Olfactory Receptor Research Articles

Psychometric Functions for α-Ionone in Young Adults.

The mathematical relationship between the ability to detect an odorant and its concentration appears for some odorants to be non-monotonic, with reversals ("notches") in performance appearing at points along the psychometric function. Like visual adaptation curves that reflect the differential sensitivities of cones and rods, such reversals may provide information about underlying olfactory receptor processes. However, the presence of such reversals is rarely acknowledged, few participants and odorants have been tested, and methodological concerns abound. In this study, we examined in detail the psychometric function for the odorant α-ionone using a sizable number of young participants and 10 log-based concentrations of alpha-ionone presented in a random fashion. A trial consisted of the counterbalanced presentation of an odorless mineral oil and a concentration of α-ionone in rapid succession using Snap & Sniff® wands. The participants reported which of the two seemed stronger and indicated their confidence on a 9-point scale. In Study 1, 24 participants completed a single 30-minute test session of 60 trials. In Study 2, 600 trials were obtained from each of nine participants over the course of ten 30-minute sessions. In both studies, notches were consistently found in the psychometric function near the 10-5 and 10-3.5 vol/vol concentrations. Participants' trial-by-trial confidence judgments corresponded with their detection performance, but their self-rated sense of smell did not. This research definitively demonstrates the presence of reliable reversals in the human α-ionone psychometric function and begs the question as to whether such reversals reflect the recruitment of receptive elements with differing response profiles.

Olfactory coding in the mosquito antennal lobe: labeled lines or combinatorial code?

Odors serve as important cues for many behaviors in mosquitoes, including host-seeking, foraging, and oviposition. They are detected by olfactory receptor neurons present on the sensory organs, whose axons take this signal to the antennal lobe, the first olfactory processing center in the insect brain. We review the organization and the functioning of the antennal lobe in mosquitoes, focusing on two populations of interneurons present there: the local neurons (LNs) and the projection neurons (PNs). LNs enable information processing in the antennal lobe by providing lateral inhibition and excitation. PNs carry the processed output to downstream neurons in the lateral horn and the mushroom body. We compare the ideas of labeled lines and combinatorial codes, and argue that the PN population encodes odors combinatorially. Throughout this review, we discuss the observations from Aedes, Anopheles, and Culex mosquitoes in the context of previous findings from Drosophila and other insects.

Functional characterization of OR51B5 and OR1G1 in human lung epithelial cells as potential drug targets for non-type 2 lung diseases

Abstract Background Hypersensitivity to odorants like perfumes can induce or promote asthma with non-type 2 inflammation for which therapeutic options are limited. Cell death of primary bronchial epithelial cells (PBECs) and the release of the pro-inflammatory cytokines interleukin-6 (IL-6) and IL-8 are key in the pathogenesis. Extra-nasal olfactory receptors (ORs) can influence cellular processes involved in asthma. This study investigated the utility of ORs in epithelial cells as potential drug targets in this context. Methods We used the A549 cell line and primary bronchial epithelial cells using air–liquid interface culture system (ALI-PBECs). OR expression was investigated by RT-PCR, Western blot, and Immunofluorescence. Effects of OR activation by specific ligands on intracellular calcium concentration, cAMP, Phospholipase C (PLC), cell viability, and IL-6 and IL-8 secretion were analyzed by calcium imaging, enzyme immunoassays, Annexin V/ propidium iodide -based fluorescence-activated cell staining or by ELISA, respectively. Results By screening A549 cells, the OR51B5 agonists Farnesol and Isononyl Alcohol and the OR1G1 agonist Nonanal increased intracellular Ca2 + . OR51B5 and OR1G1 mRNAs and proteins were detected. Both receptors showed a preferential intracellular localization. OR51B5- but not OR1G1-induced Ca2 + dependent on both cAMP and PLC signaling. Farnesol, Isononyl Alcohol, and Nonanal, all reduced cell viability and induced IL-8 and IL-6 release. The data were verified in ALI-PBECs. Conclusion ORs in the lung epithelium might be involved in airway-sensitivity to odorants. Their antagonism could represent a promising strategy in treatment of odorant-induced asthma with non-type 2 inflammation. Graphical Abstract

Bifurcation Enhances Temporal Information Encoding in the Olfactory Periphery

Living systems continually respond to signals from the surrounding environment. Survival requires that their responses adapt quickly and robustly to the changes in the environment. One particularly challenging example is olfactory navigation in turbulent plumes, where animals experience highly intermittent odor signals while odor concentration varies over many length- and timescales. Here, we show theoretically that olfactory receptor neurons (ORNs) can exploit proximity to a bifurcation point of their firing dynamics to reliably extract information about the timing and intensity of fluctuations in the odor signal, which have been shown to be critical for odor-guided navigation. Close to the bifurcation, the system is intrinsically invariant to signal variance, and information about the timing, duration, and intensity of odor fluctuations is transferred efficiently. Importantly, we find that proximity to the bifurcation is maintained by mean adaptation alone and therefore does not require any additional feedback mechanism or fine-tuning. Using a biophysical model with calcium-based feedback, we demonstrate that this mechanism can explain the measured adaptation characteristics of ORNs. Published by the American Physical Society 2024

Combinatorial Pattern Response of Bioelectronic Nose for the Detection of Real Nerve Agents.

Nerve agents are toxic organophosphorus chemicals and acetylcholinesterase inhibitors that have been used in terrorist acts. Because they exhibit fatal toxic effects in small amounts, technology is required to detect and identify them early. Research for nerve agent detection using structural simulants of real agents may not function properly for real agents depending on the selectivity of the sensor. For practical sensor applications, experiments were conducted using two toxic nerve agents, sarin and VX, which are used in terrorism and attacks. Herein, human olfactory receptors (ORs) were used as sensing materials with high selectivity and sensitivity to target substances. Through molecular dynamic simulations, the interaction results between ORs and target materials were compared, and an OR combination that could distinguish structurally similar target materials was selected. Four types of OR were combined with a graphene/MoS2-based n-type field-effect transistor platform to create a bioelectronic nose that showed remarkable sensitivity and a stable basal current to convert the biological signals of the OR with target substances into electrical signals. This study developed a nerve agent detection technology using multiple OR sensing signals, advocating combinatorial pattern recognition, which is the core of the human olfactory mechanism. The bioelectronic nose effectively distinguishes structurally similar nerve agents using pattern signals.

Targeted deletion of olfactory receptors in D. melanogaster via CRISPR/Cas9-mediated LexA knock-in

The study of olfaction in Drosophila melanogaster has greatly benefited from genetic reagents such as olfactory receptor mutant lines and GAL4 reporter lines. The CRISPR/Cas9 gene-editing system has been increasingly used to create null receptor mutants or replace coding regions with GAL4 reporters. To further expand this toolkit for manipulating fly olfactory receptor neurons (ORNs), we generated null alleles for 11 different olfactory receptors by using CRISPR/Cas9 to knock in LexA drivers, including multiple lines for receptors which have thus far lacked knock-in mutants. The targeted neuronal types represent a broad range of antennal ORNs from all four morphological sensillum classes. Additionally, we confirmed their loss-of-function phenotypes, assessed receptor haploinsufficiency, and evaluated the specificity of the LexA knock-in drivers. These receptor mutant lines have been deposited at the Bloomington Drosophila Stock Center for use by the broader scientific community.

Conserved pattern-based classification of human odorant receptor multigene family

Conserved protein-coding sequences are critical for maintaining protein function across species. Odorant receptors (ORs), a large poorly understood multigene family responsible for odor detection, lack comprehensive classification methods that reflect their functional diversity. In this study, we propose a new approach called conserved motif-based classification (CMC) for classifying ORs based on amino acid sequence similarities within conserved motifs. Specifically, we focused on three well-conserved motifs: MAYDRYVAIC in TM3, KAFSTCASH in TM6, and PMLNPFIY in TM7. Using an unsupervised clustering technique, we classified human ORs (hORs) into two main clusters with six sub-clusters. CMC partly reflects previously identified subfamilies, revealing altered residue positions among the sub-clusters. These altered positions interacted with specific residues within or adjacent to the transmembrane domain, suggesting functional implications. Furthermore, we found that the CMC correlated with both ligand responses and ectopic expression patterns, highlighting its relevance to OR function. This conserved motif-based classification will help in understanding the functions and features that are not understood by classification based solely on entire amino acid sequence similarity.

Female contact sex pheromone recognition in the German cockroach (Blattella germanica) is mediated by two male antennae-enriched sensory neuron membrane proteins.

The German cockroach Blattella germanica is a notorious urban health pest that has developed resistance to multiple pesticides. Thus, novel non-lethal pest control agents are urgently needed. Olfaction interference via disruption of sex pheromone recognition-related genes offers a promising approach. The German cockroach has a unique courtship behavior in which female adults emit contact sex pheromones (CSPs) in response to antennal touching, which subsequently triggers distinctive male sex behavioral responses. Due to the limited volatility of CSPs, the molecular mechanisms underlying their recognition and the specific olfactory pathways activated remain poorly defined. Although the odorant receptor coreceptor (Orco) is critical for most insect olfaction, sensory neuron membrane proteins (SNMPs), in particular SNMP1, also play crucial roles in sex pheromone recognition in moths and flies. While multiple SNMP1 homologs have been identified in multiple insect species, they have yet to be fully functionally characterized in cockroaches. In this study, RNA-interference (RNAi)-mediated knockdown of BgerOrco reduced both the electrophysiology responses and courtship behaviors of males, indicating CSP perception proceeds via an olfaction pathway. Similar RNAi knockdown of BgerSNMP1e and BgerSNMP1d, which are predominantly expressed in male antennae, revealed critical roles in perceiving the major component of the Blattella germanica CSP blend. Unlike BgerSNMP1e, BgerSNMP1d was also found to function in the perception of the minor CSP component. Molecular docking analyses revealed no differences in the binding affinities of BgerSNMP1d for the major and minor CSP components, whereas the binding affinities of BgerSNMP1e displayed clear selectivity for the major component. Our results show that the olfactory pathway is critical for CSP recognition and that two male-enriched SNMP genes, BgerSNMP1e and BgerSNMP1d, are crucial factors mediating the male response to CSP stimulation in German cockroaches. This study lays a foundation for studying the mechanisms of CSP recognition and provides novel molecular targets with potential to be exploited as disruptors of courtship behavior. © 2024 Society of Chemical Industry.

The heterotetrameric structure of insect odorant receptor complexes resolved

The heterotetrameric structure of insect odorant receptor complexes resolved

Revealing the off-flavors in hydro-distilled essential oils of sweet orange (Citrus sinensis) by flavoromics strategy and computational simulation

Citrus essential oils (EOs) are renowned for their aroma, but thermal extraction methods can introduce undesirable cooking and pungent odors. The specific compounds responsible for these off-flavors and their perception mechanisms remain unclear. This study investigated the flavor differences between cold pressing (CP) and hydro-distilled (HD) extracted essential oils from sweet oranges (SEOs) using flavoromics strategy. The results indicated that increased levels of alcohol compounds, particularly terpinen-4-ol, β-citronellol, geraniol, trans-carveol, and α-terpineol, were primarily responsible for the off-flavors in HD-extracted SEOs. Furthermore, molecular docking and dynamics simulations revealed that off-flavor compounds bind to olfactory receptors through hydrogen bonding and hydrophobic interactions, inducing slight structural and conformational changes that facilitate odor recognition and activate downstream signaling events. This study offers crucial insights into the mechanisms underlying off-flavor development in citrus EOs, providing valuable knowledge for optimizing extraction methods, controlling SEOs quality, and advancing flavor science.

Gene expansion in the hawkmoth Manduca sexta drives evolution of food-associated odorant receptors

Gene expansion in the hawkmoth Manduca sexta drives evolution of food-associated odorant receptors

MOR23 deficiency exacerbates hepatic steatosis in mice.

Hepatic steatosis, a common liver disorder, can progress to severe conditions such as nonalcoholic steatohepatitis and cirrhosis. While olfactory receptors are primarily known for detecting odorants, emerging evidence suggests that they also influence liver lipid metabolism. This study generated a mouse model with a specific knockout of olfactory receptor 23 (MOR23) to investigate its role in hepatic steatosis. MOR23 knockout mice on a normal diet showed a slight increase in liver weight compared to wild-type (WT) mice. When fed a high-fat diet (HFD), these knockout mice exhibited accelerated hepatic steatosis, indicated by increased liver weight and hepatic triglyceride levels. Our findings suggest that the cyclic adenosine monophosphate/protein kinase A/AMP-activated protein kinase pathway is involved in the role of MOR23, leading to the upregulation of peroxisome proliferator-activated receptor α, peroxisome proliferator-activated receptor-γ coactivator 1-α, and their target β-oxidation genes in the liver. MOR23 also appeared to regulate lipogenesis and free fatty acid uptake in HFD-fed mice, potentially by influencing sterol regulatory element-binding protein 1 activity. Notably, administering a potential MOR23 ligand, cedrene, attenuated hepatic steatosis in WT mice, but these effects were largely nullified in MOR23 knockout mice. These findings provide valuable insights into the invivo role of MOR23 in hepatic steatosis development.

Engineered odorant receptors illuminate the basis of odour discrimination.

How the olfactory system detects and distinguishes odorants with diverse physicochemical properties and molecular configurations remains poorly understood. Vertebrate animals perceive odours through G protein-coupled odorant receptors (ORs)1. In humans, around 400 ORs enable the sense of smell. The OR family comprises two main classes: class I ORs are tuned to carboxylic acids whereas class II ORs, which represent most of the human repertoire, respond to a wide variety of odorants2. A fundamental challenge in understanding olfaction is the inability to visualize odorant binding to ORs. Here we uncover molecular properties of odorant-OR interactions by using engineered ORs crafted using a consensus protein design strategy3. Because such consensus ORs (consORs) are derived from the 17 major subfamilies of human ORs, they provide a template for modelling individual native ORs with high sequence and structural homology. The biochemical tractability of consORs enabled the determination of four cryogenic electron microscopy structures of distinct consORs with specific ligand recognition properties. The structure of a class I consOR, consOR51, showed high structural similarity to the native human receptor OR51E2 and generated a homology model of a related member of the human OR51 family with high predictive power. Structures of three class II consORs revealed distinct modes of odorant-binding and activation mechanisms between class I and class II ORs. Thus, the structures of consORs lay the groundwork for understanding molecular recognition of odorants by the OR superfamily.

Transcriptional regulation of olfactory receptor OR51B5 by the TBX6.

Olfactory receptors (ORs) are G protein-coupled receptors primarily expressed in olfactory tissue, facilitating the perception of odors. Interestingly, they have also been detected in non-olfactory tissues such as the skin, where they regulate processes like collagen synthesis. This study aimed to analyze the promoter of the OR family 51 subfamily B member 5 (OR51B5) and identify the transcription factors that bind to it to understand the potential regulatory mechanisms for OR51B5 expression. We examined the promoter region spanning 2,000 base pairs upstream of the transcription start site and conducted a deletion analysis, revealing that the core promoter encompasses the region from -153 to -111 base pairs. A luciferase assay using various candidate transcription factors showed that the overexpression or knockdown of T-Box Transcription Factor 6 (TBX6) significantly regulated OR51B5 promoter activity, while other candidate transcription factors had no significant effect. Additionally, we validated TBX6 binding to the OR51B5 promoter using site-directed mutation and electrophoretic mobility shift assays. This study is the first to uncover the role of TBX transcription factors in regulating OR gene expression in mammals, which may have implications for treating related disorders.

Genomes of Microtus rodents highlight the importance of olfactory and immune systems in their fast radiation.

The characterization of genes and biological functions underlying functional diversification and the formation of species is a major goal of evolutionary biology. In this study, we investigated the fast radiation of Microtus voles, one of the most speciose group of mammals, which shows strong genetic divergence despite few readily observable morphological differences. We produced an annotated reference genome for the common vole, Microtus arvalis, and resequenced the genomes of 10 different species and evolutionary lineages spanning the Microtus speciation continuum. Our full genome sequences illustrate the recent and fast diversification of this group, and we identified genes in highly divergent genomic windows that have likely particular roles in their radiation. We found three biological functions enriched for highly divergent genes in most Microtus species and lineages: olfaction, immunity and metabolism. In particular, olfaction-related genes (mostly olfactory receptors and vomeronasal receptors) are fast evolving in all Microtus species indicating the exceptional importance of the olfactory system in the evolution of these rodents. Of note is e.g. the shared signature among vole species on Olfr1019 which has been associated with fear responses against predator odours in rodents. Our analyses provide a genome-wide basis for the further characterization of the ecological factors and processes of natural and sexual selection that have contributed to the fast radiation of Microtus voles.

Genetic Polymorphisms Associated with Fetal Hemoglobin (HbF) Levels and F-Cell Numbers: A Systematic Review of Genome-Wide Association Studies.

Elevated fetal hemoglobin (HbF), which is partly controlled by genetic modifiers, ameliorates disease severity in β hemoglobinopathies. Understanding the genetic basis of this trait holds great promise for personalized therapeutic approaches. PubMed, MedRxiv, and the GWAS Catalog were searched up to May 2024 to identify eligible GWAS studies following PRISMA guidelines. Four independent reviewers screened, extracted, and synthesized data using narrative and descriptive methods. Study quality was assessed using a modified version of the Q-Genie tool. Pathway enrichment analysis was conducted on gene lists derived from the selected GWAS studies. Out of 113 initially screened studies, 62 underwent full-text review, and 16 met the inclusion criteria for quality assessment and data synthesis. A total of 939 significant SNP-trait associations (p-value < 1 × 10-5) were identified, mapping to 133 genes (23 with overlapping variant positions) and 103 intergenic sequences. Most SNP-trait associations converged around BCL11A (chr.2), HBS1L-MYB, (chr.6), olfactory receptor and beta globin (HBB) gene clusters (chr.11), with less frequent loci including FHIT (chr.3), ALDH8A1, BACH2, RPS6KA2, SGK1 (chr.6), JAZF1 (chr.7), MMP26 (chr.11), COCH (chr.14), ABCC1 (chr.16), CTC1, PFAS (chr.17), GCDH, KLF1, NFIX, and ZBTB7A (chr.19). Pathway analysis highlighted Gene Ontology (GO) terms and pathways related to olfaction, hemoglobin and haptoglobin binding, and oxygen carrier activity. This systematic review confirms established genetic modifiers of HbF level, while highlighting less frequently associated loci as promising areas for further research. Expanding research across ethnic populations is essential for advancing personalized therapies and enhancing outcomes for individuals with sickle cell disease or β-thalassemia.

Olfactory and gustatory chemical sensor systems in the African turquoise killifish: Insights from morphology.

Smell and taste are extensively studied in fish species as essential for finding food and selecting mates while avoiding toxic substances and predators. Depending on the evolutionary position and adaptation, a discrete variation in the morphology of these sense organs has been reported in numerous teleost species. Here, for the first time, we approach the phenotypic characterization of the olfactory epithelium and taste buds in the African turquoise killifish (Nothobranchius furzeri), a model organism known for its short lifespan and use in ageing research. Our observations indicate that the olfactory epithelium of N. furzeri is organized as a simple patch, lacking the complex folding into a rosette, with an average size of approximately 600µm in length, 300µm in width, and 70µm in thickness. Three main cytotypes, including olfactory receptor neurons (CalbindinD28K), supporting cells (β-tubulin IV), and basal cells (Ki67), were identified across the epithelium. Further, we determined the taste buds' distribution and quantification between anterior (skin, lips, oral cavity) and posterior (gills, pharynx, oesophagus) systems. We identified the key cytotypes by using immunohistochemical markers, i.e. CalbindinD28K, doublecortin, and neuropeptide Y (NPY) for gustatory receptor cells, glial fibrillary acidic protein (GFAP) for supporting cells, and Ki67, a marker of cellular proliferation for basal cells. Altogether, these results indicate that N. furzeri is a microsmatic species with unique taste and olfactory features and possesses a well-developed posterior taste system compared to the anterior. This study provides fundamental insights into the chemosensory biology of N. furzeri, facilitating future investigations into nutrient-sensing mechanisms and their roles in development, survival, and ageing.

A Short Glance at the Role of Olfactory Tubercle in Odour Processing

ABSTRACTThe mammalian olfactory system is one of the most precocious sensory systems during development and is innately endowed with versatile functions distinct from other sensory systems. Perception of time‐locked olfaction‐related stimuli quickly from the external environment and encoding them accurately via the olfactory system is paramount for the survival and reproduction in the animal kingdom. The olfactory system of mammals encompasses the main and accessory parts. As one key component of the ventral striatum, the olfactory tubercle (OT), is also an important as well as indispensable sub‐region of the main olfactory system and plays a crucial role in the central processing of odours. The OT also serves as a hub linking the olfactory system with the reward system in the brain. Although extensive research has underscored the involvement of the ventral striatum in the reward and punishment process as well as motivational behaviour, the encoding mechanism of neural circuits engaged in odour detection and recognition by the OT is still largely unknown. Herein, we make a brief overview of the olfactory system and underscore the crucial role of olfactory receptors in odour detection. We also emphasize the structural and functional characterisations of the OT and corresponding neural circuits involved in odour processing.

Network of artificial olfactory receptors for spatiotemporal monitoring of toxic gas.

Excessive human exposure to toxic gases can lead to chronic lung and cardiovascular diseases. Thus, precise in situ monitoring of toxic gases in the atmosphere is crucial. Here, we present an artificial olfactory system for spatiotemporal recognition of NO2 gas flow by integrating a network of chemical receptors with a near-sensor computing. The artificial olfactory receptor features nano-islands of metal-based catalysts that cover the graphene surface on the heterostructure of an AlGaN/GaN two-dimensional electron gas (2DEG) channel. Catalytically dissociated NO2 molecules bind to graphene, thereby modulating the conductivity of the 2DEG channel. For the energy/resource-efficient gas flow monitoring, trust-region Bayesian optimization algorithm allocates many sensors optimally in a complex space. Integrated artificial neural networks on a compact microprocessor with a network of sensors provide in situ gas flow predictions. This system enhances protective measures against toxic environments through spatiotemporal monitoring of toxic gases.

Comparative analysis of chromosome-level genomes provides insights into chromosomal evolution in Chiroptera.

Chiroptera (bats) presents a fascinating model due to its remarkable variation in chromosome numbers, which range from 14 to 62. This astonishing diversity makes bats an excellent subject for studying chromosome evolution. The black-bearded tomb bat (Taphozous melanopogon) occupies a pivotal phylogenetic position within Chiroptera, emphasizing its crucial role in the systematic examination of bat chromosome evolution. In this study, we present the first chromosome-level genome of T. melanopogon within the family Emballonuridae. Together with previously published genomes, we construct a strongly supported phylogenetic tree of bats, which supports that Emballonuridae forms a basal group within Yangochiroptera. Furthermore, we reconstruct ancestral karyotypes at key nodes along the bat phylogeny and conduct a synteny analysis among the genomes of 12 bat species. Our findings identified evolutionary breakpoint regions (EBRs) that are of particular interest. Notably, some bat genomes exhibit an enrichment of genes related to host defense against microbial pathogens within EBRs. Remarkably, one species possesses multiple copies of some β-defensin genes, while six other species have experienced the loss of some β-defensin genes due to EBRs. Furthermore, some olfactory receptor genes are located in EBRs of 12 species, 4 of which have a significant enrichment in sensory perception of smell. Together, our comparative genomic analysis underscores the potential link between chromosome rearrangements and the adaptation of bats to defend against microbial pathogens.