Supersensitive odor discrimination is controlled in part by initial transient interactions between the most sensitive dorsal olfactory receptors and G-proteins

Abstract

Pairs of enantiomeric odor ligands are difficult to resolve by instrumental analyses because compounds with mirror-image molecular structures have almost identical physicochemical properties. The olfactory system, however, discriminates (–)-forms of enantiomers from their (+)-forms within seconds. To investigate key olfactory receptors for enantiomer discrimination, we compared behavioral detection and discrimination thresholds of wild-type mice with those of ?D mice that lack all dorsal olfactory receptors. Surprisingly, wild-type mice displayed an exquisite “supersensitivity” to enantiomeric pairs of wine lactones and carvones in both detection and discrimination tasks using odor plume-like flows in a Y-maze. In contrast, ?D mice showed >10¹⁰-fold reductions in enantiomer discrimination sensitivity compared to wild-type mice. ?D mice detected one or both of the (–)- and (+)-enantiomers over a wide concentration range, but were unable to discriminate them. This “enantiomer odor discrimination paradox” indicates that the most sensitive dorsal receptors play a critical role in hierarchical odor coding for enantiomer identification. In addition, to identify residues responsible for the rapid and robust response of murine olfactory receptor S6 (mOR-S6) via chimeric G?_{15_olf}, mutations of the C-terminal helix 8 were analyzed in a heterologous functional expression system. The N-terminal hydrophobic core between helix 8 and TM1?2 of mOR-S6 is important for G? activation. A point mutation of a helix 8 N-terminal acidic residue eliminated the improved response dynamics via the chimeric G?_{15_olf}. This result suggests that an N-terminal acidic residue of helix 8 is responsible for rapid G? activation. Supersensitive odor discrimination is thus largely governed by signals from the most sensitive dorsal olfactory receptors with the shortest onset latencies, which are controlled in part by initial transient interactions between the receptor C-terminal helix 8 and the G? C-terminal region.