Nature-inspired dimerization as a strategy to modulate neuropeptide pharmacology exemplified with vasopressin and oxytocin.
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ABSTRACT:
SUBMITTER: Dekan Z
PROVIDER: S-EPMC8179488 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Oxytocin and vasopressin mediate a range of physiological functions that are important for osmoregulation, reproduction, social behaviour, memory and learning. The origin of this signalling system is thought to date back ~600?million years. Oxytocin/vasopressin-like peptides have been identified in several invertebrate species and they appear to be functionally related across the entire animal kingdom. There is little information available about the biology of this peptide G protein-coupled receptor signalling system in insects. Recently over 200 insect genome/transcriptome datasets were released allowing investigation of the molecular structure and phylogenetic distribution of the insect oxytocin/vasopressin orthologue - inotocin peptides and their receptors. The signalling system is present in early arthropods and representatives of some early-diverging lineages. However, Trichoptera, Lepidoptera, Siphonaptera, Mecoptera and Diptera, lack the presence of inotocin genes, which suggests the peptide-receptor system was probably lost in their common ancestor ~280?million-years-ago. In addition we detected several losses of the inotocin signalling system in Hemiptera (white flies, scale insects and aphids), and the complete absence in spiders (Chelicerata). This unique insight into evolutionarily patterns and sequence diversity of neuroendocrine hormones will provide opportunities to elucidate the physiology of the inotocin signalling system in one of the largest group of animals.
| S-EPMC5153645 | biostudies-literature
Project description:The neuropeptides oxytocin (OXT) and vasopressin (AVP) have been identified as modulators of emotional social behaviors and associated with neuropsychiatric disorders characterized by social dysfunction. Experimental and therapeutic use of OXT and AVP via the intranasal route is the subject of extensive clinical research. However, the large-scale functional substrates directly engaged by these peptides and their functional dynamics remain elusive. By using cerebral blood volume (CBV) weighted fMRI in the mouse, we show that intranasal administration of OXT rapidly elicits the transient activation of cortical regions and a sustained activation of hippocampal and forebrain areas characterized by high oxytocin receptor density. By contrast, intranasal administration of AVP produced a robust and sustained deactivation in cortico-parietal, thalamic and mesolimbic regions. Importantly, intravenous administration of OXT and AVP did not recapitulate the patterns of modulation produced by intranasal dosing, supporting a central origin of the observed functional changes. In keeping with this notion, hippocampal local field potential recordings revealed multi-band power increases upon intranasal OXT administration. We also show that the selective OXT-derivative TGOT reproduced the pattern of activation elicited by OXT and that the deletion of OXT receptors does not affect AVP-mediated deactivation. Collectively, our data document divergent modulation of brainwide neural systems by intranasal administration of OXT and AVP, an effect that involves key substrates of social and emotional behavior. The observed divergence calls for a deeper investigation of the systems-level mechanisms by which exogenous OXT and AVP modulate brain function and exert their putative therapeutic effects.
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Project description:The identification of structurally related hypothalamic hormones that regulate blood pressure and diuresis (vasopressin, VP; CYFQNCPRG-NH2) or lactation and uterine contraction (oxytocin, OT; CYIQNCPLG-NH2) was a major advance in neuroendocrinology, recognized in the award of the Nobel Prize for Chemistry in 1955. Furthermore, the discovery of central actions of VP and OT as regulators of reproductive and social behavior in humans and other mammals has broadened interest in these neuropeptides beyond physiology into psychology. VP/OT-type neuropeptides and their G-protein coupled receptors originated in a common ancestor of the Bilateria (Urbilateria), with invertebrates typically having a single VP/OT-type neuropeptide and cognate receptor. Gene/genome duplications followed by gene loss gave rise to variety in the number of VP/OT-type neuropeptides and receptors in different vertebrate lineages. Recent advances in comparative transcriptomics/genomics have enabled discovery of VP/OT-type neuropeptides in an ever-growing diversity of invertebrate taxa, providing new opportunities to gain insights into the evolution of VP/OT-type neuropeptide function in the Bilateria. Here we review the comparative physiology of VP/OT-type neuropeptides in invertebrates, with roles in regulation of reproduction, feeding, and water/salt homeostasis emerging as common themes. For example, we highlight recent reports of roles in regulation of oocyte maturation in the sea-squirt Ciona intestinalis, extraoral feeding behavior in the starfish Asterias rubens and energy status and dessication resistance in ants. Thus, VP/OT-type neuropeptides are pleiotropic regulators of physiological processes, with evolutionarily conserved roles that can be traced back to Urbilateria. To gain a deeper understanding of the evolution of VP/OT-type neuropeptide function it may be necessary to not only determine the actions of the peptides but also to characterize the transcriptomic/proteomic/metabolomic profiles of cells expressing VP/OT-type precursors and/or VP/OT-type receptors within the framework of anatomically and functionally identified neuronal networks. Furthermore, investigation of VP/OT-type neuropeptide function in a wider range of invertebrate species is now needed if we are to determine how and when this ancient signaling system was recruited to regulate diverse physiological and behavioral processes in different branches of animal phylogeny and in contrasting environmental contexts.
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Project description:Oxytocin/vasopressin-related neuropeptides are highly conserved and play major roles in regulating social behavior across vertebrates. However, whether their insect orthologue, inotocin, regulates the behavior of social groups remains unknown. Here, we show that in the clonal raider ant Ooceraea biroi, individuals that perform tasks outside the nest have higher levels of inotocin in their brains than individuals of the same age that remain inside the nest. We also show that older ants, which spend more time outside the nest, have higher inotocin levels than younger ants. Inotocin thus correlates with the propensity to perform tasks outside the nest. Additionally, increasing inotocin pharmacologically increases the tendency of ants to leave the nest. However, this effect is contingent on age and social context. Pharmacologically treated older ants have a higher propensity to leave the nest only in the presence of larvae, whereas younger ants seem to do so only in the presence of pupae. Our results suggest that inotocin signaling plays an important role in modulating behaviors that correlate with age, such as social foraging, possibly by modulating behavioral response thresholds to specific social cues. Inotocin signaling thereby likely contributes to behavioral individuality and division of labor in ant societies.
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Project description:UnlabelledDesigner cellulosomes consist of chimeric cohesin-bearing scaffoldins for the controlled incorporation of recombinant dockerin-containing enzymes. The largest designer cellulosome reported to date is a chimeric scaffoldin that contains 6 cohesins. This scaffoldin represented a technical limit of sorts, since adding another cohesin proved problematic, owing to resultant low expression levels, instability (cleavage) of the scaffoldin polypeptide, and limited numbers of available cohesin-dockerin specificities-the hallmark of designer cellulosomes. Nevertheless, increasing the number of enzymes integrated into designer cellulosomes is critical, in order to further enhance degradation of plant cell wall material. Adaptor scaffoldins comprise an intermediate type of scaffoldin that can both incorporate various enzymes and attach to an additional scaffoldin. Using this strategy, we constructed an efficient form of adaptor scaffoldin that possesses three type I cohesins for enzyme integration, a single type II dockerin for interaction with an additional scaffoldin, and a carbohydrate-binding module for targeting to the cellulosic substrate. In parallel, we designed a hexavalent scaffoldin capable of connecting to the adaptor scaffoldin by the incorporation of an appropriate type II cohesin. The resultant extended designer cellulosome comprised 8 recombinant enzymes-4 xylanases and 4 cellulases-thereby representing a potent enzymatic cocktail for solubilization of natural lignocellulosic substrates. The contribution of the adaptor scaffoldin clearly demonstrated that proximity between the two scaffoldins and their composite set of enzymes is crucial for optimized degradation. After 72 h of incubation, the performance of the extended designer cellulosome was determined to be approximately 70% compared to that of native cellulosomes.ImportancePlant cell wall residues represent a major source of renewable biomass for the production of biofuels such as ethanol via breakdown to soluble sugars. The natural microbial degradation process, however, is inefficient for achieving cost-effective processes in the conversion of plant-derived biomass to biofuels, either from dedicated crops or human-generated cellulosic wastes. The accumulation of the latter is considered a major environmental pollutant. The development of designer cellulosome nanodevices for enhanced plant cell wall degradation thus has major impacts in the fields of environmental pollution, bioenergy production, and biotechnology in general. The findings reported in this article comprise a true breakthrough in our capacity to produce extended designer cellulosomes via synthetic biology means, thus enabling the assembly of higher-order complexes that can supersede the number of enzymes included in a single multienzyme complex.
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Project description:The related neuropeptides oxytocin and vasopressin are involved in species-typical behavior, including social recognition behavior, maternal behavior, social bonding, communication, and aggression. A wealth of evidence from animal models demonstrates significant modulation of adult social behavior by both of these neuropeptides and their receptors. Over the last decade, there has been a flood of studies in humans also implicating a role for these neuropeptides in human social behavior. Despite popular assumptions that oxytocin is a molecule of social bonding in the infant brain, less mechanistic research emphasis has been placed on the potential role of these neuropeptides in the developmental emergence of the neural substrates of behavior. This review summarizes what is known and assumed about the developmental influence of these neuropeptides and outlines the important unanswered questions and testable hypotheses. There is tremendous translational need to understand the functions of these neuropeptides in mammalian experience-dependent development of the social brain. The activity of oxytocin and vasopressin during development should inform our understanding of individual, sex, and species differences in social behavior later in life.
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Project description:The lack of drinkable water is one of the most significant risks for the future of the humanity. Estimates show that in the near future, this risk will become the origin of massive migrations leading to humanitarian disaster. As consequence, the development of solutions to provide water is becoming ever more critical, and a significant effort is devoted to identifying new sources of water. Among the developed strategies, fog harvesting, which takes advantage of atmospheric water to provide potable water, is a solution of interest due to its potential in sustainable development. Unfortunately, this approach suffers from low yield. In the present work, we take inspiration from living species to design and elaborate surfaces with high potential for water harvesting applications. This work takes advantage of 3D-printing and post-printing functionalization to elaborate a strategy that allows modelling, printing, and functionalization of surfaces to yield parahydrophobic behavior. The roughness and surface morphology of the prepared surfaces were investigated. These characteristics were then related to the observed wettability and potential of the functionalized interfaces for water harvesting applications. This work highlights significant variations in surface wettability via surface modification; strong hydrophobic behavior was observed via modification with linear carboxylic acids particularly for surfaces bearing vertical blades (plate with vertical blades and grid with vertical blades).
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Project description:Neuropeptidergic signaling is widely adopted by animals for the regulation of physiology and behavior in a rapidly changing environment. The vasopressin/oxytocin neuropeptide family originates from an ancestral peptide precursor in the antecedent of protostomian and deuterostomian animals. In vertebrates, vasopressin and oxytocin have both hormonal effects on peripheral target tissues, such as in the regulation of reproduction and water balance, and neuromodulatory actions in the central nervous system controlling social behavior and cognition. The recent identification of vasopressin/oxytocin-related signaling in C. elegans reveals that this peptidergic system is widespread among nematodes. Genetic analysis of the C. elegans nematocin system denotes vasopressin/oxytocin-like peptides as ancient neuromodulators of neuronal circuits involved in reproductive behavior and associative learning, whereas former invertebrate studies focused on conserved peripheral actions of this peptide family. Nematocin provides neuromodulatory input into the gustatory plasticity circuit as well as into distinct male mating circuits to generate a coherent mating behavior. Molecular interactions are comparable to those underlying vasopressin- and oxytocin-mediated effects in the mammalian brain. Understanding how the vasopressin/oxytocin family fine-tunes neuronal circuits for social behavior, learning and memory poses a major challenge. Functional conservation of these effects in nematodes and most likely in other invertebrates enables the development of future models to help answering this question.
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Project description:Materials can be made strong, but as such they are often brittle and prone to fracture when under stress. Inspired by the exceptionally strong and ductile structure of byssal threads found in certain mussels, we have designed and manufactured a multi-hierarchical steel, based on an inexpensive austenitic stainless steel, which defeats this "conflict" by possessing both superior strength and ductility. These excellent mechanical properties are realized by structurally introducing sandwich structures at both the macro- and nano-scales, the latter via an isometric, alternating, dual-phase crystal phases comprising nano-band austenite and nano-lamellar martensite, without change in chemical composition. Our experiments (transmission and scanning electron microscopy, electron back-scattered diffraction, nano-indentation and tensile tests) and micromechanics simulation results reveal a synergy of mechanisms underlying such exceptional properties. This synergy is key to the development of vastly superior mechanical properties, and may provide a unique strategy for the future development of new super strong and tough (damage-tolerant), lightweight and inexpensive structural materials.
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Project description:Annetocin is structurally related to an OT (oxytocin)/VP (vasopressin) family peptide, which has been isolated from the earthworm Eisenia foetida and has been shown to induce OT-like egg-laying behaviour. We now report the identification of an endogenous AnR (annetocin receptor). The deduced AnR precursor displays high sequence similarity with OT/VP receptors. Genomic analysis of the AnR gene revealed that the intron-inserted position is conserved between the AnR gene and the mammalian OT/VP receptor genes. These results indicate that AnR and mammalian OT/VP receptors share a common ancestor gene. Administration of annetocin to the AnR expressed in Xenopus oocytes induced a calcium-dependent signal transduction. Reverse transcriptase-PCR analysis and in situ hybridization showed that the AnR gene is expressed specifically in the nephridia located in the clitellum region, although the nephridia are distributed throughout the worm body. This result suggests that annetocin induces egg-laying behaviour through its action on the nephridia. This is the first description concerning the functional correlation between an invertebrate OT/VP-related peptide and egg-laying behaviour.
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