Tyramine Receptor Research Articles

Gut microbiota metabolite tyramine ameliorates high-fat diet-induced insulin resistance via increased Ca2+ signaling

The gut microbiota and their metabolites are closely linked to obesity-related diseases, such as type 2 diabetes, but their causal relationship and underlying mechanisms remain largely elusive. Here, we found that dysbiosis-induced tyramine (TA) suppresses high-fat diet (HFD)-mediated insulin resistance in both Drosophila and mice. In Drosophila, HFD increases cytosolic Ca2+ signaling in enterocytes, which, in turn, suppresses intestinal lipid levels. 16 S rRNA sequencing and metabolomics revealed that HFD leads to increased prevalence of tyrosine decarboxylase (Tdc)-expressing bacteria and resulting tyramine production. Tyramine acts on the tyramine receptor, TyrR1, to promote cytosolic Ca2+ signaling and activation of the CRTC-CREB complex to transcriptionally suppress dietary lipid digestion and lipogenesis in enterocytes, while promoting mitochondrial biogenesis. Furthermore, the tyramine-induced cytosolic Ca2+ signaling is sufficient to suppress HFD-induced obesity and insulin resistance in Drosophila. In mice, tyramine intake also improves glucose tolerance and insulin sensitivity under HFD. These results indicate that dysbiosis-induced tyramine suppresses insulin resistance in both flies and mice under HFD, suggesting a potential therapeutic strategy for related metabolic disorders, such as diabetes.

Tyramine and its Amtyr1 receptor modulate attention in honey bees (Apis mellifera).

Animals must learn to ignore stimuli that are irrelevant to survival and attend to ones that enhance survival. When a stimulus regularly fails to be associated with an important consequence, subsequent excitatory learning about that stimulus can be delayed, which is a form of nonassociative conditioning called 'latent inhibition'. Honey bees show latent inhibition toward an odor they have experienced without association with food reinforcement. Moreover, individual honey bees from the same colony differ in the degree to which they show latent inhibition, and these individual differences have a genetic basis. To investigate the mechanisms that underly individual differences in latent inhibition, we selected two honey bee lines for high and low latent inhibition, respectively. We crossed those lines and mapped a Quantitative Trait Locus for latent inhibition to a region of the genome that contains the tyramine receptor gene Amtyr1 [We use Amtyr1 to denote the gene and AmTYR1 the receptor throughout the text.]. We then show that disruption of Amtyr1 signaling either pharmacologically or through RNAi qualitatively changes the expression of latent inhibition but has little or slight effects on appetitive conditioning, and these results suggest that AmTYR1 modulates inhibitory processing in the CNS. Electrophysiological recordings from the brain during pharmacological blockade are consistent with a model that AmTYR1 indirectly regulates at inhibitory synapses in the CNS. Our results therefore identify a distinct Amtyr1-based modulatory pathway for this type of nonassociative learning, and we propose a model for how Amtyr1 acts as a gain control to modulate hebbian plasticity at defined synapses in the CNS. We have shown elsewhere how this modulation also underlies potentially adaptive intracolonial learning differences among individuals that benefit colony survival. Finally, our neural model suggests a mechanism for the broad pleiotropy this gene has on several different behaviors.

Adenylosuccinate lyase deficiency affects neurobehavior via perturbations to tyramine signaling in Caenorhabditis elegans.

Adenylosuccinate lyase deficiency is an ultrarare congenital metabolic disorder associated with muscle weakness and neurobehavioral dysfunction. Adenylosuccinate lyase is required for de novo purine biosynthesis, acting twice in the pathway at non-sequential steps. Genetic models can contribute to our understanding of the etiology of disease phenotypes and pave the way for development of therapeutic treatments. Here, we establish the first model to specifically study neurobehavioral aspects of adenylosuccinate lyase deficiency. We show that reduction of adsl-1 function in C. elegans is associated with a novel learning phenotype in a gustatory plasticity assay. The animals maintain capacity for gustatory plasticity, evidenced by a change in their behavior in response to cue pairing. However, their behavioral output is distinct from that of control animals. We link substrate accumulation that occurs upon adsl-1 deficiency to an unexpected perturbation in tyrosine metabolism and show that a lack of tyramine mediates the behavioral changes through action on the metabotropic TYRA-2 tyramine receptor. Our studies reveal a potential for wider metabolic perturbations, beyond biosynthesis of purines, to impact behavior under conditions of adenylosuccinate lyase deficiency.

Knockout of tyramine receptor 1 results in a decrease of oviposition, mating, and sex pheromone biosynthesis in female Plutella xylostella.

Mating and oviposition are essential and closely coordinated events in the reproduction of moths. Although tyramine, a biogenic amine, can affect insect reproduction by binding its receptors, the specific regulatory mechanism has not yet been fully elucidated. Plutella xylostella mutant with tyramine receptor 1 (TAR1) knockout (homozygous mutant with 7-bp deletion, Mut7) was developed by the CRISPR/Cas9 system to investigate the effect of TAR1 knockout on the reproduction of the moth. Compared with wild-type (WT), the egg yield of Mut7 female (Mut7F ) was significantly lower, no significant difference was observed in the egg size and hatching ratio between the groups. Further analysis showed that TAR1 knockout adversely affected ovary development, characterized by shorter ovarioles and fewer mature oocyte. Additionally, TAR1 knockout significantly reduced the occurrence of mating, resulting in a decrease in egg yield in Mut7F . The amounts of sex pheromones were quantified using gas chromatography-mass spectrometry. Results showed that the amounts of sex pheromone released by Mut7F were significantly lower before mating. Correspondingly, the messenger RNA (mRNA) levels of sex pheromone biosynthesis enzymes, including acetyl-CoA carboxylase (ACC) and desaturase (DES), were significantly lower in the Mut7F pheromone gland. The decreased sex pheromone biosynthesis in Mut7F , especially before re-mating, may be related to the underexpression of pheromone biosynthesis-activated neuropeptide (PBAN). Overall, this study investigated the effect of PxTAR1 on oviposition and mating of P. xylostella. We report for the first time that TAR1 knockout could reduce the sex pheromone biosynthesis. These findings provide insights for developing a novel integrated pest control strategy based on mating interference. © 2023 Society of Chemical Industry.

Target identification and acaricidal activity difference of amitraz and its metabolite DPMF in Tetranychus cinnabarinus (Boisduval).

Amitraz is a broad-spectrum formamidine acaricide proven to be effective against mites in all development stages. Under acidic conditions, amitraz is hydrolyzed to N2 -(2,4-dimethylphenyl)-N1 -methyformamidine (DPMF), an active metabolite for mite control. Octopamine and tyramine receptors are well known targets of amitraz. Until now, no research has been conducted about the amitraz target in Tetranychus cinnabarinus. This study aimed to identify the target genes of amitraz in T. cinnabarinus and reveal the mechanisms behind the differential acaricidal activities of amitraz and DPMF. Analysis of the toxicity, stress expression, target sensitivity and binding site of amitraz against T. cinnabarinus showed that TcOctβ2R was the main target gene of amitraz. DPMF had more potent acaricidal activity against T. cinnabarinus and was more effective at activating TcOctβ2R than amitraz. Furthermore, the three synergists had no significant effect on amitraz and DPMF, indicating that the detoxification metabolism was not related to the difference in acaricidal activity. In this study, TcOctβ2R was identified as the main target gene of amitraz against T. cinnabarinus. The divergence of target binding was responsible for the difference in acaricidal activity between amitraz and DPMF. The results also revealed the physiological and pharmacological functions of octopamine receptors (OARs) in T. cinnabarinus and could provide a basis for the design of new acaricides, with OARs as a special target. © 2023 Society of Chemical Industry.

Tyraminergic control of vitellogenin production and release in the blood-feeding insect, Rhodnius prolixus

In insects, the biogenic amine tyramine (TA) has been shown to control several physiological processes. Recently, the involvement of the type 1 tyramine receptor (TAR1) in reproductive processes has been demonstrated in different insects. Here, we investigate the putative role of Rhodnius prolixus TAR1 (RpTAR1) in reproduction in female R. prolixus. RpTAR1 transcript was highly expressed in tissues associated with egg development. Moreover, after a blood meal, which is the stimulus for full egg development, RpTAR1 transcript was upregulated in the ovaries and in the fat body. After RNAi-mediated RpTAR1 knockdown, an ovarian phenotype characterized by the absence or reduction of egg production was observed. Furthermore, protein and Vg accumulation in the fat body was observed, suggesting an impairment in protein release from the fat body into the hemolymph. However, even though fewer eggs were produced and laid, there was no difference in hatching ratio of those laid, in comparison to the controls, indicating that the overall low protein uptake by the ovaries did not influence the viability of individual eggs produced. Interestingly, the eggs from dsTAR1-treated insects appeared more red, indicating a higher content of RHBP compared to the control. A higher colocalization between Vg and Rab11, a marker for the recycling endosome pathway, was observed after dsTAR1 injection, suggesting that a more active lysosome degradation pathway in response to the Vg accumulation may occur. In addition to the Vg accumulation in the fat body, dsTAR1 treatment altered JH pathway. However, it remains to be elucidated whether this event is either directly related to the RpTAR1 downregulation or for a consequence to the Vg accumulation. Lastly, the RpTAR1 action on Vg synthesis and release in the fat body was monitored in the presence or absence of yohimbine, the antagonist of TAR1, in an ex-vivo experiment. Yohimbine antagonises the TAR1 stimulated release of Vg. These results provide critical information concerning the role of TAR1 in Vg synthesis and release in R. prolixus. Furthermore, this work opens the way for further investigation into innovative methods for controlling R. prolixus.

Octopamine and tyramine signalling in Aedes aegypti: Molecular characterization and insight into potential physiological roles.

In insects, the biogenic amines octopamine (OA) and tyramine (TA) are involved in controlling several physiological and behavioural processes. OA and TA act as neurotransmitters, neuromodulators or neurohormones, performing their functions by binding to specific receptors belonging to the G protein-coupled receptor (GPCR) superfamily. OA and TA along with their receptors are involved in reproduction, smell perception, metabolism, and homeostasis. Moreover, OA and TA receptors are targets for insecticides and antiparasitic agents, such as the formamidine Amitraz. In the dengue and yellow fever vector, Aedes aegypti, limited research has been reported on their OA or TA receptors. Here, we identify and molecularly characterize the OA and TA receptors in A. aegypti. Bioinformatic tools were used to identify four OA and three TA receptors in the genome of A. aegypti. The seven receptors are expressed in all developmental stages of A. aegypti; however, their highest transcript abundance is observed in the adult. Among several adult A. aegypti tissues examined, including the central nervous system, antennae and rostrum, midgut, Malpighian tubules, ovaries, and testes, the type 2 TA receptor (TAR2) transcript is most abundant in the ovaries and the type 3 TA receptor (TAR3) is enriched in the Malpighian tubules, leading us to propose putative roles for these receptors in reproduction and diuresis, respectively. Furthermore, a blood meal influenced OA and TA receptor transcript expression patterns in adult female tissues at several time points post blood meal, suggesting these receptors may play key physiological roles associated with feeding. To better understand OA and TA signalling in A. aegypti, the transcript expression profiles of key enzymes in their biosynthetic pathway, namely tyrosine decarboxylase (Tdc) and tyramine β-hydroxylase (Tβh), were examined in developmental stages, adult tissues, and brains from blood-fed females. These findings provide information for better understanding the physiological roles of OA, TA, and their receptors in A. aegypti, and additionally, may help in the development of novel strategies for the control of these human disease vectors.

Specificity of Monoterpene Interactions with Insect Octopamine and Tyramine Receptors: Insights from in Silico Sequence and Structure Comparison.

Octopamine and tyramine receptors (OARs/TARs) are interesting targets for new insecticide development due to their unique roles in insects' physiological and cellular response and their specificity to invertebrates. Monoterpene compounds that bear resemblance to the natural ligands have been shown to bind to the OARs/TARs but elicit varied responses in different insect species. Using in silico methods, we attempt to investigate the molecular basis of monoterpene interactions and their specificity in different OARs and TARs of damaging or beneficial insects. Sequence and structure comparison revealed that the OARs/TARs studied generally have more similarities in terms of structure rather than sequence identity. Together with clustering and network analyses, we also revealed that the role of IL3 might be crucial in the identification of OAR and TAR and their unique function. Among the 35 monoterpenes subjected to ensemble docking, carvacrol had the most negative average binding energies with the target insect OARs and TARs. The differences in the key interacting residues of carvacrol with insect OARs and TARs could be the origin of variation in the responses of insect species to this monoterpene. Results suggest that carvacrol may be a potential natural-product-based insecticide, targeting multiple insect pests while being nonharmful to honeybees and Asian swallowtail butterflies. This work could provide insights into the development of effective species-specific natural-product-based insecticides that are more environmentally friendly than conventional insecticides.

Resistance to amitraz in the parasitic honey bee mite Varroa destructor is associated with mutations in the β-adrenergic-like octopamine receptor

Varroa destructor is considered a major reason for high loss rate of Western honey bee (Apis mellifera) colonies. To prevent colony losses caused by V. destructor, it is necessary to actively manage the mite population. Beekeepers, particularly commercial beekeepers, have few alternative treatments other than synthetic acaricides to control the parasite, resulting in intensive treatment regimens that led to the evolution of resistance in mite populations. To investigate the mechanism of the resistance to amitraz detected in V. destructor mites from French and U.S. apiaries, we identified and characterized octopamine and tyramine receptors (the known targets of amitraz) in this species. The comparison of sequences obtained from mites collected from different apiaries with different treatment regimens, showed that the amino acid substitutions N87S or Y215H in the OctβR were associated with treatment failures reported in French or U.S. apiaries, respectively. Based on our findings, we have developed and tested two high throughput diagnostic assays based on TaqMan technology able to accurately detect mites carrying the mutations in this receptor. This valuable information may be of help for beekeepers when selecting the most suitable acaricide to manage V. destructor.

Genome-Wide Identification of Neuropeptides and Their Receptors in an Aphid Endoparasitoid Wasp, Aphidius gifuensi.

Simple SummaryNeuropeptides and their receptors play important roles in insect physiology and behavior. Due to their specificity and importance, they have been considered as the targets for new environmentally friendly insecticides. Hence, more information on genomics and transcriptomics of neuropeptide and their receptors in more insects, especially in beneficial insects, are needed to avoid the side effects of these environmentally friendly insecticides. Aphidius gifuensis is one of the most well-known aphid parasitoids and has been successfully used to control aphids such as Myzus persicae and Sitobion avenae. In this study, we systematically identified neuropeptides and their receptors from the genome and head transcriptome of A. gifuensis. Meanwhile, we also analyzed their expression patterns in response to imidacloprid exposure and in different tissues. Our results not only laid a preliminary foundation for functional studies on neuropeptide precursors and their receptors but also provided useful information for future pesticide development.In insects, neuropeptides and their receptors not only play a critical role in insect physiology and behavior but also are the potential targets for novel pesticide discoveries. Aphidius gifuensis is one of the most important and widespread aphid parasitoids, and has been successfully used to control aphid. In the present work, we systematically identified neuropeptides and their receptors from the genome and head transcriptome of A. gifuensis. A total of 35 neuropeptide precursors and 49 corresponding receptors were identified. The phylogenetic analyses demonstrated that 35 of these receptors belong to family-A, four belong to family-B, two belong to leucine-rich repeat-containing GPCRs, four belong to receptor guanylyl cyclases, and four belong to receptor tyrosine kinases. Oral ingestion of imidacloprid significantly up-regulated five neuropeptide precursors and four receptors whereas three neuropeptide precursors and eight receptors were significantly down-regulated, which indicated that these neuropeptides and their receptors are potential targets of some commercial insecticides. The RT-qPCR results showed that dopamine receptor 1, dopamine receptor 2, octopamine receptor, allatostatin-A receptor, neuropeptides capa receptor, SIFamide receptor, FMRFamide receptor, tyramine receptor and short neuropeptide F predominantly were expressed in the head whilst the expression of ion transport peptide showed widespread distribution in various tissues. The high expression levels of these genes suggest their important roles in the central nervous system. Taken together, our study provides fundamental information that may further our understanding of neuropeptidergic signaling systems in the regulation of the physiology and behavior of solitary wasps. Furthermore, this information could also aid in the design and discovery of specific and environment-friendly insecticides.

A neuronal mechanism controlling the choice between feeding and sexual behaviors in Drosophila

SummaryAnimals must express the appropriate behavior that meets their most pressing physiological needs and their environmental context. However, it is currently unclear how alternative behavioral options are evaluated and appropriate actions are prioritized. Here, we describe how fruit flies choose between feeding and courtship; two behaviors necessary for survival and reproduction. We show that sex- and food-deprived male flies prioritize feeding over courtship initiation, and manipulation of food quality or the animal’s internal state fine-tunes this decision. We identify the tyramine signaling pathway as an essential mediator of this decision. Tyramine biosynthesis is regulated by the fly’s nutritional state and acts as a satiety signal, favoring courtship over feeding. Tyramine inhibits a subset of feeding-promoting tyramine receptor (TyrR)-expressing neurons and activates P1 neurons, a known command center for courtship. Conversely, the perception of a nutritious food source activates TyrR neurons and inhibits P1 neurons. Therefore, TyrR and P1 neurons are oppositely modulated by starvation, via tyramine levels, and food availability. We propose that antagonistic co-regulation of neurons controlling alternative actions is key to prioritizing competing drives in a context- dependent manner.

Societies to genes: can we get there from here?

Understanding the organization and evolution of social complexity is a major task because it requires building an understanding of mechanisms operating at different levels of biological organization from genes to social interactions. I discuss here, a unique forward genetic approach spanning more than 30 years beginning with human-assisted colony-level selection for a single social trait, the amount of pollen honey bees (Apis mellifera L.) store. The goal was to understand a complex social trait from the social phenotype to genes responsible for observed trait variation. The approach combined the results of colony-level selection with detailed studies of individual behavior and physiology resulting in a mapped, integrated phenotypic architecture composed of correlative relationships between traits spanning anatomy, physiology, sensory response systems, and individual behavior that affect individual foraging decisions. Colony-level selection reverse engineered the architecture of an integrated phenotype of individuals resulting in changes in the social trait. Quantitative trait locus (QTL) studies combined with an exceptionally high recombination rate (60 kb/cM), and a phenotypic map, provided a genotype–phenotype map of high complexity demonstrating broad QTL pleiotropy, epistasis, and epistatic pleiotropy suggesting that gene pleiotropy or tight linkage of genes within QTL integrated the phenotype. Gene expression and knockdown of identified positional candidates revealed genes affecting foraging behavior and confirmed one pleiotropic gene, a tyramine receptor, as a target for colony-level selection that was under selection in two different tissues in two different life stages. The approach presented here has resulted in a comprehensive understanding of the structure and evolution of honey bee social organization.

Tyramine 1 Receptor Distribution in the Brain of Corbiculate Bees Points to a Conserved Function

Sucrose represents an important carbohydrate source for most bee species. In the Western honeybee (Apis mellifera) it was shown that individual sucrose responsiveness correlates with the task performed in the colony, supporting the response threshold theory which states that individuals with the lowest threshold for a task-associated stimuli will perform the associated task. Tyramine was shown to modulate sucrose responsiveness, most likely via the tyramine 1 receptor. This receptor is located in brain areas important for the processing of gustatory stimuli. We asked whether the spatial expression pattern of the tyramine 1 receptor is a unique adaptation of honeybees or if its expression represents a conserved trait. Using a specific tyramine receptor 1 antibody, we compared the spatial expression of this receptor in the brain of different corbiculate bee species, including eusocial honeybees, bumblebees, stingless bees, and the solitary bee Osmia bicornis as an outgroup. We found a similar labeling pattern in the mushroom bodies, the central complex, the dorsal lobe, and the gnathal ganglia, indicating a conserved receptor expression. With respect to sucrose responsiveness this result is of special importance. We assume that the tyramine 1 receptor expression in these neuropiles provides the basis for modulation of sucrose responsiveness. Furthermore, the tyramine 1 receptor expression seems to be independent of size, as labeling is similar in bee species that differ greatly in their body size. However, the situation in the optic lobes appears to be different. Here, the lobula of stingless bees is clearly labeled by the tyramine receptor 1 antibody, whereas this labeling is absent in other species. This indicates that the regulation of this receptor is different in the optic lobes, while its function in this neuropile remains unclear.

Molecular and pharmacological characterization of biogenic amine receptors from the diamondback moth, Plutella xylostella.

Insect biogenic amines play important roles in mediating behavioral and physiological processes. They exert their effects by binding to biogenic amine receptors (BARs), which are specific receptor proteins in the G-protein-coupled receptor superfamily. BAR genes have been cloned and characterized from multiple model insects, including Drosophila melanogaster, Anopheles gambiae, Bombyx mori, Apis mellifera and Tribolium castaneum. However, relatively little work has addressed the molecular properties, expression profiles, and pharmacological characterization of BARs from other insects, including important pests. In this study, we cloned 17 genes encoding putative biogenic amine receptor proteins from Plutella xylostella, a global pest of Brassica crops. These PxBAR genes were five octopamine receptors (PxOA1, PxOA2B1, PxOA2B2, PxOA2B3, and PxOA3), three tyramine receptors (PxTAR1A, PxTAR1B, and PxTAR2), four dopamine receptors (PxDOP1, PxDOP2, PxDOP3, and PxDopEcR), and five serotonin receptors (Px5-HT1A , Px5-HT1B , Px5-HT2A , Px5-HT2B , and Px5-HT7 ). All PxBARs showed considerable sequence identity with orthologous BARs, and phylogenetic analysis clustered the receptors within their respective groups while preserving organismal evolutionary relationships. We investigated their molecular properties and expression profiles, and pharmacologically characterized the dopamine receptor, PxDOP2. Our study provides important information and resources on biogenic amine receptors from P. xylostella, which suggests potential target sites for controlling this pest species. © 2021 Society of Chemical Industry.

Sensitivity to expression levels underlies differential dominance of a putative null allele of the Drosophila tβh gene in behavioral phenotypes.

The biogenic amine octopamine (OA) and its precursor tyramine (TA) are involved in controlling a plethora of different physiological and behavioral processes. The tyramine-β-hydroxylase (tβh) gene encodes the enzyme catalyzing the last synthesis step from TA to OA. Here, we report differential dominance (from recessive to overdominant) of the putative null tβhnM18 allele in 2 behavioral measures in Buridan’s paradigm (walking speed and stripe deviation) and in proboscis extension (sugar sensitivity) in the fruit fly Drosophila melanogaster. The behavioral analysis of transgenic tβh expression experiments in mutant and wild-type flies as well as of OA and TA receptor mutants revealed a complex interaction of both aminergic systems. Our analysis suggests that the different neuronal networks responsible for the 3 phenotypes show differential sensitivity to tβh gene expression levels. The evidence suggests that this sensitivity is brought about by a TA/OA opponent system modulating the involved neuronal circuits. This conclusion has important implications for standard transgenic techniques commonly used in functional genetics.

Characterization of Halyomorpha halys TAR1 reveals its involvement in (E)-2-decenal pheromone perception.

In insects, tyramine receptor 1 (TAR1) has been shown to control several physiological functions, including olfaction. We investigated the molecular and functional profile of the Halyomorpha halys type 1 tyramine receptor gene (HhTAR1) and its role in olfactory functions of this pest. Molecular and pharmacological analyses confirmed that the HhTAR1 gene codes for a true TAR1. RT-qPCR analysis revealed that HhTAR1 is expressed mostly in adult brain and antennae as well as in early development stages (eggs, 1st and 2nd instar nymphs). In particular, among the antennomeres that compose a typical H. halys antenna, HhTAR1 was more expressed in flagellomeres. Scanning electron microscopy investigation revealed the type and distribution of sensilla on adult H. halys antennae: both flagellomeres appear rich in trichoid and grooved sensilla, known to be associated with olfactory functions. Through an RNAi approach, topically delivered HhTAR1 dsRNA induced a 50% downregulation in gene expression after 24 h in H. halys 2nd instar nymphs. An innovative behavioural assay revealed that HhTAR1 RNAi-silenced 2nd instar nymphs were less susceptible to the alarm pheromone component (E)-2 decenal as compared with controls. These results provide critical information concerning the role of TAR1 in olfaction regulation, especially alarm pheromone reception, in H. halys. Furthermore, considering the emerging role of TAR1 as target of biopesticides, this work opens the way for further investigation on innovative methods for controlling H. halys.

Trimethylamine modulates dauer formation, neurodegeneration, and lifespan through tyra-3/daf-11 signaling in Caenorhabditis elegans.

In the nematode Caenorhabditis elegans, signals derived from bacteria in the diet, the animal's major nutrient source, can modulate both behavior and healthspan. Here we describe a dual role for trimethylamine (TMA), a human gut flora metabolite, which acts as a nutrient signal and a neurotoxin. TMA and its associated metabolites are produced by the human gut microbiome and have been suggested to serve as risk biomarkers for diabetes and cardiovascular diseases. We demonstrate that the tyramine receptor TYRA‐3, a conserved G protein‐coupled receptor (GPCR), is required to sense TMA and mediate its responses. TMA activates guanylyl cyclase DAF‐11 signaling through TYRA‐3 in amphid neurons (ASK) and ciliated neurons (BAG) to mediate food‐sensing behavior. Bacterial mutants deficient in TMA production enhance dauer formation, extend lifespan, and are less preferred as a food source. Increased levels of TMA lead to neural damage in models of Parkinson's disease and shorten lifespan. Our results reveal conserved signaling pathways modulated by TMA in C. elegans that are likely to be relevant for its effects in mammalian systems.

The Insect Type 1 Tyramine Receptors: From Structure to Behavior.

Tyramine is a neuroactive compound that acts as neurotransmitter, neuromodulator, and neurohormone in insects. Three G protein-coupled receptors, TAR1-3, are responsible for mediating the intracellular pathway in the complex tyraminergic network. TAR1, the prominent player in this system, was initially classified as an octopamine receptor which can also be activated by tyramine, while it later appeared to be a true tyramine receptor. Even though TAR1 is currently considered as a well-defined tyramine receptor and several insect TAR1s have been characterized, a defined nomenclature is still inconsistent. In the last years, our knowledge on the structural, biochemical, and functional properties of TAR1 has substantially increased. This review summarizes the available information on TAR1 from different insect species in terms of basic structure, its regulation and signal transduction mechanisms, and its distribution and functions in the brain and the periphery. A special focus is given to the TAR1-mediated intracellular signaling pathways as well as to their physiological role in regulating behavioral traits. Therefore, this work aims to correlate, for the first time, the physiological relevance of TAR1 functions with the tyraminergic system in insects. In addition, pharmacological studies have shed light on compounds with insecticidal properties having TAR1 as a target and on the emerging trend in the development of novel strategies for pest control.

Forager age and foraging state, but not cumulative foraging activity, affect biogenic amine receptor gene expression in the honeybee mushroom bodies.

Foraging behavior is crucial for the development of a honeybee colony. Biogenic amines are key mediators of learning and the transition from in-hive tasks to foraging. Foragers vary considerably in their behavior, but whether and how this behavioral diversity depends on biogenic amines is not yet well understood. For example, forager age, cumulative foraging activity or foraging state may all be linked to biogenic amine signaling. Furthermore, expression levels may fluctuate depending on daytime. We tested if these intrinsic and extrinsic factors are linked to biogenic amine signaling by quantifying the expression of octopamine, dopamine and tyramine receptor genes in the mushroom bodies, important tissues for learning and memory. We found that older foragers had a significantly higher expression of Amdop1, Amdop2, AmoctαR1, and AmoctβR1 compared to younger foragers, whereas Amtar1 showed the opposite pattern. Surprisingly, our measures of cumulative foraging activity were not related to the expression of the same receptor genes in the mushroom bodies. Furthermore, we trained foragers to collect sucrose solution at a specific time of day and tested if the foraging state of time-trained foragers affected receptor gene expression. Bees engaged in foraging had a higher expression of Amdop1 and AmoctβR3/4 than inactive foragers. Finally, the expression of Amdop1, Amdop3, AmoctαR1, and Amtar1 also varied with daytime. Our results show that receptor gene expression in forager mushroom bodies is complex and depends on both intrinsic and extrinsic factors.

Correlation between octopaminergic signalling and foraging task specialisation in honeybees.

Regulation of pollen and nectar foraging in honeybees is linked to differences in the sensitivity to the reward. Octopamine (OA) participates in the processing of reward-related information in the bee brain, being a candidate to mediate and modulate the division of labour among pollen and nectar foragers. Here we tested the hypothesis that OA affects the resource preferences of foragers. We first investigated whether oral administration of OA is involved in the transition from nectar to pollen foraging. We quantified the percentage of OA-treated bees that switched from a sucrose solution to a pollen feeder when the sugar concentration was decreased experimentally. We also evaluated if feeding the colonies sucrose solution containing OA increases the rate of bees collecting pollen. Finally, we quantified OA and tyramine (TYR) receptor genes expression of pollen and nectar foragers in different parts of the brain, as a putative mechanism that affects the decision-making process regarding the resource type collected. Adding OA in the food modified the probability that foragers switch from nectar to pollen collection. The proportion of pollen foragers also increased after feeding colonies with OA-containing food. Furthermore, the expression level of the AmoctαR1 was upregulated in foragers arriving at pollen sources compared with those arriving at sugar-water feeders. Using age-matched pollen and nectar foragers that returned to the hive, we detected an upregulated expression of a TYR receptor gene in the suboesophageal ganglia. These findings support our prediction that OA signalling affects the decision in honeybee foragers to collect pollen or nectar.