Allosteric modulation of a human odorant receptor

Odor perception is first determined by how the myriad of environmental volatiles are detected at the periph-ery 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 odor-ants capable of enhancing its activity in binary mixtures. Chemical and pharmacological characterization indicate that specific a-b unsaturated aliphatic aldehydes act as positive allosteric modulators. Sensory ex-periments 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 en-coded in the peripheral olfactory system.

Automated summary

Odor perception is determined by the detection of environmental volatiles at the periphery of the olfactory system. Combinatorial activation of odorant receptors allows discrimination of numerous odorants, and recent studies indicate inhibitory modulation of receptor activity in the presence of odorant mixtures. Human OR5AN1 plays a role in musk detection and certain odorants act as positive allosteric modulators, enhancing its activity in binary mixtures. This allosteric modulation of odorant receptors is perceptually relevant and adds complexity to odor coding in the peripheral olfactory system.