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Laurence J Zwiebel - One of the best experts on this subject based on the ideXlab platform.
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functional characterization of Odorant Receptors in the ponerine ant harpegnathos saltator
Proceedings of the National Academy of Sciences of the United States of America, 2017Co-Authors: Jesse Slone, Gregory M Pask, Jocelyn G Millar, Shelley L Berger, Danny Reinberg, Stephen T Ferguson, Juergen Liebig, Anandasankar Ray, Laurence J ZwiebelAbstract:Animals use a variety of sensory modalities-including visual, acoustic, and chemical-to sense their environment and interact with both conspecifics and other species. Such communication is especially critical in eusocial insects such as honey bees and ants, where cooperation is critical for survival and reproductive success. Various classes of chemoReceptors have been hypothesized to play essential roles in the origin and evolution of eusociality in ants, through their functional roles in pheromone detection that characterizes reproductive status and colony membership. To better understand the molecular mechanisms by which chemoReceptors regulate social behaviors, we investigated the roles of a critical class of chemoReceptors, the Odorant Receptors (ORs), from the ponerine ant Harpegnathos saltator in detecting cuticular hydrocarbon pheromones. In light of the massive OR expansion in ants (∼400 genes per species), a representative survey based on phylogenetic and transcriptomic criteria was carried out across discrete Odorant receptor subfamilies. Responses to several classes of semiochemicals are described, including cuticular hydrocarbons and mandibular gland components that act as H. saltator pheromones, and a range of more traditional general Odorants. When viewed through the prism of caste-specific OR enrichment and distinctive OR subfamily Odorant response profiles, our findings suggest that whereas individual HsOrs appear to be narrowly tuned, there is no apparent segregation of tuning responses within any discrete HsOr subfamily. Instead, the HsOR gene family as a whole responds to a broad array of compounds, including both cuticular hydrocarbons and general Odorants that are likely to mediate distinct behaviors.
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novel high throughput screens of anopheles gambiae Odorant Receptors reveal candidate behaviour modifying chemicals for mosquitoes
Physiological Entomology, 2012Co-Authors: David C Rinker, Patrick L Jones, Michael Rutzler, Jason R Pitts, Gray Camp, Lujuan Sun, Daniel C Dorset, David Weaver, Laurence J ZwiebelAbstract:Despite many decades of multilateral global efforts, a significant portion of the world population continues to be plagued with one or more mosquito-vectored diseases. These include malaria and filariasis as well as numerous arboviral-associated illnesses including Dengue and Yellow fevers. The dynamics of disease transmission by mosquitoes is complex, and involves both vector competence and vectorial capacity. One area of intensive effort is the study of chemosensory-driven behaviours in the malaria vector mosquito Anopheles gambiae Giles, the modulation of which are likely to provide opportunities for disease reduction. In this context recent studies have characterized a large divergent family of An. gambiae Odorant Receptors (AgORs) that play critical roles in olfactory signal transduction. This work has facilitated high-throughput, cell-based calcium mobilization screens of AgOR-expressing HEK cells that have identified a large number of conventional AgOR ligands, as well as the first non-conventional Orco (olfactory receptor co-receptor) family agonist. As such, ligand-mediated modulation serves as a proof-of-concept demonstration that AgORs represent viable targets for high-throughput screening and for the eventual development of behaviour-modifying olfactory compounds. Such attractants or repellents could foster malaria reduction programmes.
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heteromeric anopheline Odorant Receptors exhibit distinct channel properties
PLOS ONE, 2011Co-Authors: Gregory M Pask, Laurence J Zwiebel, Patrick L Jones, Michael Rutzler, David C RinkerAbstract:Background: Insect Odorant Receptors (ORs) function as Odorant-gated ion channels consisting of a conventional, Odorantbinding OR and the Orco coreceptor. While Orco can function as a homomeric ion channel, the role(s) of the conventional OR in heteromeric OR complexes has largely focused only on Odorant recognition. Results: To investigate other roles of Odorant-binding ORs, we have employed patch clamp electrophysiology to investigate the properties of the channel pore of several OR complexes formed by a range of different Odorant-specific Anopheles gambiae ORs (AgOrs) each paired with AgOrco. These studies reveal significant differences in cation permeability and ruthenium red susceptibility among different AgOr complexes. Conclusions: With observable differences in channel function, the data support a model in which the Odorant-binding OR also affects the channel pore. The variable effect contributed by the conventional OR on the conductive properties of Odorant-gated sensory channels adds additional complexity to insect olfactory signaling, with differences in odor coding beginning with ORs on the periphery of the olfactory system.
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conservation of indole responsive Odorant Receptors in mosquitoes reveals an ancient olfactory trait
Chemical Senses, 2011Co-Authors: Jonathan D. Bohbot, Guirong Wang, Gregory M Pask, Patrick L Jones, Jason R Pitts, Laurence J ZwiebelAbstract:Aedes aegypti and Anopheles gambiae are among the best-characterized mosquito species within the Culicinae and Anophelinae mosquito clades which diverged ∼150 million years ago. Despite this evolutionary distance, the olfactory systems of these mosquitoes exhibit similar morphological and physiological adaptations. Paradoxically, mosquito Odorant Receptors, which lie at the heart of chemosensory signal transduction pathways, belong to a large and highly divergent gene family. We have used 2 heterologous expression systems to investigate the functional characteristics of a highly conserved subset of Ors between Ae. aegypti and An. gambiae to investigate whether protein homology correlates with Odorant-induced activation. We find that these Receptors share similar Odorant response profiles and that indole, a common and ecologically relevant olfactory cue, elicits strong responses from these homologous Receptors. The identification of other highly conserved members of this Or clade from mosquito species of varying phylogenetic relatedness supports a model in which high sensitivity to indole represents an ancient ecological adaptation that has been preserved as a result of its life cycle importance. These results provide an understanding of how similarities and disparities among homologous OR proteins relate to olfactory function, which can lead to greater insights into the design of successful strategies for the control of mosquito-borne diseases.
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a cluster of candidate Odorant Receptors from the malaria vector mosquito anopheles gambiae
Chemical Senses, 2002Co-Authors: A N Fox, R J Pitts, Laurence J ZwiebelAbstract:Olfaction is critical to the host preference selection behavior of many disease-transmitting insects, including the mosquito Anopheles gambiae sensu stricto (hereafter A. gambiae), one of the major vectors for human malaria. In order to more fully understand the molecular biology of olfaction in this insect, we have previously identified several members member of a family of candidate Odorant receptor proteins from A. gambiae (AgORs). Here we report the cloning and characterization of an additional AgOR gene, denoted as AgOr5, which shows significant similarity to putative Odorant Receptors in A. gambiae and Drosophila melanogaster and which is selectively expressed in olfactory organs. AgOr5 is tightly clustered within the A. gambiae genome to two other highly homologous candidate Odorant Receptors, suggesting that these genes are derived from a common ancestor. Analysis of the developmental expression within members of this AgOR gene cluster reveals considerable variation between these AgORs as compared to candidate Odorant Receptors from D. melanogaster.
Hiroaki Matsunami - One of the best experts on this subject based on the ideXlab platform.
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mammalian class i Odorant Receptors exhibit a conserved vestibular binding pocket
Cellular and Molecular Life Sciences, 2019Co-Authors: Caroline Bushdid, Hiroaki Matsunami, Claire A De March, Jeremie Topin, Jerome GolebiowskiAbstract:Odorant Receptors represent the largest family of mammalian G protein-coupled Receptors. Phylogenetically, they are split into two classes (I and II). By analyzing the entire subclass I Odorant Receptors sequences, we identified two class I-specific and highly conserved motifs. These are predicted to face each other at the extra-cellular portion of the transmembrane domain, forming a vestibular site at the entrance to the orthosteric-binding cavity. Molecular dynamics simulation combined with site-directed mutagenesis and in vitro functional assays confirm the functional role of this vestibular site in ligand-driven activation. Mutations at this part of the receptor differentially affect the receptor response to four agonists. Since this vestibular site is involved in ligand recognition, it could serve ligand design that targets specifically this sub-genome of mammalian Odorant Receptors.
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agonists of g protein coupled Odorant Receptors are predicted from chemical features
Journal of Physical Chemistry Letters, 2018Co-Authors: Caroline Bushdid, Hiroaki Matsunami, Jerome Golebiowski, C A De March, Sebastien FiorucciAbstract:Predicting the activity of chemicals for a given Odorant receptor is a longstanding challenge. Here the activity of 258 chemicals on the human G-protein-coupled Odorant receptor (OR)51E1, also known as prostate-specific G-protein-coupled receptor 2 (PSGR2), was virtually screened by machine learning using 4884 chemical descriptors as input. A systematic control by functional in vitro assays revealed that a support vector machine algorithm accurately predicted the activity of a screened library. It allowed us to identify two novel agonists in vitro for OR51E1. The transferability of the protocol was assessed on OR1A1, OR2W1, and MOR256-3 Odorant Receptors, and, in each case, novel agonists were identified with a hit rate of 39–50%. We further show how ligands’ efficacy is encoded into residues within OR51E1 cavity using a molecular modeling protocol. Our approach allows widening the chemical spaces associated with Odorant Receptors. This machine-learning protocol based on chemical features thus represents ...
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numerical models and in vitro assays to study Odorant Receptors
Methods of Molecular Biology, 2018Co-Authors: Caroline Bushdid, Hiroaki Matsunami, Claire A De March, Jerome GolebiowskiAbstract:Unraveling the sense of smell relies on understanding how Odorant Receptors recognize Odorant molecules. Given the vastness of the Odorant chemical space and the complexity of the Odorant receptor space, computational methods are in line to propose rules connecting them. We hereby propose an in silico and an in vitro approach, which, when combined are extremely useful for assessing chemogenomic links. In this chapter we mostly focus on the mining of already existing data through machine learning methods. This approach allows establishing predictions that map the chemical space and the receptor space. Then, we describe the method for assessing the activation of Odorant Receptors and their mutants through luciferase reporter gene functional assays.
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responsiveness of g protein coupled Odorant Receptors is partially attributed to the activation mechanism
Proceedings of the National Academy of Sciences of the United States of America, 2015Co-Authors: Claire A De March, Kaylin A Adipietro, Jerome Golebiowski, Hiroaki MatsunamiAbstract:Mammals detect and discriminate numerous odors via a large family of G protein-coupled Odorant Receptors (ORs). However, little is known about the molecular and structural basis underlying OR response properties. Using site-directed mutagenesis and computational modeling, we studied ORs sharing high sequence homology but with different response properties. When tested in heterologous cells by diverse Odorants, MOR256-3 responded broadly to many Odorants, whereas MOR256-8 responded weakly to a few Odorants. Out of 36 mutant MOR256-3 ORs, the majority altered the responses to different Odorants in a similar manner and the overall response of an OR was positively correlated with its basal activity, an indication of ligand-independent receptor activation. Strikingly, a single mutation in MOR256-8 was sufficient to confer both high basal activity and broad responsiveness to this receptor. These results suggest that broad responsiveness of an OR is at least partially attributed to its activation likelihood.
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mammalian Odorant Receptors functional evolution and variation
Current Opinion in Neurobiology, 2015Co-Authors: Yue Jiang, Hiroaki MatsunamiAbstract:In mammals, the perception of smell starts with the activation of Odorant Receptors (ORs) by volatile molecules in the environment. The mammalian OR repertoire has been subject to rapid evolution, and is highly diverse within the human population. Recent advances in the functional expression and ligand identification of ORs allow for functional analysis of OR evolution, and reveal that changes in OR protein sequences translate into high degrees of functional variations. Moreover, in several cases the functional variation of a single OR affects the perception of its cognate odor ligand, providing clues as to how an odor is coded at the receptor level.
Walter S Leal - One of the best experts on this subject based on the ideXlab platform.
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Odorant Receptors from culex quinquefasciatus and aedes aegypti sensitive to floral compounds
Insect Biochemistry and Molecular Biology, 2019Co-Authors: Fangfang Zeng, Pingxi Xu, Walter S LealAbstract:Abstract Mosquitoes rely heavily on the olfactory system to find a host for a bloodmeal, plants for a source of energy and suitable sites for oviposition. Here, we examined a cluster of eight Odorant Receptors (ORs), which includes one OR, CquiOR1, previously identified to be sensitive to plant-derived compounds. We cloned 5 ORs from Culex quinquefasciatus and two ORs from Aedes aegypti, ie, CquiOR2, CquiOR4, CquiOR5, CquiOR84, CquiOR85, AaegOR14, and AaegOR15 and then deorphanized these Receptors using the Xenopus oocyte recording system and a large panel of Odorants. 2-Phenylethanol, phenethyl formate, and phenethyl propionate were the best ligands for CquiOR4 somewhat resembling the profile of AaegOR15, which gave the strongest responses to phenethyl propionate, phenethyl formate, and acetophenone. In contrast, the best ligands for CquiOR5 were linalool, PMD, and linalool oxide. CquiOR4 was predominantly expressed in antennae of nonblood fed female mosquitoes, with transcript levels significantly reduced after a blood meal. 2-Phenylethanol showed repellency activity comparable to that of DEET at 1%. RNAi experiments suggest that at least in part 2-phenylethanol-elicited repellency is mediated by CquiOR4 activation.
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deet and other repellents are inhibitors of mosquito Odorant Receptors for oviposition attractants
Insect Biochemistry and Molecular Biology, 2019Co-Authors: Pingxi Xu, Fangfang Zeng, Robert H Bedoukian, Walter S LealAbstract:Abstract In addition to its primary function as an insect repellent, DEET has many “off-label” properties, including a deterrent effect on the attraction of gravid female mosquitoes. DEET negatively affects oviposition sites. While deorphanizing Odorant Receptors (ORs) using the Xenopus oocyte recording system, we have previously observed that DEET generated outward (inhibitory) currents on ORs sensitive to oviposition attractants. Here, we systematically investigated these inhibitory currents. We recorded dose-dependent outward currents elicited by DEET and other repellents on ORs from Culex quinquefasciatus, Aedes aegypti, and Anopheles gambiae. Similar responses were observed with other plant-derived and plant-inspired compounds, including methyl jasmonate and methyl dihydrojasmolate. Inward (regular) currents elicited by skatole upon activation of CquiOR21 were modulated when this oviposition attractant was coapplied with a repellent. Compounds that generate outward currents in ORs sensitive to oviposition attractants elicited inward currents in a DEET-sensitive receptor, CquiOR136. The best ligand for this receptor, methyl dihydrojasmolate, showed repellency activity but was not as strong as DEET in our test protocol.
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Odorant Receptors from culex quinquefasciatus and aedes aegypti sensitive to floral compounds
bioRxiv, 2019Co-Authors: Fangfang Zeng, Pingxi Xu, Walter S LealAbstract:Mosquitoes rely heavily on the olfactory system to find a host for a bloodmeal, plants for a source of energy and suitable sites for oviposition. Here, we examined a cluster of 8 Odorant Receptors (ORs), which includes one OR, CquiOR1, previously identified to be sensitive to plant-derived compounds. We cloned 5 ORs from Culex quinquefasciatus and 2 ORs from Aedes aegypti, ie, CquiOR2, CquiOR4, CquiOR5, CquiOR84, CquiOR85, AaegOR14, and AaegOR15 and then deorphanized these Receptors using the Xenopus oocyte recording system and a large panel of Odorants. 2-Phenylethanol, phenethyl formate, and phenethyl propionate were the best ligands for CquiOR4 somewhat resembling the profile of AaegOR15, which gave the strongest responses to phenethyl propionate, phenethyl formate, and acetophenone. In contrast, the best ligands for CquiOR5 were linalool, PMD, and linalool oxide. CquiOR4 was predominantly expressed in antennae of nonblood fed female mosquitoes, with transcript levels significantly reduced after a blood meal. 2-Phenylethanol showed repellency activity comparable to that of DEET at 1%. RNAi experiments suggest that at least in part 2-phenylethanol-elicited repellency is mediated by CquiOR4 activation.
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deet and other repellents are inhibitors of mosquito Odorant Receptors for oviposition attractants
bioRxiv, 2019Co-Authors: Pingxi Xu, Fangfang Zeng, Robert H Bedoukian, Walter S LealAbstract:Abstract In addition to its primary function as an insect repellent, DEET has many “off-label” properties, including a deterrent effect on attraction of gravid female mosquitoes. DEET negatively affects oviposition sites. While deorphanizing Odorant Receptors (ORs) using the Xenopus oocyte recording system, we have previously observed that DEET generated outward (inhibitory) currents on ORs sensitive to oviposition attractants. Here, we systematically investigated these inhibitory currents. We recorded dose-dependent outward currents elicited by DEET and other repellents on ORs from Culex quinquefasciatus, Aedes aegypti, and Anopheles gambiae. Similar responses were observed with other plant-derived and plant-inspired compounds, including methyl jasmonate and methyl dihydrojasmolate. Inward (regular) currents elicited by skatole upon activation of CquiOR21 were modulated when this oviposition attractant was coapplied with a repellent. Compounds that generate outward currents in ORs sensitive to oviposition attractants elicited inward currents in a DEET-sensitive receptor, CquiOR136. The best ligand for this receptor, methyl dihydrojasmolate, showed repellency activity, but was not as strong as DEET in our test protocol.
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silent generic and plant kairomone sensitive Odorant Receptors from the southern house mosquito
Journal of Insect Physiology, 2013Co-Authors: Young Moo Choo, David Hughes, Charles W Luetje, Julien Pelletier, Fernando R Sujimoto, Fen Zhu, Elizabeth Atungulu, Anthony J Cornel, Walter S LealAbstract:The Southern house mosquito Culex quinquefasciatus has the largest repertoire of Odorant Receptors (ORs) of all mosquitoes and dipteran species whose genomes have been sequenced to date. Previously, we have identified and de-orphanized two ORs expressed in female antennae, CquiOR2 and CquiOR10, which are sensitive to oviposition attractants. In view of a new nomenclature for the Culex genome (VectorBase) we renamed these ORs as CquiOR21 (formerly CquiOR10) and CquiOR121 (CquiOR2). In addition, we selected ORs from six different phylogenetic groups for deorphanization. We cloned four of them by using cDNA from female antennae as a template. Attempts to clone CquiOR87 and CquiOR110 were unsuccessful either because they are pseudogenes or are not expressed in adult female antennae, the main olfactory tissue. By contrast, CquiOR1, CquiOR44, CquiOR73, and CquiOR161 were highly expressed in female antennae. To de-orphanize these ORs, we employed the Xenopus oocyte recording system. CquiORx-CquiOrco-expressed oocytes were challenged with a panel of 90 compounds, including known oviposition attractants, human and vertebrate host Odorants, plant kairomones, and naturally occurring repellents. While CquiOR161 did not respond to any test compound in two different laboratories, CquiOR1 showed the features of a generic OR, with strong responses to 1-octen-3-ol and other ligands. CquiOR44 and CquiOR73 showed preference to plant-derived terpenoids and phenolic compounds, respectively. While fenchone was the best ligand for the former, 3,5-dimethylphenol elicited the strongest responses in the latter. The newly de-orphanized ORs may be involved in reception of plant kairomones and/or natural repellents.
Bill S Hansson - One of the best experts on this subject based on the ideXlab platform.
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putative ligand binding sites of two functionally characterized bark beetle Odorant Receptors
BMC Biology, 2021Co-Authors: Jothi Kumar Yuvaraj, Rebecca Roberts, Yonathan Sonntag, Xiaoqing Hou, Ewald Grossewilde, Ales Machara, Bill S Hansson, Urban Johanson, Dandan Zhang, Christer LofstedtAbstract:Bark beetles are major pests of conifer forests, and their behavior is primarily mediated via olfaction. Targeting the Odorant Receptors (ORs) may thus provide avenues towards improved pest control. Such an approach requires information on the function of ORs and their interactions with ligands, which is also essential for understanding the functional evolution of these Receptors. Hence, we aimed to identify a high-quality complement of ORs from the destructive spruce bark beetle Ips typographus (Coleoptera, Curculionidae, Scolytinae) and analyze their antennal expression and phylogenetic relationships with ORs from other beetles. Using 68 biologically relevant test compounds, we next aimed to functionally characterize ecologically important ORs, using two systems for heterologous expression. Our final aim was to gain insight into the ligand-OR interaction of the functionally characterized ORs, using a combination of computational and experimental methods. We annotated 73 ORs from an antennal transcriptome of I. typographus and report the functional characterization of two ORs (ItypOR46 and ItypOR49), which are responsive to single enantiomers of the common bark beetle pheromone compounds ipsenol and ipsdienol, respectively. Their responses and antennal expression correlate with the specificities, localizations, and/or abundances of olfactory sensory neurons detecting these enantiomers. We use homology modeling and molecular docking to predict their binding sites. Our models reveal a likely binding cleft lined with residues that previously have been shown to affect the responses of insect ORs. Within this cleft, the active ligands are predicted to specifically interact with residues Tyr84 and Thr205 in ItypOR46. The suggested importance of these residues in the activation by ipsenol is experimentally supported through site-directed mutagenesis and functional testing, and hydrogen bonding appears key in pheromone binding. The emerging insight into ligand binding in the two characterized ItypORs has a general importance for our understanding of the molecular and functional evolution of the insect OR gene family. Due to the ecological importance of the characterized Receptors and widespread use of ipsenol and ipsdienol in bark beetle chemical communication, these ORs should be evaluated for their potential use in pest control and biosensors to detect bark beetle infestations.
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putative ligand binding sites of two functionally characterized bark beetle Odorant Receptors
bioRxiv, 2020Co-Authors: Jothi Kumar Yuvaraj, Rebecca Roberts, Yonathan Sonntag, Xiaoqing Hou, Ewald Grossewilde, Ales Machara, Bill S Hansson, Urban Johanson, Christer Lofstedt, Martin AnderssonAbstract:Bark beetle behavior is to a large extent mediated via olfaction. Targeting the Odorant Receptors (ORs) may thus provide avenues towards improved pest control during outbreaks. Such an approach requires information on the function of Receptors and their interactions with ligands. Hence, we annotated 73 ORs from an antennal transcriptome of the spruce bark beetle Ips typographus and report the functional characterization of two ORs (ItypOR46 and ItypOR49), which are selective for single enantiomers of the common bark beetle pheromone compounds ipsenol and ipsdienol, respectively. We use homology modeling and molecular docking to predict their binding sites. The importance of residues Tyr84 and Thr205 in ItypOR46 in the activation by ipsenol is experimentally supported, and hydrogen bonding appears key in pheromone binding. The biological significance of the characterized ORs positions them as prime targets for pest control and use in biosensors to detect bark beetle infestations.
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Calmodulin affects sensitization of Drosophila melanogaster Odorant Receptors
Frontiers Media S.A., 2016Co-Authors: Latha Emukunda, Bill S Hansson, Fabio Emiazzi, Vardanush Esargsyan, Dieter EwicherAbstract:Flying insects have developed a remarkably sensitive olfactory system to detect faint and turbulent odor traces. This ability is linked to the olfactory Receptors class of Odorant Receptors (ORs), occurring exclusively in winged insects. ORs form heteromeric complexes of an Odorant specific receptor protein (OrX) and a highly conserved co-receptor protein (Orco). The ORs form ligand gated ion channels that are tuned by intracellular signaling systems. Repetitive subthreshold odor stimulation of olfactory sensory neurons sensitizes insect ORs. This OR sensitization process requires Orco activity. In the present study we first asked whether OR sensitization can be monitored with heterologously expressed OR proteins. Using electrophysiological and calcium imaging methods we demonstrate that D. melanogaster OR proteins expressed in CHO cells show sensitization upon repeated weak stimulation. This was found for OR channels formed by Orco as well as by Or22a or Or56a and Orco. Moreover, we show that inhibition of calmodulin (CaM) action on OR proteins, expressed in CHO cells, abolishes any sensitization. Finally, we investigated the sensitization phenomenon using an ex vivo preparation of olfactory sensory neurons (OSNs) expressing Or22a inside the fly’s antenna. Using calcium imaging, we observed sensitization in the dendrites as well as in the soma. Inhibition of calmodulin with W7 disrupted the sensitization within the outer dendritic shaft, whereas the sensitization remained in the other OSN compartments. Taken together, our results suggest that CaM action is involved in sensitizing the OR complex and that this mechanisms accounts for the sensitization in the outer dendrites, whereas further mechanisms contribute to the sensitization observed in the other OSN compartments. The use of heterologously expressed OR proteins appears to be suitable for further investigations on the mechanistic basis of OR sensitization, while investigations on native neurons are required to study the presently unknown additional mechanisms involved in OSN sensitization
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drosophila Odorant Receptors are both ligand gated and cyclic nucleotide activated cation channels
Nature, 2008Co-Authors: Dieter Wicher, Ronny Schafer, Rene Bauernfeind, Marcus C Stensmyr, Regine Heller, Stefan H Heinemann, Bill S HanssonAbstract:In many organisms, from worms to humans, olfactory cues are detected by large families of seven transmembrane-spanning Receptors, which have until now been classified as G protein-coupled Receptors. Insects, however, have evolved a surprisingly simple and efficient sense of smell in which the Odorant Receptors require a second component — the ion-channel-forming chaperone protein Or83b — for correct function. In the first of two related papers, Sato et al. show that these heteromeric Receptors form ligand-gated cation channels that are not dependent on G protein-coupled second messengers, and speculate that other seven transmembrane-spanning proteins may show similar ion channel activity. Wicher et al. show that, in addition to direct channel activation, ligand binding to Odorant Receptors causes G protein-coupled channel activation. This work has implications for the search for insect Odorant receptor inhibitors for possible use in controlling host seeking behaviour of disease carrying insects such as the mosquito. Olfactory cues are detected by large families of seven transmembrane-spanning Receptors, which have until now been classified as G-protein-coupled Receptors. In insects, these Odorant Receptors require a second protein (Or83b) for correct function. The second of two related papers shows that, in addition to direct channel activation, ligand binding to Odorant Receptors causes G-protein-coupled channel activation. From worm to man, many Odorant signals are perceived by the binding of volatile ligands to Odorant Receptors1 that belong to the G-protein-coupled receptor (GPCR) family2. They couple to heterotrimeric G-proteins, most of which induce cAMP production3. This second messenger then activates cyclic-nucleotide-gated ion channels to depolarize the olfactory receptor neuron, thus providing a signal for further neuronal processing. Recent findings, however, have challenged this concept of Odorant signal transduction in insects, because their Odorant Receptors, which lack any sequence similarity to other GPCRs4, are composed of conventional Odorant Receptors (for example, Or22a), dimerized with a ubiquitously expressed chaperone protein5, such as Or83b in Drosophila6. Or83b has a structure akin to GPCRs, but has an inverted orientation in the plasma membrane4,7. However, G proteins are expressed in insect olfactory receptor neurons8, and olfactory perception is modified by mutations affecting the cAMP transduction pathway9. Here we show that application of Odorants to mammalian cells co-expressing Or22a and Or83b results in non-selective cation currents activated by means of an ionotropic and a metabotropic pathway, and a subsequent increase in the intracellular Ca2+ concentration. Expression of Or83b alone leads to functional ion channels not directly responding to Odorants, but being directly activated by intracellular cAMP or cGMP. Insect Odorant Receptors thus form ligand-gated channels as well as complexes of Odorant-sensing units and cyclic-nucleotide-activated non-selective cation channels. Thereby, they provide rapid and transient as well as sensitive and prolonged Odorant signalling.
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drosophila Odorant Receptors are both ligand gated and cyclic nucleotide activated cation channels
Nature, 2008Co-Authors: Dieter Wicher, Ronny Schafer, Rene Bauernfeind, Marcus C Stensmyr, Regine Heller, Stefan H Heinemann, Bill S HanssonAbstract:From worm to man, many Odorant signals are perceived by the binding of volatile ligands to Odorant Receptors that belong to the G-protein-coupled receptor (GPCR) family. They couple to heterotrimeric G-proteins, most of which induce cAMP production. This second messenger then activates cyclic-nucleotide-gated ion channels to depolarize the olfactory receptor neuron, thus providing a signal for further neuronal processing. Recent findings, however, have challenged this concept of Odorant signal transduction in insects, because their Odorant Receptors, which lack any sequence similarity to other GPCRs, are composed of conventional Odorant Receptors (for example, Or22a), dimerized with a ubiquitously expressed chaperone protein, such as Or83b in Drosophila. Or83b has a structure akin to GPCRs, but has an inverted orientation in the plasma membrane. However, G proteins are expressed in insect olfactory receptor neurons, and olfactory perception is modified by mutations affecting the cAMP transduction pathway. Here we show that application of Odorants to mammalian cells co-expressing Or22a and Or83b results in non-selective cation currents activated by means of an ionotropic and a metabotropic pathway, and a subsequent increase in the intracellular Ca(2+) concentration. Expression of Or83b alone leads to functional ion channels not directly responding to Odorants, but being directly activated by intracellular cAMP or cGMP. Insect Odorant Receptors thus form ligand-gated channels as well as complexes of Odorant-sensing units and cyclic-nucleotide-activated non-selective cation channels. Thereby, they provide rapid and transient as well as sensitive and prolonged Odorant signalling.
Dieter Wicher - One of the best experts on this subject based on the ideXlab platform.
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Functional properties of insect olfactory Receptors: ionotropic Receptors and Odorant Receptors
Cell and Tissue Research, 2021Co-Authors: Dieter Wicher, Fabio MiazziAbstract:The majority of insect olfactory Receptors belong to two distinct protein families, the ionotropic Receptors (IRs), which are related to the ionotropic glutamate receptor family, and the Odorant Receptors (ORs), which evolved from the gustatory receptor family. Both receptor types assemble to heteromeric ligand-gated cation channels composed of odor-specific receptor proteins and co-receptor proteins. We here present in short the current view on evolution, function, and regulation of IRs and ORs. Special attention is given on how their functional properties can meet the environmental and ecological challenges an insect has to face.
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insect Odorant Receptors function and regulation
2021Co-Authors: Dieter Wicher, Fabio MiazziAbstract:Abstract Insect Odorant Receptors (ORs) are related to the gustatory receptor family and have probably evolved with the terrestrialization of insects. They form heteromeric ligand-gated cation channels composed of odor-specific OR proteins and a co-receptor protein (Orco). This chapter describes what is currently known about the functional properties of ORs, and how their performance can adapt to meet the environmental and ecological challenges that insects face while exploring their odor worlds.
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tuning insect Odorant Receptors
Frontiers in Cellular Neuroscience, 2018Co-Authors: Dieter WicherAbstract:Among the insect olfactory Receptors the Odorant Receptors (ORs) evolved in parallel to the onset of insect flight. A special property of this receptor type is the capability to adjust sensitivity of odor detection according to previous odor contacts. This article presents a current view on regulatory processes affecting the performance of ORs and proposes a model of mechanisms contributing to OR sensitization.
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drosophila Odorant Receptors are both ligand gated and cyclic nucleotide activated cation channels
Nature, 2008Co-Authors: Dieter Wicher, Ronny Schafer, Rene Bauernfeind, Marcus C Stensmyr, Regine Heller, Stefan H Heinemann, Bill S HanssonAbstract:In many organisms, from worms to humans, olfactory cues are detected by large families of seven transmembrane-spanning Receptors, which have until now been classified as G protein-coupled Receptors. Insects, however, have evolved a surprisingly simple and efficient sense of smell in which the Odorant Receptors require a second component — the ion-channel-forming chaperone protein Or83b — for correct function. In the first of two related papers, Sato et al. show that these heteromeric Receptors form ligand-gated cation channels that are not dependent on G protein-coupled second messengers, and speculate that other seven transmembrane-spanning proteins may show similar ion channel activity. Wicher et al. show that, in addition to direct channel activation, ligand binding to Odorant Receptors causes G protein-coupled channel activation. This work has implications for the search for insect Odorant receptor inhibitors for possible use in controlling host seeking behaviour of disease carrying insects such as the mosquito. Olfactory cues are detected by large families of seven transmembrane-spanning Receptors, which have until now been classified as G-protein-coupled Receptors. In insects, these Odorant Receptors require a second protein (Or83b) for correct function. The second of two related papers shows that, in addition to direct channel activation, ligand binding to Odorant Receptors causes G-protein-coupled channel activation. From worm to man, many Odorant signals are perceived by the binding of volatile ligands to Odorant Receptors1 that belong to the G-protein-coupled receptor (GPCR) family2. They couple to heterotrimeric G-proteins, most of which induce cAMP production3. This second messenger then activates cyclic-nucleotide-gated ion channels to depolarize the olfactory receptor neuron, thus providing a signal for further neuronal processing. Recent findings, however, have challenged this concept of Odorant signal transduction in insects, because their Odorant Receptors, which lack any sequence similarity to other GPCRs4, are composed of conventional Odorant Receptors (for example, Or22a), dimerized with a ubiquitously expressed chaperone protein5, such as Or83b in Drosophila6. Or83b has a structure akin to GPCRs, but has an inverted orientation in the plasma membrane4,7. However, G proteins are expressed in insect olfactory receptor neurons8, and olfactory perception is modified by mutations affecting the cAMP transduction pathway9. Here we show that application of Odorants to mammalian cells co-expressing Or22a and Or83b results in non-selective cation currents activated by means of an ionotropic and a metabotropic pathway, and a subsequent increase in the intracellular Ca2+ concentration. Expression of Or83b alone leads to functional ion channels not directly responding to Odorants, but being directly activated by intracellular cAMP or cGMP. Insect Odorant Receptors thus form ligand-gated channels as well as complexes of Odorant-sensing units and cyclic-nucleotide-activated non-selective cation channels. Thereby, they provide rapid and transient as well as sensitive and prolonged Odorant signalling.
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drosophila Odorant Receptors are both ligand gated and cyclic nucleotide activated cation channels
Nature, 2008Co-Authors: Dieter Wicher, Ronny Schafer, Rene Bauernfeind, Marcus C Stensmyr, Regine Heller, Stefan H Heinemann, Bill S HanssonAbstract:From worm to man, many Odorant signals are perceived by the binding of volatile ligands to Odorant Receptors that belong to the G-protein-coupled receptor (GPCR) family. They couple to heterotrimeric G-proteins, most of which induce cAMP production. This second messenger then activates cyclic-nucleotide-gated ion channels to depolarize the olfactory receptor neuron, thus providing a signal for further neuronal processing. Recent findings, however, have challenged this concept of Odorant signal transduction in insects, because their Odorant Receptors, which lack any sequence similarity to other GPCRs, are composed of conventional Odorant Receptors (for example, Or22a), dimerized with a ubiquitously expressed chaperone protein, such as Or83b in Drosophila. Or83b has a structure akin to GPCRs, but has an inverted orientation in the plasma membrane. However, G proteins are expressed in insect olfactory receptor neurons, and olfactory perception is modified by mutations affecting the cAMP transduction pathway. Here we show that application of Odorants to mammalian cells co-expressing Or22a and Or83b results in non-selective cation currents activated by means of an ionotropic and a metabotropic pathway, and a subsequent increase in the intracellular Ca(2+) concentration. Expression of Or83b alone leads to functional ion channels not directly responding to Odorants, but being directly activated by intracellular cAMP or cGMP. Insect Odorant Receptors thus form ligand-gated channels as well as complexes of Odorant-sensing units and cyclic-nucleotide-activated non-selective cation channels. Thereby, they provide rapid and transient as well as sensitive and prolonged Odorant signalling.
