A transcriptional rheostat couples past activity to future sensory responses.

Animals traversing different environments encounter both stable background stimuli and novel cues, which are thought to be detected by primary sensory neurons and then distinguished by downstream brain circuits. Here, we show that each of the ∼1,000 olfactory sensory neuron (OSN) subtypes in the mouse harbors a distinct transcriptome whose content is precisely determined by interactions between its odorant receptor and the environment. This transcriptional variation is systematically organized to support sensory adaptation: expression levels of more than 70 genes relevant to transforming odors into spikes continuously vary across OSN subtypes, dynamically adjust to new environments over hours, and accurately predict acute OSN-specific odor responses. The sensory periphery therefore separates salient signals from predictable background via a transcriptional rheostat whose moment-to-moment state reflects the past and constrains the future; these findings suggest a general model in which structured transcriptional variation within a cell type reflects individual experience.

An Engineered orco Mutation Produces Aberrant Social Behavior and Defective Neural Development in Ants.

Ants exhibit cooperative behaviors and advanced forms of sociality that depend on pheromone-mediated communication. Odorant receptor neurons (ORNs) express specific odorant receptors (ORs) encoded by a dramatically expanded gene family in ants. In most eusocial insects, only the queen can transmit genetic information, restricting genetic studies. In contrast, workers in Harpegnathos saltator ants can be converted into gamergates (pseudoqueens) that can found entire colonies. This feature facilitated CRISPR-Cas9 generation of germline mutations in orco, the gene that encodes the obligate co-receptor of all ORs. orco mutations should significantly impact olfaction. We demonstrate striking functions of Orco in odorant perception, reproductive physiology, and social behavior plasticity. Surprisingly, unlike in other insects, loss of OR functionality also dramatically impairs development of the antennal lobe to which ORNs project. Therefore, the development of genetics in Harpegnathos establishes this ant species as a model organism to study the complexity of eusociality.

Recent Advances in Behavioral (Epi)Genetics in Eusocial Insects.

Eusocial insects live in societies in which distinct family members serve specific roles in maintaining the colony and advancing the reproductive ability of a few select individuals. Given the genetic similarity of all colony members, the diversity of morphologies and behaviors is surprising. Social communication relies on pheromones and olfaction, as shown by mutants of orco, the universal odorant receptor coreceptor, and through electrophysiological analysis of neuronal responses to pheromones. Additionally, neurohormonal factors and epigenetic regulators play a key role in caste-specific behavior, such as foraging and caste switching. These studies start to allow an understanding of the molecular mechanisms underlying social behavior and provide a technological foundation for future studies of eusocial insects. In this review, we highlight recent findings in eusocial insects that advance our understanding of genetic and epigenetic regulations of social behavior and provide perspectives on future studies using cutting-edge technologies.

Functional Characterization Supports Multiple Evolutionary Origins of Pheromone Receptors in Bark Beetles.

Chemical communication using pheromones is thought to have contributed to the diversification and speciation of insects. The species-specific pheromones are detected by specialized pheromone receptors (PRs). Whereas the evolution and function of PRs have been extensively studied in Lepidoptera, only a few PRs have been identified in beetles, which limits our understanding of their evolutionary histories and physiological functions. To shed light on these questions, we aimed to functionally characterize potential PRs in the spruce bark beetle Ips typographus ("Ityp") and explore their evolutionary origins and molecular interactions with ligands. Males of this species release an aggregation pheromone comprising 2-methyl-3-buten-2-ol and (4S)-cis-verbenol, which attracts both sexes to attacked trees. Using two systems for functional characterization, we show that the highly expressed odorant receptor (OR) ItypOR41 responds specifically to (4S)-cis-verbenol, with structurally similar compounds eliciting minor responses. We next targeted the closely related ItypOR40 and ItypOR45. Whereas ItypOR40 was unresponsive, ItypOR45 showed an overlapping response profile with ItypOR41, but a broader tuning. Our phylogenetic analysis shows that these ORs are present in a different OR clade as compared to all other known beetle PRs, suggesting multiple evolutionary origins of PRs in bark beetles. Next, using computational analyses and experimental validation, we reveal two amino acid residues (Gln179 and Trp310) that are important for ligand binding and pheromone specificity of ItypOR41 for (4S)-cis-verbenol, possibly via hydrogen bonding to Gln179. Collectively, our results shed new light on the origins, specificity, and ligand binding mechanisms of PRs in beetles.

An odorant receptor mediates the avoidance of Plutella xylostella against parasitoid.

BACKGROUND: Ecosystems are brimming with myriad compounds, including some at very low concentrations that are indispensable for insect survival and reproduction. Screening strategies for identifying active compounds are typically based on bioassay-guided approaches. RESULTS: Here, we selected two candidate odorant receptors from a major pest of cruciferous plants-the diamondback moth Plutella xylostella-as targets to screen for active semiochemicals. One of these ORs, PxylOR16, exhibited a specific, sensitive response to heptanal, with both larvae and adult P. xylostella displaying heptanal avoidance behavior. Gene knockout studies based on CRISPR/Cas9 experimentally confirmed that PxylOR16 mediates this avoidance. Intriguingly, rather than being involved in P. xylostella-host plant interaction, we discovered that P. xylostella recognizes heptanal from the cuticular volatiles of the parasitoid wasp Cotesia vestalis, possibly to avoid parasitization. CONCLUSIONS: Our study thus showcases how the deorphanization of odorant receptors can drive discoveries about their complex functions in mediating insect survival. We also demonstrate that the use of odorant receptors as a screening platform could be efficient in identifying new behavioral regulators for application in pest management.

A cilia-bound unconventional secretory pathway for Drosophila odorant receptors.

BACKGROUND: Post-translational transport is a vital process which ensures that each protein reaches its site of function. Though most do so via an ordered ER-to-Golgi route, an increasing number of proteins are now shown to bypass this conventional secretory pathway. RESULTS: In the Drosophila olfactory sensory neurons (OSNs), odorant receptors (ORs) are trafficked from the ER towards the cilia. Here, we show that Or22a, a receptor of various esters and alcoholic compounds, reaches the cilia partially through unconventional means. Or22a frequently present as puncta at the somatic cell body exit and within the dendrite prior to the cilia base. These rarely coincide with markers of either the intermediary ER-Golgi-intermediate-compartment (ERGIC) or Golgi structures. ERGIC and Golgi also displayed axonal localization biases, a further indication that at least some measure of OR transport may occur independently of their involvement. Additionally, neither the loss of several COPII genes involved in anterograde trafficking nor ERGIC itself affected puncta formation or Or22a transport to the cilium. Instead, we observed the consistent colocalization of Or22a puncta with Grasp65, the sole Drosophila homolog of mammalian GRASP55/Grh1, a marker of the unconventional pathway. The numbers of both Or22a and Grasp65-positive puncta were furthermore increased upon nutritional starvation, a condition known to enhance Golgi-bypassing secretory activity. CONCLUSIONS: Our results demonstrate an alternative route of Or22a transport, thus expanding the repertoire of unconventional secretion mechanisms in neurons.

Few chemoreceptor genes in the ambrosia beetle Trypodendron lineatum may reflect its specialized ecology.

BACKGROUND: Chemoreception is crucial for insect fitness, underlying for instance food-, host-, and mate finding. Chemicals in the environment are detected by receptors from three divergent gene families: odorant receptors (ORs), gustatory receptors (GRs), and ionotropic receptors (IRs). However, how the chemoreceptor gene families evolve in parallel with ecological specializations remains poorly understood, especially in the order Coleoptera. Hence, we sequenced the genome and annotated the chemoreceptor genes of the specialised ambrosia beetle Trypodendron lineatum (Coleoptera, Curculionidae, Scolytinae) and compared its chemoreceptor gene repertoires with those of other scolytines with different ecological adaptations, as well as a polyphagous cerambycid species. RESULTS: We identified 67 ORs, 38 GRs, and 44 IRs in T. lineatum ('Tlin'). Across gene families, T. lineatum has fewer chemoreceptors compared to related scolytines, the coffee berry borer Hypothenemus hampei and the mountain pine beetle Dendroctonus ponderosae, and clearly fewer receptors than the polyphagous cerambycid Anoplophora glabripennis. The comparatively low number of chemoreceptors is largely explained by the scarcity of large receptor lineage radiations, especially among the bitter taste GRs and the 'divergent' IRs, and the absence of alternatively spliced GR genes. Only one non-fructose sugar receptor was found, suggesting several sugar receptors have been lost. Also, we found no orthologue in the 'GR215 clade', which is widely conserved across Coleoptera. Two TlinORs are orthologous to ORs that are functionally conserved across curculionids, responding to 2-phenylethanol (2-PE) and green leaf volatiles (GLVs), respectively. CONCLUSIONS: Trypodendron lineatum reproduces inside the xylem of decaying conifers where it feeds on its obligate fungal mutualist Phialophoropsis ferruginea. Like previous studies, our results suggest that stenophagy correlates with small chemoreceptor numbers in wood-boring beetles; indeed, the few GRs may be due to its restricted fungal diet. The presence of TlinORs orthologous to those detecting 2-PE and GLVs in other species suggests these compounds are important for T. lineatum. Future functional studies should test this prediction, and chemoreceptor annotations should be conducted on additional ambrosia beetle species to investigate whether few chemoreceptors is a general trait in this specialized group of beetles.

The trilogy of human musk receptors: linking receptor activation, genotype, and sensory perception.

The scent of musk plays a unique role in the history of perfumery. Musk odorants comprise 6 diverse chemical classes and perception differences in strength and quality among human panelists have long puzzled the field of olfaction research. Three odorant receptors (OR) had recently been described for musk odorants: OR5AN1, OR1N2, and OR5A2. High functional expression of the difficult-to-express human OR5A2 was achieved by a modification of the C-terminal domain and the link between sensory perception and receptor activation for the trilogy of these receptors and their key genetic variants was investigated: All 3 receptors detect only musky smelling compounds among 440 commercial fragrance compounds. OR5A2 is the key receptor for the classes of polycyclic and linear musks and for most macrocylic lactones. A single P172L substitution reduces the sensitivity of OR5A2 by around 50-fold. In parallel, human panelists homozygous for this mutation have around 40-60-fold higher sensory detection threshold for selective OR5A2 ligands. For macrocyclic lactones, OR5A2 could further be proven as the key OR by a strong correlation between in vitro activation and the sensory detection threshold in vivo. OR5AN1 is the dominant receptor for the perception of macrocyclic ketones such as muscone and some nitromusks, as panelists with a mutant OR5A2 are still equally sensitive to these ligands. Finally, OR1N2 appears to be an additional receptor involved in the perception of the natural (E)-ambrettolide. This study for the first time links OR activation to sensory perception and genetic polymorphisms for this unique class of odorants.

Receptors underlying an odorant's valence across concentrations in Drosophila larvae.

Odorants interact with receptors expressed in specialized olfactory neurons, and neurons of the same class send their axons to distinct glomeruli in the brain. The stereotypic spatial glomerular activity map generates recognition and the behavioral response for the odorant. The valence of an odorant changes with concentration, typically becoming aversive at higher concentrations. Interestingly, in Drosophila larvae, the odorant (E)-2-hexenal is aversive at low concentrations and attractive at higher concentrations. We investigated the molecular and neural basis of this phenomenon, focusing on how activities of different olfactory neurons conveying opposing effects dictate behaviors. We identified the repellant neuron in the larvae as one expressing the olfactory receptor Or7a, whose activation alone at low concentrations of (E)-2-hexenal elicits an avoidance response in an Or7a-dependent manner. We demonstrate that avoidance can be overcome at higher concentrations by activation of additional neurons that are known to be attractive, most notably odorants that are known activators of Or42a and Or85c. These findings suggest that in the larval stage, the attraction-conveying neurons can overcome the aversion-conveying channels for (E)-2-hexenal.

Odor exposure during imprinting periods increases odorant-specific sensitivity and receptor gene expression in coho salmon (Oncorhynchus kisutch).

Pacific salmon are well known for their homing migrations; juvenile salmon learn odors associated with their natal streams prior to seaward migration, and then use these retained odor memories to guide them back from oceanic feeding grounds to their river of origin to spawn several years later. This memory formation, termed olfactory imprinting, involves (at least in part) sensitization of the peripheral olfactory epithelium to specific odorants. We hypothesized that this change in peripheral sensitivity is due to exposure-dependent increases in the expression of odorant receptor (OR) proteins that are activated by specific odorants experienced during imprinting. To test this hypothesis, we exposed juvenile coho salmon, Oncorhynchus kisutch, to the basic amino acid odorant l-arginine during the parr-smolt transformation (PST), when imprinting occurs, and assessed sensitivity of the olfactory epithelium to this and other odorants. We then identified the coho salmon ortholog of a basic amino acid odorant receptor (BAAR) and determined the mRNA expression levels of this receptor and other transcripts representing different classes of OR families. Exposure to l-arginine during the PST resulted in increased sensitivity to that odorant and a specific increase in BAAR mRNA expression in the olfactory epithelium relative to other ORs. These results suggest that specific increases in ORs activated during imprinting may be an important component of home stream memory formation and this phenomenon may ultimately be useful as a marker of successful imprinting to assess management strategies and hatchery practices that may influence straying in salmon.

Molecular basis of camphor repellency in Hyphantria cunea.

The plant-derived camphor has been used as a natural insect repellent against various insects for >500 years. However, the repellency mechanism behind camphor remains less understood. In this study, we aimed to identify the camphor receptor in Hyphantria cunea by deorphanizing 7 odorant receptors (ORs). The results showed that HcunOR46 is narrowly tuned to Camphor and is only conserved within the family Noctuidae. Further analysis through behavioral and electroantennograms (EAG) assays indicated that H. cunea adults are more sensitive to camphor than larvae, both behaviorally and electrophysiologically. This difference may be due to the lower expression of HcunOR46 at the larval stage. Additionally, a feeding assay indicated that camphor repellency could be related to camphor toxicity to larvae, with the lethal concentration 50 (LC50) value of 69.713 µg/µL. These results suggest that H. cunea may detect camphor through a distinct olfactory pathway from Culicinae mosquitos, providing a novel camphor-based pest management strategy for H. cunea.

The function of OforOrco in the allogrooming behavior of Odontotermes formosanus (Shiraki) induced by Serratia marcescens Bizio (SM1).

Termites are consistently confronted with a complex microbial environment. In addition to the role of their innate immune system in resisting pathogen infection, social immune behavior also plays a significant role in helping termites withstand the stress caused by pathogenic microorganisms. The allogrooming behavior among different individuals is commonly observed in termites, and it plays a crucial role in the social immune interaction network. In the case of Odontotermes formosanus (Shiraki), Orco is specifically involved in detecting pheromones and volatile chemicals released by termites to communicate with each other. Nonetheless, the function of Orco in the social immunity remains unreported in O. formosanus. Consequently, in this study, we recorded the allogrooming behavior of O. formosanus workers under SM1 stress. The results indicated a significant increase in allogrooming behavior due to SM1 infection. The allogrooming behavior of workers under SM1 stress was significantly increased after the addition of soldiers. Compared with pronotum group treated by SM1, SM1 treatment of workers' heads significantly reduced the allogrooming behavior among workers. In addition, we found that SM1 could greatly increase the expression of OforOrco. Furthermore, interfering with OforOrco could markedly reduce the allogrooming behavior among workers under SM1 stress, and increase the mortality of worker under SM1 stress. This study demonstrated the significant role of OforOrco in the social immunity of O. formosanus, which offers a theoretical foundation for the advancement of research on termite RNA biopesticides, and the integration of RNA interference (RNAi) with pathogens. This study is valuable for elucidating the social immune behavior and interaction network of termites.

Functional analysis of three odorant receptors in Plutella xylostella response to repellent activity of 2,3-dimethyl-6-(1-hydroxy)-pyrazine.

Plutella xylostella is an important pest showing resistance to various chemical pesticides, development of botanical pesticides is an effective strategy to resolve above problem and decrease utilization of chemical pesticides. Previous study showed that 2,3-dimethyl-6-(1-hydroxy)-pyrazine has significant repellent activity to P. xylostella adult which mainly effect to the olfactory system, however the molecular targets and mechanism are still unclear. Based on the RNA-Seq and RT-qPCR data, eight ORs (Odorant receptor) in P. xylostella were selected as candidate targets response to repellent activity of 2,3-dimethyl-6-(1-hydroxy)-pyrazine. Here, most of the ORs in P. xylostella were clustered into three branches, which showed similar functions such as recognition, feeding, and oviposition. PxylOR29, PxylOR31, and PxylOR46 were identified as the potential molecular targets based on the results of repellent activity and EAG response tests to the adults which have been injected with dsRNA, respectively. Additionally, the three ORs were higher expressed in antenna of P. xylostella, followed by those in the head segment. Furthermore, it was found that the bindings between these three ORs and 2,3-dimethyl-6-(1-hydroxy)-pyrazine mainly depend on the hydrophobic effect of active cavities, and the binding to PxylOR31 was more stabler and easier with an energy of -16.34 kcal/mol, together with the π-π T-shaped interaction at PHE195 site. These findings pave the way for the complete understanding of pyrazine repellent mechanisms.

Sex Differences in Antennal Transcriptome of Hyphantria cunea and Analysis of Odorant Receptor Expression Profiles.

Insects rely on olfaction for mating, finding oviposition sites, and locating hosts. Hyphantria cunea is a serious pest that severely damages forests. Differential expression analysis of olfactory-related genes between males and females is the basis for elucidating the functions of olfactory-related proteins in H. cunea. In this study, Illumina HiSeqTM 4000 high-throughput sequencing technology was used to perform transcriptome sequencing of the antennal tissues of adult male and female H. cunea. Functional annotation was conducted using the NR, Swiss-Prot, KOG, KEGG, and GO databases, and the results showed that the antennal transcriptome of adult H. cunea contained 50,158 unigenes. Differential expression analysis identified 3923 genes that were significantly differentially expressed between male and female antennae. A total of 221 olfactory-related genes were annotated, and 96 sex-biased genes were identified, including 13 odorant receptors (ORs), 48 odorant binding proteins (OBPs), 7 chemosensory proteins (CSPs), 10 ionotropic receptors (IRs), 10 sensory neuron membrane proteins (SNMPs), 2 gustatory receptors (GRs), and 6 odorant-degrading enzymes (ODEs), indicating that there were differences in olfaction between male and female H. cunea. Quantitative real-time PCR was used to verify the expression levels of 21 putative general odorant receptor genes in male and female antennae. HcunOR4 and HcunOR5 showed female-biased expression; HcunOR48, HcunOR49 and HcunOR50 showed male-biased expression. The results were consistent with the transcriptome differential analysis. The screening of male-biased odorant receptor genes might provide a theoretical basis for the functional characterization of odorant receptors for recognizing sex pheromones in H. cunea.

Odorant Receptors Expressing and Antennal Lobes Architecture Are Linked to Caste Dimorphism in Asian Honeybee, Apis cerana (Hymenoptera: Apidae).

Insects heavily rely on the olfactory system for food, mating, and predator evasion. However, the caste-related olfactory differences in Apis cerana, a eusocial insect, remain unclear. To explore the peripheral and primary center of the olfactory system link to the caste dimorphism in A. cerana, transcriptome and immunohistochemistry studies on the odorant receptors (ORs) and architecture of antennal lobes (ALs) were performed on different castes. Through transcriptomesis, we found more olfactory receptor genes in queens and workers than in drones, which were further validated by RT-qPCR, indicating caste dimorphism. Meanwhile, ALs structure, including volume, surface area, and the number of glomeruli, demonstrated a close association with caste dimorphism. Particularly, drones had more macroglomeruli possibly for pheromone recognition. Interestingly, we found that the number of ORs and glomeruli ratio was nearly 1:1. Also, the ORs expression distribution pattern was very similar to the distribution of glomeruli volume. Our results suggest the existence of concurrent plasticity in both the peripheral olfactory system and ALs among different castes of A. cerana, highlighting the role of the olfactory system in labor division in insects.

Antenna-Biased Odorant Receptor PstrOR17 Mediates Attraction of Phyllotreta striolata to (S)-Cis-Verbenol and (-)-Verbenone.

Phyllotreta striolata, the striped flea beetle, is one of the most destructive pests in Brassicaceae plants worldwide. Given the drawbacks associated with long-term use of chemical insecticides, green strategies based on chemical ecology are an effective alternative for beetle control. However, the lack of information on beetle ecology has hindered the development of effective biocontrol strategies. In this report, we identified two odorants, (S)-cis-verbenol and (-)-verbenone, which displayed significant attraction for P. striolata (p < 0.05), indicating their great potential for P. striolata management. Using the Drosophila "empty neuron" system, an antenna-biased odorant receptor, PstrOR17, was identified as responsible for the detection of (-)-verbenone and (S)-cis-verbenol. Furthermore, the interactions between PstrOR17 and (-)-verbenone or (S)-cis-verbenol were predicted via modeling and molecular docking. Finally, we used RNAi to confirm that PstrOR17 is essential for the detection of (-)-verbenone and (S)-cis-verbenol to elicit an attraction effect. Our results not only lay a foundation for the development of new and effective nonchemical insecticide strategies based on (S)-cis-verbenol and (-)-verbenone, but also provide new insight into the molecular basis of odorant recognition in P. striolata.

iBio-GATS-A Semi-Automated Workflow for Structural Modelling of Insect Odorant Receptors.

Insects utilize seven transmembrane (7TM) odorant receptor (iOR) proteins, with an inverted topology compared to G-protein coupled receptors (GPCRs), to detect chemical cues in the environment. For pest biocontrol, chemical attractants are used to trap insect pests. However, with the influx of invasive insect pests, novel odorants are urgently needed, specifically designed to match 3D iOR structures. Experimental structural determination of these membrane receptors remains challenging and only four experimental iOR structures from two evolutionarily distant organisms have been solved. Template-based modelling (TBM) is a complementary approach, to generate model structures, selecting templates based on sequence identity. As the iOR family is highly divergent, a different template selection approach than sequence identity is needed. Bio-GATS template selection for GPCRs, based on hydrophobicity correspondence, has been morphed into iBio-GATS, for template selection from available experimental iOR structures. This easy-to-use semi-automated workflow has been extended to generate high-quality models from any iOR sequence from the selected template, using Python and shell scripting. This workflow was successfully validated on Apocrypta bakeri Orco and Machilis hrabei OR5 structures. iBio-GATS models generated for the fruit fly iOR, OR59b and Orco, yielded functional ligand binding results concordant with experimental mutagenesis findings, compared to AlphaFold2 models.

Interactions among key residues regulate mammalian odorant receptor trafficking.

Odorant receptors (ORs) expressed in mammalian olfactory sensory neurons are essential for the sense of smell. However, structure-function studies of many ORs are hampered by unsuccessful heterologous expression. To understand and eventually overcome this bottleneck, we performed heterologous expression and functional assays of over 80 OR variants and chimeras. Combined with literature data and machine learning, we found that the transmembrane domain 4 (TM4) and its interactions with neighbor residues are important for OR functional expression. The data highlight critical roles of T4.62 therein. ORs that fail to reach the cell membrane can be rescued by modifications in TM4. Consequently, such modifications in MOR256-3 (Olfr124) also alter OR responses to odorants. T1614.62 P causes the retention of MOR256-3 in the endoplasmic reticulum (ER), while T1614.62 P/T1484.49 A reverses the retention and makes receptor trafficking to cell membrane. This study offers new clues toward wide-range functional studies of mammalian ORs.

The gut odorant receptor and taste receptor make sense of dietary components: A focus on gut hormone secretion.

Odorant receptors (ORs) and taste receptors (TRs) are expressed primarily in the nose and tongue in which they transduce electrical signals to the brain. Advances in deciphering the dietary component-sensing mechanisms in the nose and tongue prompted research on the role of gut chemosensory cells. Acting as the pivotal interface between the body and dietary cues, gut cells "smell" and "taste" dietary components and metabolites by taking advantage of chemoreceptors-ORs and TRs, to maintain physiological homeostasis. Here, we reviewed this novel field, highlighting the latest discoveries pertinent to gut ORs and TRs responding to dietary components, their impacts on gut hormone secretion, and the mechanisms involved. Recent studies indicate that gut cells sense dietary components including fatty acid, carbohydrate, and phytochemical by activating relevant ORs, thereby modulating GLP-1, PYY, CCK, and 5-HT secretion. Similarly, gut sweet, umami, and bitter receptors can regulate the gut hormone secretion and maintain homeostasis in response to dietary components. A deeper understanding of the favorable influence of dietary components on gut hormone secretion via gut ORs and TRs, coupled with the facts that gut hormones are involved in diverse physiological or pathophysiological phenomena, may ultimately lead to a promising treatment for various human diseases.

Ectopic odorant receptors responding to flavor compounds in skin health and disease: Current insights and future perspectives.

Skin, the largest organ of human body, acts as a barrier to protect body from the external environment and is exposed to a myriad of flavor compounds, especially food- and plant essential oil-derived odorant compounds. Skin cells are known to express various chemosensory receptors, such as transient potential receptors, adenosine triphosphate receptors, taste receptors, and odorant receptors (ORs). We aim to provide a review of this rapidly developing field and discuss latest discoveries related to the skin ORs activated by flavor compounds, their impacts on skin health and disease, odorant ligands interacting with ORs exerting specific biological effects, and the mechanisms involved. ORs are recently found to be expressed in skin tissue and cells, such as keratinocytes, melanocytes, and fibroblasts. To date, several ectopic skin ORs responding to flavor compounds, are involved in different skin biological processes, such as wound healing, hair growth, melanin regulation, pressure stress, skin barrier function, atopic dermatitis, and psoriasis. The recognition of physiological role of skin ORs, combined with the fact that ORs belong to a highly druggable protein family (G protein-coupled receptors), underscores the potential of skin ORs responding to flavor compounds as a novel regulating strategy for skin health and disease.