Allosteric modulation of a human odorant receptor

Odor perception is first determined by how the myriad of environmental volatiles are detected at the periphery of the olfactory system. The combinatorial activation of dedicated odorant receptors generates enough encoding power for the discrimination of tens of thousands of odorants. Recent studies have revealed that odorant receptors undergo widespread inhibitory modulation of their activity when presented with mixtures of odorants, a property likely required to maintain discrimination and ensure sparsity of the code for complex mixtures. Here, we establish the role of human OR5AN1 in the detection of musks and identify distinct odorants capable of enhancing its activity in binary mixtures. Chemical and pharmacological characterization indicate that specific α-β unsaturated aliphatic aldehydes act as positive allosteric modulators. Sensory experiments show decreased odor detection threshold in humans, suggesting that allosteric modulation of odorant receptors is perceptually relevant and likely adds another layer of complexity to how odors are encoded in the peripheral olfactory system. [Display omitted] •Musk receptor OR5AN1 appears to drive the detection threshold of its ligands•Volatile, unsaturated aliphatic aldehydes can enhance the activity of OR5AN1•Similar to other class A GPCRs, odorant receptors undergo allosteric modulation•Allosteric modulation of ORs likely increases olfactory discrimination Widespread odorant receptor inhibition increases the sparsity of the olfactory code required to discriminate odorant mixtures. With the identification of positive allosteric modulators, Trimmer et al. show that a human musk receptor can also be enhanced by small volatile molecules, adding another layer to the encoding capacity of the olfactory system.