Potential Firing Research Articles

Voltage-gated sodium channels in excitable cells as drug targets.

Excitable cells - including neurons, muscle cells and cardiac myocytes - are unique in expressing high densities of voltage-gated sodium (NaV) channels. This molecular adaptation enables these cells to produce action potentials, and is essential to their function. With the advent of the molecular revolution, the concept of 'the' sodium channel has been supplanted by understanding that excitable cells in mammals can express any of nine different forms of sodium channels (NaV1.1-NaV1.9). Selective expression in particular types of cells, together with a key role in controlling action potential firing, makes some of these NaV subtypes especially attractive molecular targets for drug development. Although these different channel subtypes display a common overall structure, differences in their amino acid sequences have provided a basis for the development of subtype-specific drugs. This approach has resulted in exciting progress in the development of drugs for epilepsy, cardiac disorders and pain. In this Review, we discuss recent progress in the development of drugs that selectively target each of the sodium channel subtypes.

Axin-binding domain of glycogen synthase kinase 3β facilitates functional interactions with voltage-gated Na+channel Nav1.6.

Voltage-gated Na+ (Nav) channels are the primary determinants of the action potential in excitable cells. Nav channels rely on a wide and diverse array of intracellular protein-protein interactions (PPIs) to achieve their full function. Glycogen synthase kinase 3β (GSK3β) has been previously identified as a modulator of Nav1.6-encoded currents and neuronal excitability through PPI formation with Nav1.6 and phosphorylation of its C-terminal domain (CTD). Here, we hypothesized that GSK3β functions as a scaffold in a regulatory PPI complex with the Nav1.6 CTD. Mutagenesis screening using the split-luciferase complementation assay indicated that the axin-binding domain (ABD) of GSK3β (262-299) is necessary for complex formation between the Nav1.6 CTD and GSK3β, and that residues within this domain are drivers of GSK3β-mediated regulation of the channel. Overexpression of an ABD-GFP fusion construct in human embryonic kidney 293cells stably expressing Nav1.6 significantly reduced Nav1.6 nanocluster density compared with GFP alone. In addition, overexpression of the ABD-GFP fusion construct ablates GSK3β-mediated potentiation of Nav1.6-encoded currents and alters channel kinetics. Finally, invivo AAV-mediated overexpression of the ABD-GFP construct in the CA1 hippocampal region induced a reduction in maximal action potential firing and an increase in action potential current threshold in a manner resembling previously reported effects of GSK3β silencing in neurons. Taken together, these results not only suggest that GSK3β-mediated regulation of Nav1.6 extends beyond transient phosphorylation but also implicates the ABD as a critical regulatory domain that facilitates GSK3β's functional effects on Nav1.6 and neuronal excitability.

Sub-hourly forecasting of fire potential using machine learning on time series of surface weather variables

Background Rapidly developing pre-fire weather conditions contributing to sudden fire outbreaks can have devastating consequences. Accurate short-term forecasting is important for timely evacuations and effective fire suppression measures. Aims This study aims to introduce a novel machine learning-based approach for forecasting fire potential and to test its performance in the Sunshine Coast region of Queensland, Australia, over a period of 15 years from 2002 to 2017. Methods By analysing real-time data from local weather stations at a sub-hourly temporal resolution, we aimed to identify distinct weather patterns occurring hours to days before fires. We trained random forest machine learning models to classify pre-fire conditions. Key results The models achieved high out-of-sample accuracy, with a 47% higher accuracy than the standard fire danger index for the region. When simulating real forecasting conditions, the model anticipated 75% of the fires (11 out of 15). Conclusions This method provides objective, quantifiable information, enhancing the precision and effectiveness of fire warning systems. Implications The proposed forecasting approach supports decision-makers in implementing timely evacuations and effective fire suppression measures, ultimately reducing the impact of fires.

Where Do Fires Burn More Intensely? Modeling and Mapping Maximum MODIS Fire Radiative Power from Aboveground Biomass by Fuel Type in Mexico

Mapping potential fire intensity is a fundamental tool for fire management planning. Despite the wide use of Fire Radiative Power (FRP) as an indicator of expected fire intensity and fire emissions, very few studies have spatially analyzed the role of remotely sensed proxies of vegetation productivity to explain FRP. The current study aimed at modeling and mapping the relationships between aboveground biomass and Moderate Resolution Imaging Spectroradiometer (MODIS) maximum FRP, at 1 km pixel, in 2011–2020, for each of 46 fuel regions in the entirety of Mexico. Maximum FRP–biomass relationships supported a novel hypothesis of varying constraints of fire intensity. In lower-productivity areas, such as semiarid shrub- and grass-dominated ecosystems, fine fuel loads limited fire occurrence and FRP was positively related to biomass. In the more productive areas, such as temperate or tropical forests, a humped relationship of FRP against biomass was observed, suggesting an intermediate-productivity hypothesis of maximum fire intensity within those regions. In those areas, the highest fire intensity was observed in the intermediate biomass areas, where surface (timber understory) and crown fuel availability, together with higher wind penetration, can result in crown fires. On the contrary, within the most productive areas, the lowest intensity occurred, likely due to weather and fuel (timber litter) limitations.

Infra-red remote sensing inversion technology for hidden fire sources in mine fire areas – joint GSO and PSO algorithms

Mine fires have always been a serious challenge to mining safety, and the existence of hidden fire sources in mine fire areas is one of the key factors causing coal seam spontaneous combustion. Hidden fire source refers to the potential fire source that cannot be easily detected by traditional detection means in the mine. They gradually accumulate heat in the complex environment of the mine. If not detected and dealt with in time, it can lead to a serious mine fire. However, traditional fire detection methods are difficult to detect hidden fire sources in the early stages, and in severe cases, can lead to catastrophic mine fires. Therefore, this study proposes a combined firefly optimisation algorithm and particle swarm optimisation algorithm for infra-red remote sensing inversion of hidden fire sources in mine fire areas, and verifies it. The results indicated that the inversion model could accurately obtain the location and intensity information of hidden fire sources. The joint algorithm exhibited higher accuracy and faster convergence speed during the training process, with an accuracy of 97.64% and an average temperature error of only 0.73°C. The average accuracy of the inversion model optimised by the joint algorithm improved to 99.48%, the average calculation time reduced to 7.25 seconds, and the efficiency has been improved by 51.92%. This study innovatively combines infra-red remote sensing inversion technology with intelligent algorithms to improve the efficiency and accuracy of detecting hidden fire sources in mine fire areas, which helps to reduce safety risks and economic losses caused by mine fires.

Noise-induced hearing loss enhances Ca2+-dependent spontaneous bursting activity in lateral cochlear efferents.

Exposure to loud and/or prolonged noise damages cochlear hair cells and triggers downstream changes in synaptic and electrical activity in multiple brain regions, resulting in hearing loss and altered speech comprehension. It remains unclear however whether or not noise exposure also compromises the cochlear efferent system, a feedback pathway in the brain that fine-tunes hearing sensitivity in the cochlea. We examined the effects of noise-induced hearing loss on the spontaneous action potential (AP) firing pattern in mouse lateral olivocochlear (LOC) neurons. This spontaneous firing exhibits a characteristic burst pattern dependent on Ca2+ channels, and we therefore also examined the effects of noise-induced hearing loss on the function of these and other ion channels. The burst pattern was sustained by an interaction between inactivating Ca2+ currents contributed largely by L-type channels, and steady outward currents mediated by Ba2+-sensitive inwardly-rectifying and two-pore domain K+ channels. One week following exposure to loud broadband noise, hearing thresholds were significantly elevated, and the duration of AP bursts was increased, likely as a result of an enhanced Ca2+ current. Additional effects of noise-induced hearing loss included alteration of Ca2+-dependent inactivation of Ca2+ currents and a small elevation of outward K+ currents. We propose that noise-induced hearing loss enhances efferent activity and may thus amplify the release of neurotransmitters and neuromodulators (i.e., neuropeptides), potentially altering sensory coding within the damaged cochlea.

Design and Development of LPG Monitoring and Leakage Detection System

This study focuses the design and developed of an LPG Monitoring and Leakage Detection System, with the goal of enhancing safety in areas where LPG is utilized by identifying gas leaks and monitoring gas levels in real time. The project employs an Arduino-based sensor system to automate the detection of gas leaks, emphasizing functionality, durability, and safety. The proposed system is assessed for its effectiveness in providing early warnings to avert potential accidents, fires, or health hazards linked to LPG leaks. The system was tested by 30 participants who regularly used LPG for cooking and possessed basic electronics knowledge, enabling them to evaluate the project's materials, functionality, and operation. The results indicated that the system is highly effective in detecting LPG and other combustible gases, which can pose significant safety risks. The device includes a display that indicates the amount of gas detected and the concentration percentage, offering real-time data on gas levels. In the event of a gas leak, the system activates a buzzer to alert users immediately, thereby minimizing the risk of accidents

Short-term impacts of operational fuel treatments on modelled fire behaviour and effects in seasonally dry forests of British Columbia, Canada

Background In response to increasing risk of extreme wildfire across western North America, forest managers are proactively implementing fuel treatments. Aims We assessed the efficacy of alternative combinations of thinning, pruning and residue fuel management to mitigate potential fire behaviour and effects in seasonally dry forests of interior British Columbia, Canada. Methods Across five community forests, we measured stand attributes before and after fuel treatments in 2021 and 2022, then modelled fire behaviour and effects using the Fire and Fuels Extension to the Forest Vegetation Simulator. Key results For our study area, field measurements combined with fire behaviour modelling indicated: (1) low-intensity thinning from below reduced potential of passive crown fire, whereas high-intensity thinning reduced potential of passive and active crown fire; (2) pruning after thinning from below did not further reduce potential of passive crown fire; and (3) chipping or pile burning of residue fuel mitigated potential of passive crown fire, but fire effects associated with chipping remain a concern. Conclusions and implications There is limited prior research on the impacts of fuel treatments in western Canada. This research contributes to better understanding the potential impacts of fuel treatments in the fire-prone forests of interior British Columbia.

GABAB Receptor Modulation of Membrane Excitability in Human Pluripotent Stem Cell-Derived Sensory Neurons by Baclofen and α-Conotoxin Vc1.1.

GABAB receptor (GABABR) activation is known to alleviate pain by reducing neuronal excitability, primarily through inhibition of high voltage-activated (HVA) calcium (CaV2.2) channels and potentiating G protein-coupled inwardly rectifying potassium (GIRK) channels. Although the analgesic properties of small molecules and peptides have been primarily tested on isolated murine dorsal root ganglion (DRG) neurons, emerging strategies to develop, study, and characterise human pluripotent stem cell (hPSC)-derived sensory neurons present a promising alternative. In this study, hPSCs were efficiently differentiated into peripheral DRG-induced sensory neurons (iSNs) using a combined chemical and transcription factor-driven approach via a neural crest cell intermediate. Molecular characterisation and transcriptomic analysis confirmed the expression of key DRG markers such as BRN3A, ISLET1, and PRPH, in addition to GABABR and ion channels including CaV2.2 and GIRK1 in iSNs. Functional characterisation of GABABR was conducted using whole-cell patch clamp electrophysiology, assessing neuronal excitability under current-clamp conditions in the absence and presence of GABABR agonists baclofen and α-conotoxin Vc1.1. Both baclofen (100 μM) and Vc1.1 (1 μM) significantly reduced membrane excitability by hyperpolarising the resting membrane potential and increasing the rheobase for action potential firing. In voltage-clamp mode, baclofen and Vc1.1 inhibited HVA Ca2+ channel currents, which were attenuated by the selective GABABR antagonist CGP 55845. However, modulation of GIRK channels by GABABRs was not observed in the presence of baclofen or Vc1.1, suggesting that functional GIRK1/2 channels were not coupled to GABABRs in hPSC-derived iSNs. This study is the first to report GABABR modulation of membrane excitability in iSNs by baclofen and Vc1.1, highlighting their potential as a future model for studying analgesic compounds.

Evaluation of mechanisms involved in regulation of intrinsic excitability by extracellular calcium in CA1 pyramidal neurons of rat.

It is well recognized that changes in the extracellular concentration of calcium ions influence the excitability of neurons, yet what mechanism(s) mediate these effects is still a matter of debate. Using patch-clamp recordings from rat hippocampal CA1 pyramidal neurons, we examined the contribution of G-proteins and intracellular calcium-dependent signaling mechanisms to changes in intrinsic excitability evoked by altering the extracellular calcium concentration from physiological (1.2 mM) to a commonly used experimental (2 mM) level. We find that the inhibitory effect on intrinsic excitability of calcium ions is mainly expressed as an increased threshold for action potential firing (with no significant effect on resting membrane potential) that is not blocked by either the G-protein inhibitor GDPβS or the calcium chelator BAPTA. Our results therefore argue that in the concentration range studied, G-protein coupled calcium-sensing receptors, non-selective cation conductances, and intracellular calcium signaling pathways are not involved in mediating the effect of extracellular calcium ions on intrinsic excitability. Analysis of the derivative of the action potential, dV/dt versus membrane potential, indicates a current shift towards more depolarized membrane potentials at the higher calcium concentration. Our results are thus consistent with a mechanism in which extracellular calcium ions act directly on the voltage-gated sodium channels by neutralizing negative charges on the extracellular surface of these channels to modulate the threshold for action potential activation.

Conotoxin kM-RIIIJ reveals interplay between Kv1-channels and persistent sodium currents in proprioceptive DRG neurons

Voltage-gated potassium channels (VGKCs) comprise the largest and most complex families of ion channels. Approximately 70 genes encode VGKC alpha subunits, which assemble into functional tetrameric channel complexes. These subunits can also combine to form heteromeric channels, significantly expanding the potential diversity of VGKCs. The functional expression and physiological role of heteromeric K-channels have remained largely unexplored due to the lack of tools to probe their functions. Conotoxins, from predatory cone snails, have high affinity and specificity for heteromeric combinations of K-channels and show great promise for defining their physiological roles. In this work, using conotoxin kM-RIIIJ as a pharmacological probe, we explore the expression and physiological functions of heteromeric Kv1.2 channels using constellation pharmacology platform. We report that heteromers of Kv1.2/1.1 are highly expressed in proprioceptive neurons found in the dorsal root ganglion (DRG). Inhibition of Kv1.2/1.1 heteromers leads to an influx of calcium ions, suggesting that these channels regulate neuronal excitability. We also present evidence that Kv1.2/1.1 heteromers counteract persistent sodium currents, and that inhibiting these channels leads to tonic firing of action potentials. Additionally, kM-RIIIJ impaired proprioception in mice, uncovering a previously unrecognized physiological function of heteromeric Kv1.2/1.1 channels in proprioceptive sensory neurons of the DRG.

Action Potential Firing Patterns Regulate Dopamine Release via Voltage-Sensitive Dopamine D2 Autoreceptors in Mouse Striatum In Vivo.

Dopamine (DA) in the striatum is vital for motor and cognitive behaviors. Midbrain dopaminergic neurons generate both tonic and phasic action potential (AP) firing patterns in behavior mice. Besides AP numbers, whether and how different AP firing patterns per se modulate DA release remain largely unknown. Here by using in vivo and ex vivo models, it is shown that the AP frequency per se modulates DA release through the D2 receptor (D2R), which contributes up to 50% of total DA release. D2R has a voltage-sensing site at D131 and can be deactivated in a frequency-dependent manner by membrane depolarization. This voltage-dependent D2R inhibition of DA release is mediated via the facilitation of voltage-gated Ca2+ channels (VGCCs). Collectively, this work establishes a novel mechanism that APs per se modulate DA overflow by disinhibiting the voltage-sensitive autoreceptor D2R and thus the facilitation of VGCCs, providing a pivotal pathway and insight into mammalian DA-dependent functions in vivo.

Layered double hydroxide reinforced thermal expansion fire extinguishing agent for potential solid fire prevention

In this work, phosphorus-decorated Zn-Al-CO3 layered double hydroxide (PLDH) was prepared via a co-precipitation strategy and thus introduced into intumescent flame retardant dispersion to fabricate PLDH-reinforced thermal expansion fire extinguishing agent (FEA@PLDH). It was found that the phosphorus-containing unit was successfully anchored onto the PLDH. The prepared FEA@PLDH solution with a viscosity of 146 mPa·s exhibited good interfacial compatibility with the ethylene-vinyl acetate (EVA) surface. Taking advantage of the synergistic catalytic carbonization and expanded insulating barrier effects of FEA@PLDH, the corresponding coated EVA (EVA-FEA@PLDH1) with 1 wt% of PLDH could form a continuous and compact carbonaceous block layer under fire or high-temperature conditions. Meanwhile, the LOI for EVA-FEA@PLDH1 was increased from 22.0% to 32.0% and reached the UL-94 rating of V0. Moreover, EVA-FEA@PLDH1 showed delayed TTI (77 s) and TPHRR (146 s), with 6% and 44% reductions in THR and TSP, respectively, and 43% increment in residual char, as compared to the EVA-FEA. In addition, fire resistance experiment revealed that EVA-FEA@PLDH1 could withstand the ∼1300 °C flame for 467 s longer than that of the EVA-FEA (171 s). This research provides an intriguing fire extinguishing agent for the potential fire prevention of flammable polymer materials.

Silacrown ethers as ion transport modifiers and preliminary observations of cardiovascular cell line response.

Crown ethers have been shown to have physiological effects ascribed to their ionophoric properties. However, high levels of toxicity precluded interest in their evaluation as therapeutic agents. We prepared new silacrown analogs of crown ethers. These initial studies focused on examples of large ring silacrown ethers having at least fourteen ring atoms with at least one lipophilic or hydrophobic substituent on the ring and/or on the silicon atom. The synthesis of silacrown ethers, ionophoric behavior, toxicity studies, and preliminary pharmacodynamic studies in cardiac myocyte cell lines are presented and compared to their carbon analogs. We report the effects of these compounds in HL-1 cells, an atrial muscle cell line with plasma membrane and sarcoplasmic reticulum Ca2+ channels that give rise to spontaneous Ca2+ transients driven by action potentials. Dicyclohexano-18-crown-6 and the silacrown equivalent dimethylsila-17-cyclohexanocrown-6 were both found to rapidly inhibit the Ca2+ transients after acute treatment, and these effects were reversed when extracellular KCl was increased to cause plasma membrane depolarization. The data suggest that the silacrowns can mimic the effects of crown ethers with similar ring sizes, and this appears to be due to their effects on membrane potential and suppression of action potential firing.

Intrinsic adaptive plasticity in mouse and human sensory neurons.

In response to changes in activity induced by environmental cues, neurons in the central nervous system undergo homeostatic plasticity to sustain overall network function during abrupt changes in synaptic strengths. Homeostatic plasticity involves changes in synaptic scaling and regulation of intrinsic excitability. Increases in spontaneous firing and excitability of sensory neurons are evident in some forms of chronic pain in animal models and human patients. However, whether mechanisms of homeostatic plasticity are engaged in sensory neurons of the peripheral nervous system (PNS) is unknown. Here, we show that sustained depolarization (induced by 24-h incubation in 30 mM KCl) induces compensatory changes that decrease the excitability of mouse and human sensory neurons without directly opposing membrane depolarization. Voltage-clamp recordings show that sustained depolarization produces no significant alteration in voltage-gated potassium currents, but a robust reduction in voltage-gated sodium currents, likely contributing to the overall decrease in neuronal excitability. The compensatory decrease in neuronal excitability and reduction in voltage-gated sodium currents reversed completely following a 24-h recovery period in a normal medium. Similar adaptive changes were not observed in response to 24 h of sustained action potential firing induced by optogenetic stimulation at 1 Hz, indicating the need for prolonged depolarization to drive engagement of this adaptive mechanism in sensory neurons. Our findings show that mouse and human sensory neurons are capable of engaging adaptive mechanisms to regulate intrinsic excitability in response to sustained depolarization in a manner similar to that described in neurons in the central nervous system.

Was fire use a cultural trait of the Gravettian? New micro-archaeological data from Fuente del Salín cave (Val de San Vicente, Cantabria)

Micro-archaeological data from sites located in central and eastern Europe show that, in comparison with other Upper Paleolithic hunter-gatherers, Gravettian foragers used fire more intensively and for a wider range of purposes. At these sites, this shift in pyrotechnology overlaps with the onset of periglacial conditions. Gravettian occupations of non-periglacial regions have been poorly investigated with micro-archaeological methods, and it remains to be further demonstrated whether these foragers also made a similar intensive and multipurpose use of fire. To further investigate this topic, we studied the sequence preserved at the cave of Fuente del Salín, in Cantabria, where previous excavations unearthed potential fire residues of Gravettian age. Using micromorphology, µ-X-ray fluorescence, and Scanning Electron Microscopy we reconstructed multiple phases of human visits to the site. Our results show that, during the main Gravettian occupation, foragers made intensive use of fire, as indicated by abundant heated bones and seashells, charcoals, amorphous char, fat-derived char, and in situ remains of potential stacked open hearths as well as burnt grass beddings. The intensive burning, systematic reuse of combustion features, and multiple purposes of the fires at Fuente del Salín are comparable with Gravettian sites from central and eastern Europe, indicating that these fire-use behaviors probably do not reflect a regional adaptation to periglacial environments but a cultural trait of the Gravettian tradition across Europe.

The cation channel mechanisms of subthreshold inward depolarizing currents in the mice VTA dopaminergic neurons and their roles in the chronic-stress-induced depression-like behavior

The slow-intrinsic-pacemaker dopaminergic (DA) neurons originating in the ventral tegmental area (VTA) are implicated in various mood- and emotion-related disorders, such as anxiety, fear, stress and depression. Abnormal activity of projection-specific VTA DA neurons is the key factor in the development of these disorders. Here, we describe the crucial role of the NALCN and TRPC6, non-selective cation channels in mediating the subthreshold inward depolarizing current and driving the firing of action potentials of VTA DA neurons in physiological conditions. Furthermore, we demonstrate that down-regulation of TRPC6 protein expression in the VTA DA neurons likely contributes to the reduced activity of projection-specific VTA DA neurons in chronic mild unpredictable stress (CMUS) depressive mice. In consistent with these, selective knockdown of TRPC6 channels in the VTA DA neurons conferred mice with depression-like behavior. This current study suggests down-regulation of TRPC6 expression/function is involved in reduced VTA DA neuron firing and chronic stress-induced depression-like behavior of mice.

The cation channel mechanisms of subthreshold inward depolarizing currents in the mice VTA dopaminergic neurons and their roles in the chronic-stress-induced depression-like behavior.

The slow-intrinsic-pacemaker dopaminergic (DA) neurons originating in the ventral tegmental area (VTA) are implicated in various mood- and emotion-related disorders, such as anxiety, fear, stress and depression. Abnormal activity of projection-specific VTA DA neurons is the key factor in the development of these disorders. Here, we describe the crucial role of the NALCN and TRPC6, non-selective cation channels in mediating the subthreshold inward depolarizing current and driving the firing of action potentials of VTA DA neurons in physiological conditions. Furthermore, we demonstrate that down-regulation of TRPC6 protein expression in the VTA DA neurons likely contributes to the reduced activity of projection-specific VTA DA neurons in chronic mild unpredictable stress (CMUS) depressive mice. In consistent with these, selective knockdown of TRPC6 channels in the VTA DA neurons conferred mice with depression-like behavior. This current study suggests down-regulation of TRPC6 expression/function is involved in reduced VTA DA neuron firing and chronic stress-induced depression-like behavior of mice.

Mapping Variable Wildfire Source Areas Through Inverse Modeling

Global climate change is leading to increased wildfire activity in many parts of the world, and with increasing development, a heightened threat to communities in the wildland urban interface. Evaluating the potential for fire to affect communities and critical infrastructure is essential for effective response decision-making and resource prioritization, including evacuation planning, with changing weather conditions during the fire season. Using a receptor–pathway–source assessment framework, we estimate the potential source area from which a wildfire could spread to a community in British Columbia by projecting fire growth outward from the community’s perimeter. The outer perimeter of the source area is effectively an evacuation trigger line for the forecast period. The novel aspects of our method are inverting fire growth in both space and time by reversing the wind direction, the time course of hourly weather, and slope and aspect inputs to a time-evolving fire growth simulation model Prometheus. We also ran a forward simulation from the perimeter of a large fire that was threatening the community to the community edge and back. In addition, we conducted a series of experiments to examine the influence of varying environmental conditions and ignition patterns on the invertibility of fire growth simulations. These cases demonstrate that time-evolving fire growth simulations can be inverted for practical purposes, although caution is needed when interpreting results in areas with extensive non-fuel cover or complex community perimeters. The advantages of this method over conventional simulation from a fire source are that it can be used for pre-attack planning before fire arrival, and following fire arrival, it does not require having an up-to-the-minute map of the fire location. The advantage over the use of minimum travel time methods for inverse modeling is that it allows for changing weather during the forecast period. This procedure provides a practical tool to inform real-time wildfire response decisions around communities, including resource allocation and evacuation planning, that could be implemented with several time-evolving fire growth models.

Structure-guided design of a peripherally restricted chemogenetic system.

Designer receptors exclusively activated by designer drugs (DREADDs) are chemogenetic tools for remotely controlling cellular signaling, neural activity, behavior, and physiology. Using a structure-guided approach, we provide a peripherally restricted Gi-DREADD, hydroxycarboxylic acid receptor DREADD (HCAD), whose native receptor is minimally expressed in the brain, and a chemical actuator that does not cross the blood-brain barrier (BBB). This was accomplished by combined mutagenesis, analoging via an ultra-large make-on-demand library, structural determination of the designed DREADD receptor via cryoelectron microscopy (cryo-EM), and validation of HCAD function. Expression and activation of HCAD in dorsal root ganglion (DRG) neurons inhibit action potential (AP) firing and reduce both acute and tissue-injury-induced inflammatory pain. The HCAD chemogenetic system expands the possibilities for studying numerous peripheral systems with little adverse effects on the central nervous system (CNS). The structure-guided approach used to generate HCAD also has the potential to accelerate the development of emerging chemogenetic tools for basic and translational sciences.