Single-Neuron Comparison of the Olfactory Receptor Response to Deuterated and Nondeuterated Odorants

The mammalian olfactory receptors (ORs) constitute a large subfamily of the Class A G-protein coupled receptors (GPCRs). The molecular details of how these receptors convert odorant chemical information into neural signal are unknown, but are predicted by analogy to other GPCRs to involve stabilization of the activated form of the OR by the odorant. An alternative hypothesis maintains that the vibrational modes of an odorant’s bonds constitute the main determinant for OR activation, and that odorants containing deuterium in place of hydrogen should activate different sets of OR family members. Experiments using heterologously expressed ORs have failed to show different responses for deuterated odorants, but experiments in the sensory neuron environment have been lacking. We tested the response to deuterated and nondeuterated versions of p-cymene, 1-octanol, 1-undecanol, and octanal in dissociated mouse olfactory receptor neurons (ORNs) by calcium imaging. In all, we tested 23 812 cells, including a subset expressing recombinant mouse olfactory receptor 2 (Olfr2/OR-I7), and found that nearly all of the 1610 odorant-responding neurons were unable to distinguish the D- and H-odorants. These results support the conclusion that if mammals can perceive deuterated odorants differently, the difference arises from the receptor-independent steps of olfaction. Nevertheless, 0.81% of the responding ORNs responded differently to D- and H-odorants, and those in the octanal experiments responded selectively to H-octanal at concentrations from 3 to 100 μM. The few ORs responding differently to H and D may be hypersensitive to one of the several H/D physicochemical differences, such as the difference in H/D hydrophobicity.