Most sensory systems are primarily specialized to detect one sensory modality. Here we report that olfactory sensory neurons (OSNs) in the mammalian nose can detect two distinct modalities transmitted by chemical and mechanical stimuli. As revealed by patch-clamp recordings, many OSNs respond not only to odorants, but also to mechanical stimuli delivered by pressure ejections of odorfree Ringer solution. The mechanical responses correlate directly with the pressure intensity and show several properties similar to those induced by odorants, including onset latency, reversal potential and adaptation to repeated stimulation. Blocking adenylyl cyclase or knocking out the cyclic nucleotide-gated channel CNGA2 eliminates the odorant and the mechanical responses, suggesting that both are mediated by a shared cAMP cascade. We further show that this mechanosensitivity enhances the firing frequency of individual neurons when they are weakly stimulated by odorants and most likely drives the rhythmic activity (theta oscillation) in the olfactory bulb to synchronize with respiration.Receptor cells within each sensory system are specialized to detect a certain modality (for example, vision, hearing, touch, taste or smell) and to convert external stimuli into intracellular signals. Odor detection via the olfactory system relies on a large family of odorant receptors expressed in the olfactory sensory neurons (OSNs) within the neuroepithelium of the nose 1 . These odorant receptors initiate a cAMP pathway that enables olfactory signal transduction 2 . Binding of odor molecules to odorant receptors sequentially activates a specific G protein (Golf) and adenylyl cyclase type III (ACIII), which increases the intracellular cAMP level. Later opening of specific cyclic nucleotide-gated (CNG) channels by cAMP depolarizes the sensory neurons and triggers action potentials, which then permits odor information to reach the olfactory bulb in the brain.In addition to processing the convergent odor inputs from numerous OSNs, the olfactory bulb shows rhythmic activity (theta-band oscillation) coupled with respiration even in the absence of odorants, suggesting that the bulb also receives airflow information 3-8 . The mechanism underlying the rhythmic activity is not fully understood, although both peripheral and centrifugal sources are implicated 6,9-12 . Nonetheless, air intake, especially in the form of Correspondence should be addressed to M.M. (minghong@mail.med.upenn.edu.). AUTHOR CONTRIBUTIONS X.G. performed the recordings in the septal organ, L.C.S. performed the recordings in the main olfactory epithelium, J.T. performed the recordings in the olfactory bulb, M.L. supervised the bulb recordings, and M.M. supervised the whole project and drafted the manuscript. COMPETING INTERESTS STATEMENTThe authors declare that they have no competing financial interests. We show that the mechanosensitivity enhances the neuronal activity of individual OSNs when they are weakly stimulated by odorants. Furthermore, the mechanosensitivity of the...

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The current consensus model in mammalian olfaction is that the detection of millions of odorants requires a large number of odorant receptors (ORs) and that each OR interacts selectively with a small subset of odorants, which are typically related in structure. Here, we report the odorant response properties of an OR that deviates from this model: SR1, a mouse OR that is abundantly expressed in sensory neurons of the septal organ and also of the main olfactory epithelium. Patch-clamp recordings reveal that olfactory sensory neurons (OSNs) that express SR1 respond to many, structurally unrelated odorants, and over a wide concentration range. Most OSNs expressing a gene-targeted SR1 locus that lacks the SR1 coding sequence do not show this broad responsiveness. Gene transfer in the heterologous expression system Hana3A confirms the broad response profile of SR1. There may be other mouse ORs with such broad response profiles.

In mammals, the sense of smell is modulated by the status of satiety, which is mainly signaled by blood-circulating peptide hormones. However, the underlying mechanisms linking olfaction and food intake are poorly understood. Here we investigated the effects of two anorectic peptides, insulin and leptin, on the functional properties of olfactory sensory neurons (OSNs). Using patch-clamp recordings, we analyzed the spontaneous activity of rat OSNs in an in vitro intact epithelium preparation. Bath perfusion of insulin and leptin significantly increased the spontaneous firing frequency in 91.7% (n = 24) and 75.0% (n = 24) of the cells, respectively. When the activity was electrically evoked, both peptides shortened the latency to the first action potential by approximately 25% and decreased the interspike intervals by approximately 13%. While insulin and leptin enhanced the electrical excitability of OSNs in the absence of odorants, they surprisingly reduced the odorant-induced activity in the olfactory epithelium. Insulin and leptin decreased the peak amplitudes of isoamyl acetate-induced electroolfactogram (EOG) signals to 46 and 38%, respectively. When measured in individual cells by patch-clamp recordings, insulin and leptin decreased odorant-induced transduction currents and receptor potentials. Therefore by increasing the spontaneous activity but reducing the odorant-induced activity of OSNs, an elevated insulin and leptin level (such as after a meal) may result in a decreased global signal-to-noise ratio in the olfactory epithelium, which matches the smell ability to the satiety status.

Mechanosensitive cells are essential for organisms to sense the external and internal environments, and a variety of molecules have been implicated as mechanical sensors. Here we report that odorant receptors (ORs), a large family of G protein-coupled receptors, underlie the responses to both chemical and mechanical stimuli in mouse olfactory sensory neurons (OSNs). Genetic ablation of key signaling proteins in odor transduction or disruption of OR-G protein coupling eliminates mechanical responses. Curiously, OSNs expressing different OR types display significantly different responses to mechanical stimuli. Genetic swap of putatively mechanosensitive ORs abolishes or reduces mechanical responses of OSNs. Furthermore, ectopic expression of an OR restores mechanosensitivity in loss-of-function OSNs. Lastly, heterologous expression of an OR confers mechanosensitivity to its host cells. These results indicate that certain ORs are both necessary and sufficient to cause mechanical responses, revealing a previously unidentified mechanism for mechanotransduction. , but our understanding of the mechanical sensors is still limited. We previously discovered that some OSNs in the mammalian nose responded to mechanical stimulation (4), a feature that may allow the nose to carry an afferent signal of breathing to the brain and facilitate binding of orofacial sensation (5). In the current study, we aim to identify the mechanical sensor(s) and mechanotransduction pathway in OSNs.In mammals, smell perception depends on a large family of ORs expressed in OSNs. Out of a repertoire of >1,000 ORs (6, 7), each OSN expresses a single type, which determines its response profile and central target in the brain. Binding of odorant molecules with specific ORs activates the olfactory G protein G olf , which in turn activates type III adenylyl cyclase (ACIII). ACIII activation causes increased production of cAMP, which opens a cyclic nucleotide-gated cation (CNG) channel. The inward current via the CNG channel is further amplified by Cl − outflow through a calcium-activated Cl − channel. This transduction cascade leads to depolarization of OSNs, which fire action potentials carrying the odor information to the brain (8). OSNs expressing the same OR are scattered in one of the few broadly defined zones in the olfactory epithelium, but their axons typically converge onto a pair of glomeruli in the olfactory bulb (9).Here we report that disruption of the olfactory signal transduction cascade completely eliminates mechanical responses in OSNs. OSNs expressing different receptor types display differential responses to mechanical stimuli. For instance, I7, M71, and SR1 neurons have much stronger mechanical responses than MOR23 and mOR-EG neurons. Loss-of-function mutation of the I7 receptor, genetic switch of the M71 receptor, or ablation of the SR1 receptor, abolishes or dramatically reduces mechanical responses in the host OSNs. Furthermore, ectopic expression of the I7 receptor restores mechanosensitivity in loss-of-function mutant I7 cells. ...