Abstract
Olfactory receptor neurons (ORNs) use odour-induced intracellular cAMP surge to gate cyclic nucleotide-gated nonselective cation (CNG) channels in cilia. Prolonged exposure to cAMP causes calmodulin-dependent feedback-adaptation of CNG channels and attenuates neural responses. On the other hand, the odour-source searching behaviour requires ORNs to be sensitive to odours when approaching targets. How ORNs accommodate these conflicting aspects of cAMP responses remains unknown. Here, we discover that olfactory marker protein (OMP) is a major cAMP buffer that maintains the sensitivity of ORNs. Upon the application of sensory stimuli, OMP directly captured and swiftly reduced freely available cAMP, which transiently uncoupled downstream CNG channel activity and prevented persistent depolarization. Under repetitive stimulation, OMP-/- ORNs were immediately silenced after burst firing due to sustained depolarization and inactivated firing machinery. Consequently, OMP-/- mice showed serious impairment in odour-source searching tasks. Therefore, cAMP buffering by OMP maintains the resilient firing of ORNs.
Highlights
Despite various hyposmic phenotypes demonstrated by mice lacking olfactory marker protein (OMP), no direct interactions have been identified between OMP and cAMP signalling proteins[26,27,28,29,30,31,32]
We assessed the direct physical interaction between OMP and cAMP in vitro by performing bioluminescence resonance energy transfer (BRET) experiments, in which luminescence energy from luciferase was transferred to fluorescent molecules in very close proximity (Fig. 2a, b)
Renilla luciferase (Rluc, 36 kDa, energy donor, emission peak at 480 nm) was fused to OMP (Rluc-OMP, 55 kDa; Supplementary Fig. 2a, b) such that BRET would occur in tight proximity to fluorescent 8NBD-cAMP (Fig. 2b; Supplementary Fig. 2a, b)
Summary
Wrong licks/mouse f j7 Empty Solution Reward Empty WT L(+) Het L(+) KO L(+). While the KO mice wandered around far less actively and sometimes stopped without digging any holes or even eating the visible food (KO, Fig. 10c, d), indicating that the KO mice challenged with PDEi visually noticed a novel object but were not able to recognise it as food due to severe hyposmia. Following PDEi administration, the Het mice noticed the object but did not begin to eat; rather, they restlessly wandered and sniffed around the arena.
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