配体的感觉检测阈值高出约 40-60 倍。对于大环内酯，通过体外激活与体内感觉检测阈值之间的强相关性，可以进一步证明OR5A2是关键的OR。 OR5AN1 是感知大环酮（例如麝香酮和一些硝基麝香）的主要受体，因为具有突变 OR5A2 的小组成员仍然对这些配体同样敏感。最后，OR1N2 似乎是参与天然 (E)-ambrttolide 感知的额外受体。这项研究首次将 OR 激活与此类独特气味剂的感官知觉和遗传多态性联系起来。