Transmission Of Chemical Signals Research Articles

Single vesicle chemistry reveals partial release happens at the mechanical stress-induced exocytosis

Neuronal activity can be modulated by mechanical stress in the central nervous system (CNS) in neurodegenerative diseases, for example Alzheimer's disease. However, the impact of mechanical stress on chemical signal transmission, especially the storage and release of neurotransmitter in neuron vesicles, has not been fully clarified. In this study, a nanotip conical carbon fiber microelectrode (CFME) and a disk CFME are placed in and on a cell, respectively. The nanotip conical CFME functions for both the mechanical stress and the quantification of transmitter storage in single vesicles, while the disk CFME is used to monitor the transmitter release during exocytosis induced by mechanical stress at the same cell. By comparing the vesicular transmitter storage with its release during mechanical stress-induced exocytosis at the same cell, we find the release ratio of transmitter in chromaffin cells varies from 27 % to 100 %, while for PC12 cells from 30 % to 100 %. Our results indicate that the exocytosis of cells responding to mechanical stress shows individual difference obviously, with a significant population exhibiting partial release mode. The variation of Ca2+ channels and mechanosensitive ion channels on cell membrane may both contribute to this variation. Our discovery not only shows mechanical stress can change the transmission of cellular chemical signals at the vesicle level, but also provides an important reference perspective for the study of nervous system regulation and nervous system diseases.

Advances in electrode interface materials and modification technologies for brain-computer interfaces.

Recent advances in neuroelectrode interface materials and modification technologies are reviewed. Brain-computer interface is the new method of human-computer interaction, which not only can realise the exchange of information between the human brain and external devices, but also provides a brand-new means for the diagnosis and treatment of brain-related diseases. The neural electrode interface part of brain-computer interface is an important area for electrical, optical and chemical signal transmission between brain tissue system and external electronic devices, which determines the performance of brain-computer interface. In order to solve the problems of insufficient flexibility, insufficient signal recognition ability and insufficient biocompatibility of traditional rigid electrodes, researchers have carried out extensive studies on the neuroelectrode interface in terms of materials and modification techniques. This paper introduces the biological reactions that occur in neuroelectrodes after implantation into brain tissue and the decisive role of the electrode interface for electrode function. Following this, the latest research progress on neuroelectrode materials and interface materials is reviewed from the aspects of neuroelectrode materials and modification technologies, firstly taking materials as a clue, and then focusing on the preparation process of neuroelectrode coatings and the design scheme of functionalised structures.

Linking Bacterial Rhizosphere Communities of Two Pioneer Species, Brachystegia boehmii and B. spiciformis, to the Ecological Processes of Miombo Woodlands

Miombo is the most extensive ecosystem in southern Africa, being strongly driven by fire, climate, herbivory, and human activity. Soils are major regulating and supporting services, sequestering nearly 50% of the overall carbon and comprising a set of yet unexploited functions. In this study, we used next-generation Illumina sequencing to assess the patterns of bacterial soil diversity in two pioneer Miombo species, Brachystegia boehmii and Brachystegia spiciformis, along a fire gradient, in ferric lixisol and cambic arenosol soils. In total, 21 phyla, 51 classes, 98 orders, 193 families, and 520 genera were found, revealing a considerably high and multifunctional diversity with a strong potential for the production of bioactive compounds and nutrient mobilization. Four abundant genera characterized the core microbiome among plant species, type of soils, or fire regime: Streptomyces, Gaiella, Chthoniobacter, and Bacillus. Nevertheless, bacterial networks revealed a higher potential for mutualistic interactions and transmission of chemical signals among phylotypes from low fire frequency sites than those from high fire frequency sites. Ecological networks also revealed the negative effects of frequent fires on the complexity of microbial communities. Functional predictions revealed the core “house-keeping” metabolisms contributing to the high bacterial diversity found, suggesting its importance to the functionality of this ecosystem.

Male gopher tortoise (Gopherus polyphemus) concentration-dependent social responses to diluted mental gland pheromones

In complex terrestrial environments, chemical signals can be the most important sensory modality for locating conspecifics for potential mating opportunities, especially in spatially segregated populations or habitats. Organisms must evolve chemical signals to maximize the efficacy of conveying information, particularly in creating trails or mate-choice cues. Long-distance transmission of chemical signals may be an increasingly important management concern for small and fractured populations or potentially threatened species, such as gopher tortoises in the southeastern U.S. Mental gland secretions have been shown to have pheromonal function in gopher tortoises, suggesting a potential role as trail or marking pheromones, allowing males to track females or other males to find females. In this study, male gopher tortoises were given paired presentations of a negative control (distilled water) with serial dilutions (1:4, 1:20, 1:100, and 1:500) of male mental gland secretions. Male tortoises were able to discern treatment differences up to 1:20 diluted secretions, responding with an array of social behaviors (e.g. for the 1:20 dilution trial, carapace alignment and head bobbing occurred more frequently for the mental gland secretion relative to the control; p < 0.01). Multivariate principal components analysis yielded PC1 (including, approach, carapace alignment, head bobbing, tasting air, sniffing, and doubleback) that differed by treatment (p = 0.0007) and also was higher for the 1:20 diluted presentation relative to the 1:500 diluted presentation (p = 0.04). This study provides insight into gopher tortoise ecology, mate-choice, and the utility of environmentally diluted mental gland secretions in the external environment when seeking mating opportunities.

Collective Behavior of Urease pH Clocks in Nano- and Microvesicles Controlled by Fast Ammonia Transport.

The transmission of chemical signals via an extracellular solution plays a vital role in collective behavior in cellular biological systems and may be exploited in applications of lipid vesicles such as drug delivery. Here, we investigated chemical communication in synthetic micro- and nanovesicles containing urease in a solution of urea and acid. We combined experiments with simulations to demonstrate that the fast transport of ammonia to the external solution governs the pH–time profile and synchronizes the timing of the pH clock reaction in a heterogeneous population of vesicles. This study shows how the rate of production and emission of a small basic product controls pH changes in active vesicles with a distribution of sizes and enzyme amounts, which may be useful in bioreactor or healthcare applications.

Spatiotemporal Regulation of Hydrogel Actuators by Autocatalytic Reaction Networks.

Regulating hydrogel actuators with chemical reaction networks is instrumental for constructing life-inspired smart materials. Herein, hydrogel actuators are engineered that are regulated by the autocatalytic front of thiols. The actuators consist of two layers. The first layer, which is regular polyacrylamide hydrogel, is in a strained conformation. The second layer, which is polyacrylamide hydrogel with disulfide crosslinks, maintains strain in the first layer. When thiols released by the autocatalytic front reduce disulfide crosslinks, the hydrogel actuates by releasing the mechanical strain in the first layer. The autocatalytic front is sustained by the reaction network, which uses thiouronium salts, disulfides of β-aminothiols, and maleimide as starting components. The gradual actuation by the autocatalytic front enables movements such as gradual unrolling, screwing, and sequential closing of "fingers." This actuation also allows the transmission of chemical signals in a relay fashion and the conversion of a chemical signal to an electrical signal. Locations and times of spontaneous initiation of autocatalytic fronts can be preprogrammed in the spatial distribution of the reactants in the hydrogel. To approach the functionality of living matter, the actuators triggered by an autocatalytic front can be integrated into smart materials regulated by chemical circuits.

Recent Progress in Quantitatively Monitoring Vesicular Neurotransmitter Release and Storage With Micro/Nanoelectrodes.

Exocytosis is one of the essential steps for chemical signal transmission between neurons. In this process, vesicles dock and fuse with the plasma membrane and release the stored neurotransmitters through fusion pores into the extracellular space, and all of these steps are governed with various molecules, such as proteins, ions, and even lipids. Quantitatively monitoring vesicular neurotransmitter release in exocytosis and initial neurotransmitter storage in individual vesicles is significant for the study of chemical signal transmission of the central nervous system (CNS) and neurological diseases. Electrochemistry with micro/nanoelectrodes exhibits great spatial–temporal resolution and high sensitivity. It can be used to examine the exocytotic kinetics from the aspect of neurotransmitters and quantify the neurotransmitter storage in individual vesicles. In this review, we first introduce the recent advances of single-cell amperometry (SCA) and the nanoscale interface between two immiscible electrolyte solutions (nanoITIES), which can monitor the quantity and release the kinetics of electrochemically and non-electrochemically active neurotransmitters, respectively. Then, the development and application of the vesicle impact electrochemical cytometry (VIEC) and intracellular vesicle impact electrochemical cytometry (IVIEC) and their combination with other advanced techniques can further explain the mechanism of neurotransmitter storage in vesicles before exocytosis. It has been proved that these electrochemical techniques have great potential in the field of neuroscience.

Redox switching of an artificial transmembrane signal transduction system.

Transmission of chemical signals across lipid bilayer membranes can be achieved using membrane-anchored molecules, where molecular motion across the bilayer is controlled by switching the polarity of two different head groups. An external redox signal delivered by ascorbic acid was used to trigger membrane translocation in a synthetic transduction system.

Development of a microbe domestication pod (MD Pod) for in situ cultivation of micro-encapsulated marine bacteria.

Microbial marine natural products hold significant potential for the discovery of new bioactive therapeutics such as antibiotics. Unfortunately, this discovery is hindered by the inability to culture the majority of microbes using traditional laboratory approaches. While many new methods have been developed to increase cultivability, a high-throughput in situ incubation chamber capable of simultaneously isolating individual microbes while allowing cellular communication has not previously been reported. Development of such a device would expedite the discovery of new microbial taxa and, thus, facilitate access to their associated natural products. In this study, this concept is achieved by the development of a new device termed by the authors as the microbe domestication (MD) Pod. The MD Pod enables single-cell cultivation by isolating marine bacterial cells in agarose microbeads produced using microfluidics, while allowing potential transmission of chemical signals between cells during in situ incubation in a chamber, or "Pod," that is deployed in the environment. The design of the MD Pod was optimized to ensure the use of biocompatible materials, allow for simple assembly in a field setting, and maintain sterility throughout incubation. The encapsulation process was designed to ensure that the viability of marine sediment bacteria was not adversely impacted by the encapsulation process. The process was validated using representative bacteria isolated from temperate marine sediment samples: Marinomonas polaris, Psychrobacter aquimaris, and Bacillus licheniformis. The overall process appeared to promote metabolic activity of most representative species. Thus, microfluidic encapsulation of marine bacteria and subsequent in situ incubation in the MD Pod is expected to accelerate marine natural products discovery by increasing the cultivability of marine bacteria.

Drugs That Regulate Local Cell Signaling: AKAP Targeting as a Therapeutic Option.

Cells respond to environmental cues by mobilizing signal transduction cascades that engage protein kinases and phosphoprotein phosphatases. Correct organization of these enzymes in space and time enables the efficient and precise transmission of chemical signals. The cyclic AMP-dependent protein kinase A is compartmentalized through its association with A-kinase anchoring proteins (AKAPs). AKAPs are a family of multivalent scaffolds that constrain signaling enzymes and effectors at subcellular locations to drive essential physiological events. More recently, it has been recognized that defective signaling in certain endocrine disorders and cancers proceeds through pathological AKAP complexes. Consequently, pharmacologically targeting these macromolecular complexes unlocks new therapeutic opportunities for a growing number of clinical indications. This review highlights recent findings on AKAP signaling in disease, particularly in certain cancers, and offers an overview of peptides and small molecules that locally regulate AKAP-binding partners.

Trapping in and Escape from Branched Structures of Neuronal Dendrites

We present a coarse-grained model for stochastic transport of noninteracting chemical signals inside neuronal dendrites and show how first-passage properties depend on the key structural factors affected by neurodegenerative disorders or aging: the extent of the tree, the topological bias induced by segmental decrease of dendrite diameter, and the trapping probabilities in biochemical cages and growth cones. We derive an exact expression for the distribution of first-passage times, which follows a universal exponential decay in the long-time limit. The asymptotic mean first-passage time exhibits a crossover from power-law to exponential scaling upon reducing the topological bias. We calibrate the coarse-grained model parameters and obtain the variation range of the mean first-passage time when the geometrical characteristics of the dendritic structure evolve during the course of aging or neurodegenerative disease progression (a few disorders for which clear trends for the pathological changes of dendritic structure have been reported in the literature are chosen and studied). We prove the validity of our analytical approach under realistic fluctuations of structural parameters by comparison to the results of Monte Carlo simulations. Moreover, by constructing local structural irregularities, we analyze the resulting influence on transport of chemical signals and formation of heterogeneous density patterns. Because neural functions rely on chemical signal transmission to a large extent, our results open the possibility of establishing a direct link between the disease progression and neural functions.

Visualization of synaptic vesicle dynamics with fluorescence proteins.

Synaptic vesicle (SV) will be transported to the bouton along the axon, once it is formed in a cell body. After docking in the active zone, neurotransmitters will be released upon the stimulation, and then transmission of chemical signals will be initiated. Presently, many advanced technologies and burgeoning molecular sensors are being used to explore the synaptic transmission. These studies provide a new sight into the presynaptic structure and its function. The present review summarizes the application of fluorescent proteins (FPs) for SV tracking and recycling. Some FPs and relevant imaging technologies such as fluorescence resonance energy transfer (FRET), fluorescence recovery after photobleaching (FRAP) and fluorescence lifetime imaging microscopy (FLIM), are introduced here. In addition, some examples are also analyzed to visualize the dynamics of SVs in living cells with the help of some FPs.

Local Chemical Stimulation of Neurons with the Fluidic Force Microscope (FluidFM).

Physiological communication between neurons is dependent on the exchange of neurotransmitters at the synapses. Although this chemical signal transmission targets specific receptors and allows for subtle adaptation of the action potential, in vitro neuroscience typically relies on electrical currents and potentials to stimulate neurons. The electric stimulus is unspecific and the confinement of the stimuli within the media is technically difficult to control and introduces large artifacts in electric recordings of the activity. Here, we present a local chemical stimulation platform that resembles in vivo physiological conditions and can be used to target specific receptors of synapses. Neurotransmitters were dispensed using the force-controlled fluidic force microscope (FluidFM) nanopipette, which provides exact positioning and precise liquid delivery. We show that controlled release of the excitatory neurotransmitter glutamate induces spiking activity in primary rat hippocampal neurons, as measured by concurrent electrical and optical recordings using a microelectrode array and a calcium-sensitive dye, respectively. Furthermore, we characterized the glutamate dose response of neurons by applying stimulation pulses of glutamate with concentrations from 0 to 0.5 mm. This new stimulation approach, which combines FluidFM for gentle and precise positioning with a microelectrode array read-out, makes it possible to modulate the activity of individual neurons chemically and simultaneously record their induced activity across the entire neuronal network. The presented platform not only offers a more physiological alternative compared with electrical stimulation, but also provides the possibility to study the effects of the local application of neuromodulators and other drugs.

Astroglia as a cellular target for neuroprotection and treatment of neuro-psychiatric disorders.

Astrocytes are key homeostatic cells of the central nervous system. They cooperate with neurons at several levels, including ion and water homeostasis, chemical signal transmission, blood flow regulation, immune and oxidative stress defense, supply of metabolites and neurogenesis. Astroglia is also important for viability and maturation of stem‐cell derived neurons. Neurons critically depend on intrinsic protective and supportive properties of astrocytes. Conversely, all forms of pathogenic stimuli which disturb astrocytic functions compromise neuronal functionality and viability. Support of neuroprotective functions of astrocytes is thus an important strategy for enhancing neuronal survival and improving outcomes in disease states. In this review, we first briefly examine how astrocytic dysfunction contributes to major neurological disorders, which are traditionally associated with malfunctioning of processes residing in neurons. Possible molecular entities within astrocytes that could underpin the cause, initiation and/or progression of various disorders are outlined. In the second section, we explore opportunities enhancing neuroprotective function of astroglia. We consider targeting astrocyte‐specific molecular pathways which are involved in neuroprotection or could be expected to have a therapeutic value. Examples of those are oxidative stress defense mechanisms, glutamate uptake, purinergic signaling, water and ion homeostasis, connexin gap junctions, neurotrophic factors and the Nrf2‐ARE pathway. We propose that enhancing the neuroprotective capacity of astrocytes is a viable strategy for improving brain resilience and developing new therapeutic approaches.

Controlled membrane translocation provides a mechanism for signal transduction and amplification.

Transmission and amplification of chemical signals across lipid bilayer membranes is of profound significance in many biological processes, from the development of multicellular organisms to information processing in the nervous system. In biology, membrane-spanning proteins are responsible for the transmission of chemical signals across membranes, and signal transduction is often associated with an amplified signalling cascade. The ability to reproduce such processes in artificial systems has potential applications in sensing, controlled drug delivery and communication between compartments in tissue-like constructs of synthetic vesicles. Here we describe a mechanism for transmitting a chemical signal across a membrane based on the controlled translocation of a synthetic molecular transducer from one side of a lipid bilayer membrane to the other. The controlled molecular motion has been coupled to the activation of a catalyst on the inside of a vesicle, which leads to a signal-amplification process analogous to the biological counterpart.

Volume Transmission in Central Dopamine and Noradrenaline Neurons and Its Astroglial Targets

Already in the 1960s the architecture and pharmacology of the brainstem dopamine (DA) and noradrenaline (NA) neurons with formation of vast numbers of DA and NA terminal plexa of the central nervous system (CNS) indicated that they may not only communicate via synaptic transmission. In the 1980s the theory of volume transmission (VT) was introduced as a major communication together with synaptic transmission in the CNS. VT is an extracellular and cerebrospinal fluid transmission of chemical signals like transmitters, modulators etc. moving along energy gradients making diffusion and flow of VT signals possible. VT interacts with synaptic transmission mainly through direct receptor-receptor interactions in synaptic and extrasynaptic heteroreceptor complexes and their signaling cascades. The DA and NA neurons are specialized for extrasynaptic VT at the soma-dendrtitic and terminal level. The catecholamines released target multiple DA and adrenergic subtypes on nerve cells, astroglia and microglia which are the major cell components of the trophic units building up the neural-glial networks of the CNS. DA and NA VT can modulate not only the strength of synaptic transmission but also the VT signaling of the astroglia and microglia of high relevance for neuron-glia interactions. The catecholamine VT targeting astroglia can modulate the fundamental functions of astroglia observed in neuroenergetics, in the Glymphatic system, in the central renin-angiotensin system and in the production of long-distance calcium waves. Also the astrocytic and microglial DA and adrenergic receptor subtypes mediating DA and NA VT can be significant drug targets in neurological and psychiatric disease.

Spatiotemporal effects of a bioautocatalytic chemical wave revealed by time-resolved mass spectrometry

Mass spectrometry has been implemented as an on-line detection tool to monitor transmission of chemical signals due to natural processes such as diffusion and convection as well as a bienzymatic autocatalytic process.

Crystal structures of a pentameric ligand-gated ion channel provide a mechanism for activation

Pentameric ligand-gated ion channels mediate fast chemical transmission of nerve signals. The structure of a bacterial proton-gated homolog has been established in its open and locally closed conformations at acidic pH. Here we report its crystal structure at neutral pH, thereby providing the X-ray structures of the two end-points of the gating mechanism in the same pentameric ligand-gated ion channel. The large structural variability in the neutral pH structure observed in the four copies of the pentamer present in the asymmetric unit has been used to analyze the intrinsic fluctuations in this state, which are found to prefigure the transition to the open state. In the extracellular domain (ECD), a marked quaternary change is observed, involving both a twist and a blooming motion, and the pore in the transmembrane domain (TMD) is closed by an upper bend of helix M2 (as in locally closed form) and a kink of helix M1, both helices no longer interacting across adjacent subunits. On the tertiary level, detachment of inner and outer β sheets in the ECD reshapes two essential cavities at the ECD-ECD and ECD-TMD interfaces. The first one is the ligand-binding cavity; the other is close to a known divalent cation binding site in other pentameric ligand-gated ion channels. In addition, a different crystal form reveals that the locally closed and open conformations coexist as discrete ones at acidic pH. These structural results, together with site-directed mutagenesis, physiological recordings, and coarse-grained modeling, have been integrated to propose a model of the gating transition pathway.

Habitat-Dependent Species Recognition in Hybridizing Newts

Many species breed in heterogeneous environments where conditions affecting signaling fidelity may vary. Species recognition may be impaired under particular environmental conditions enhancing the hybridization risk. We investigated the influence of habitat on species recognition efficiency in two hybridizing newts, Lissotriton vulgaris and L. helveticus. The former is considered to be an open habitat species where the two species are in sympatry, whereas the latter also breeds in forest ponds where dissolved humic acids attenuate wavelength transmission, especially in the UV range. Because UV sexual signalling occurs in L. vulgaris, we predicted that species recognition would be reduced in water stained by humic acids. We conducted two-choice preference tests in males and females in stained and clear water. Females of both species preferred the conspecific male in clear water but not in stained water. Males did not show species recognition in either treatment. In both newts, visual species recognition is likely to depend upon habitat. Resorting to chemical communication may offset the loss of visual information but the same environmental factors that affect the transmission of visual signal can also affect the transmission of chemical signals. This environmental disruption of species recognition may account for the general avoidance of forest ponds by L. vulgaris in sympatry with L. helveticus. Stochastic variations of visual conditions in ponds may also explain the ongoing hybridization between two long diverged species that exhibit many and well differentiated sexual ornaments, and more generally between taxa naturally experiencing strong variations of their sensory environment.

Vesicular Neurotransmitter Transporters: An Approach for Studying Transporters With Purified Proteins

Vesicular storage and subsequent release of neurotransmitters are the key processes of chemical signal transmission. In this process, vesicular neurotransmitter transporters are responsible for loading the signaling molecules. The use of a "clean biochemical" approach with purified, recombinant transporters has helped in the identification of novel vesicular neurotransmitter transporters and in the analysis of the control of signal transmission.