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Lithium–sulfur batteries hold great promise as energy storage systems, but the shuttle effect of lithium polysulfides (LiPS) and large volume variation limit their capacity and cycle life. We have developed CoFe alloy wrapped in N-doped porous carbon spheres (e-CF@NC) with a core–shell structure through simple copolymerization and pyrolysis. The nitrogen-doped porous carbon shell provides electron and ion transport channels and more active sites for electrolyte ion adsorption. The high chemically stable carbon can limit the segregation of polysulfides, further improving the battery cycling stability. Besides, the inside CoFe alloy particles catalyze the conversion between LiPS and Li2S, speeding up reaction kinetics and reducing solvation of active sites. Consequently, lithium–sulfur batteries with e-CF@NC-2 as the cathode display a high initial specific capacity of 1146 mA h g−1 at 0.1 C, excellent rate performance (891 mA h g−1 at 1 C, 741 mA h g−1 at 2 C), and satisfied cycle stability (average capacity decay rate of 0.033% per cycle at 1 C for 300 cycles), demonstrating significant application potential. [ABSTRACT FROM AUTHOR]

To mimic the intricate and adaptive functionalities of biological ion channels, electrohydrodynamic ion transport has been studied extensively, albeit mostly, across uniformly charged nanochannels. Here, we analyze the ion transport under coupled electric field and pressure across heterogeneously charged nanopores with oppositely charged sections on their lateral surface. We only consider such pores with symmetric hourglass-like and cylindrical shapes to focus on the effects of the non-uniform surface charge distribution. Finite-element simulations of a continuum model demonstrate that a pressure applied in either direction of the pore-axis equally suppresses or amplifies the ionic conductance, depending on the electric field polarity, by distorting the quasi-static distribution of ions in the pore. The resulting anomalous mechanical deactivation and activation of ionic current under opposite voltage biases exhibit the functional modularity of our setup, while their intensities are highly tunable, substantially greater than those of analogous behaviors in other nanochannels, and fundamentally correlated to ionic current rectification (ICR) in our pores. A detailed study of ICR subsequently reveals its counterintuitive non-monotonous variations, in the pores, with the magnitude of applied voltage and the pore length, that can help optimize their diode-like behavior. We further illustrate that while the hourglass-shaped nanopores yield the more efficient mechanical suppressors of ion transport, their cylindrical analogs are the superior rectifiers and mechanical amplifiers of ion conduction. Therefore, this article provides a blueprint for the strategic design of nanofluidic circuits to attain a robust, modular, and tunable control of ion transport under external electrical and mechanical stimuli. [ABSTRACT FROM AUTHOR]

Inspired by biological channels, achieving precise separation of ion/water and ion/ion requires finely tuned pore sizes at molecular dimensions and deliberate exposure of charged groups. Covalent organic frameworks (COFs), a class of porous crystalline materials, offer well-defined nanoscale pores and diverse structures, making them excellent candidates for nanofluidic channels that facilitate ion and water transport. In this study, we perform molecular simulations to investigate the structure and kinetics of water and ions confined within the typical COFs with varied exposure of charged groups. The COFs exhibit vertically arrayed nanochannels, enabling diffusion coefficients of water molecules within COFs to remain within the same order of magnitude as in the bulk. The motion of water molecules manifests in two distinct modes, creating a mobile hydration layer around acid groups. The ion diffusion within COFs displays a notable disparity between monovalent (M+) and divalent (M2+) cations. As a result, the selectivity of M+/M2+ can exceed 100, while differentiation among M+ is less pronounced. In addition, our simulations indicate a high rejection (R > 98%) in COFs, indicating their potential as ideal materials for desalination. The chemical flexibility of COFs indicates that would hold significant promise as candidates for advanced artificial ion channels and separation membranes. [ABSTRACT FROM AUTHOR]

Thermosensation requires the activation of a unique collection of ion channels and receptors that work in concert to transmit thermal information. It is widely accepted that transient receptor potential melastatin 8 (TRPM8) activation is required for normal cold sensing; however, recent studies have illuminated major roles for other ion channels in this important somatic sensation. In addition to TRPM8, other TRP channels have been reported to contribute to cold transduction mechanisms in diverse sensory neuron populations, with both leak- and voltage-gated channels being identified for their role in the transmission of cold signals. Whether the same channels that contribute to physiological cold sensing also mediate noxious cold signaling remains unclear; however, recent work has found a conserved role for the kainite receptor, GluK2, in noxious cold sensing across species. Additionally, cold-sensing neurons likely engage in functional crosstalk with nociceptors to give rise to cold pain. This Review will provide an update on our understanding of the relationship between various ion channels in the transduction and transmission of cold and highlight areas where further investigation is required.

The proton transport in one-dimensional (1D) confined water chains has been extensively studied as a model for ion channels in cell membrane and fuel cell. However, the mechanistic understanding of the proton transfer (PT) process in 1D water chains remains incomplete. In this study, we demonstrate that the two limiting structures of the hydrated excess proton, H5O2+ (Zundel) and H3O+ (linear H7O3+), undergo a change in dominance as the water chain grows, causing two co-existing and opposing PT mechanisms. Specifically, H5O2+ is stable in the middle of the chain, whereas H3O+ serves as a transition state (TS). Except for this region, H3O+ is stabilized while H5O2+ serves as a TS. The interaction analysis shows that the electrostatic interaction plays a crucial role in the difference in PT mechanisms. Our work fills a knowledge gap between the various PT mechanisms reported in bulk water and long 1D water chains, contributing to a deeper understanding of biological ion channels at the atomic level. [ABSTRACT FROM AUTHOR]

Ion channels are proteins that play a significant role in physiological processes, including neuronal excitability and signal transduction. However, the precise mechanisms by which these proteins facilitate ion diffusion through cell membranes are not well understood. This is because experimental techniques to characterize ion channel activity operate on a time scale too large to understand the role of the various protein conformations on diffusion. Meanwhile, computational approaches operate on a time scale too short to rationalize the observed behavior at the microscopic scale. In this paper, we present a continuous-time random walk model that aims to bridge the scales between the atomistic models of ion channels and the experimental measurement of their conductance. We show how diffusion slows down in complex systems by using 3D lattices that map out the pore geometry of two channels: Nav1.7 and gramicidin. We also introduce spatial and dynamic site disorder to account for system heterogeneity beyond the mean field approximation. Computed diffusion coefficients show that an increase in spatial disorder slows down diffusion kinetics, while dynamic disorder has the opposite effect. Our results imply that microscopic or phenomenological models based on the potential of mean force data overlook the functional importance of protein dynamics on ion diffusion through channels. [ABSTRACT FROM AUTHOR]

Ion channels play key roles in human physiology and are important targets in drug discovery. The atomic-scale structures of ion channels provide invaluable insights into a fundamental understanding of the molecular mechanisms of channel gating and modulation. Recent breakthroughs in deep learning-based computational methods, such as AlphaFold, RoseTTAFold, and ESMFold have transformed research in protein structure prediction and design. We review the application of AlphaFold, RoseTTAFold, and ESMFold to structural modeling of ion channels using representative voltage-gated ion channels, including human voltage-gated sodium (NaV) channel - NaV1.8, human voltage-gated calcium (CaV) channel - CaV1.1, and human voltage-gated potassium (KV) channel - KV1.3. We compared AlphaFold, RoseTTAFold, and ESMFold structural models of NaV1.8, CaV1.1, and KV1.3 with corresponding cryo-EM structures to assess details of their similarities and differences. Our findings shed light on the strengths and limitations of the current state-of-the-art deep learning-based computational methods for modeling ion channel structures, offering valuable insights to guide their future applications for ion channel research.

Cells establish the asymmetrical distribution of phospholipids and alter their distribution by phospholipid scrambling (PLS) to adapt to environmental changes. Here, we demonstrate that a protein complex, consisting of the ion channel Tmem63b and the thiamine transporter Slc19a2, induces PLS upon calcium (Ca2+) stimulation. Through revival screening using a CRISPR sgRNA library on high PLS cells, we identify Tmem63b as a PLS-inducing factor. Ca2+ stimulation-mediated PLS is suppressed by deletion of Tmem63b, while human disease-related Tmem63b mutants induce constitutive PLS. To search for a molecular link between Ca2+ stimulation and PLS, we perform revival screening on Tmem63b-overexpressing cells, and identify Slc19a2 and the Ca2+-activated K+ channel Kcnn4 as PLS-regulating factors. Deletion of either of these genes decreases PLS activity. Biochemical screening indicates that Tmem63b and Slc19a2 form a heterodimer. These results demonstrate that a Tmem63b/Slc19a2 heterodimer induces PLS upon Ca2+ stimulation, along with Kcnn4 activation.

Connexin hemichannels were identified as the first members of the eukaryotic large-pore channel family that mediate permeation of both atomic ions and small molecules between the intracellular and extracellular environments. The conventional view is that their pore is a large passive conduit through which both ions and molecules diffuse in a similar manner. In stark contrast to this notion, we demonstrate that the permeation of ions and of molecules in connexin hemichannels can be uncoupled and differentially regulated. We find that human connexin mutations that produce pathologies and were previously thought to be loss-of-function mutations due to the lack of ionic currents are still capable of mediating the passive transport of molecules with kinetics close to those of wild-type channels. This molecular transport displays saturability in the micromolar range, selectivity, and competitive inhibition, properties that are tuned by specific interactions between the permeating molecules and the N-terminal domain that lies within the pore-a general feature of large-pore channels. We propose that connexin hemichannels and, likely, other large-pore channels, are hybrid channel/transporter-like proteins that might switch between these two modes to promote selective ion conduction or autocrine/paracrine molecular signaling in health and disease processes.

The liquid-to-vapor transition can occur under unexpected conditions in nanopores, opening the door to fundamental questions and new technologies. The physics of boiling in confinement is progressively introduced, starting from classical nucleation theory, passing through nanoscale effects, and terminating with the material and external parameters that affect the boiling conditions. The relevance of boiling in specific nanoconfined systems is discussed, focusing on heterogeneous lyophobic systems, chromatographic columns, and ion channels. The current level of control of boiling in nanopores enabled by microporous materials such as metal organic frameworks and biological nanopores paves the way to thrilling theoretical challenges and to new technological opportunities in the fields of energy, neuromorphic computing, and sensing. [ABSTRACT FROM AUTHOR]

In search of the cause behind the similarities often seen in the fragmentation of PANHs, vacuum ultraviolet (VUV) photodissociation of two pairs of isomers quinoline–isoquinoline and 2-naphthylamine-3-methyl-quinoline are studied using the velocity map imaging technique. The internal energy dependence of all primary fragmentation channels is obtained for all four target molecules. The decay dynamics of the four molecules is studied by comparing their various experimental signatures. The dominant channel for the first pair of isomers is found to be hydrogen cyanide (HCN) neutral loss, while the second pair of isomers lose HCNH neutral as its dominant channel. Despite this difference in their primary decay products and the differences in the structures of the four targets, various similarities in their experimental signatures are found, which could be explained by isomerization mechanisms to common structures. The fundamental role of these isomerization in controlling different dissociative channels is explored via a detailed analysis of the experimental photoelectron–photoion coincidences and the investigation of the theoretical potential energy surface. These results add to the notion of a universal PANH fragmentation mechanism and suggests the seven member isomerization as a key candidate for this universal mechanism. The balance between isomerization, dissociation, and other key mechanistic processes in the reaction pathways, such as hydrogen migrations, is also highlighted for the four molecules. [ABSTRACT FROM AUTHOR]

The collective migration of keratinocytes during wound healing requires both the generation and transmission of mechanical forces for individual cellular locomotion and the coordination of movement across cells. Leader cells along the wound edge transmit mechanical and biochemical cues to ensuing follower cells, ensuring their coordinated direction of migration across multiple cells. Despite the observed importance of mechanical cues in leader cell formation and in controlling coordinated directionality of cell migration, the underlying biophysical mechanisms remain elusive. The mechanically-activated ion channel PIEZO1 was recently identified to play an inhibitory role during the reepithelialization of wounds. Here, through an integrative experimental and mathematical modeling approach, we elucidate PIEZO1's contributions to collective migration. Time-lapse microscopy reveals that PIEZO1 activity inhibits leader cell formation at the wound edge. To probe the relationship between PIEZO1 activity, leader cell formation and inhibition of reepithelialization, we developed an integrative 2D continuum model of wound closure that links observations at the single cell and collective cell migration scales. Through numerical simulations and subsequent experimental validation, we found that coordinated directionality plays a key role during wound closure and is inhibited by upregulated PIEZO1 activity. We propose that PIEZO1-mediated retraction suppresses leader cell formation which inhibits coordinated directionality between cells during collective migration.

The inner ear is the hub where hair cells (HCs) transduce sound, gravity, and head acceleration stimuli to the brain. Hearing and balance rely on mechanosensation, the fastest sensory signals transmitted to the brain. The mechanoelectrical transducer (MET) channel is the entryway for the sound-balance-brain interface, but the channel-complex composition is not entirely known. Here, we report that the mouse utilizes Piezo1 (Pz1) and Piezo2 (Pz2) isoforms as MET-complex components. The Pz channels, expressed in HC stereocilia, and cell lines are co-localized and co-assembled with MET complex partners. Mice expressing non-functional Pz1 and Pz2 at the ROSA26 locus have impaired auditory and vestibular traits that can only be explained if the Pzs are integral to the MET complex. We suggest that Pz subunits constitute part of the MET complex and that interactions with other MET complex components yield functional MET units to generate HC MET currents.

[Display omitted] Hypothesis: We hypothesize that simultaneous incorporation of ion channel peptides (in this case, potassium channel as a model) and hydrophobic magnetite Fe 3 O 4 nanoparticles (hFe 3 O 4 NPs) within lipidic hexagonal mesophases, and aligning them using an external magnetic field can significantly enhance ion transport through lipid membranes. Experiments: In this study, we successfully characterized the incorporation of gramicidin membrane ion channels and hFe 3 O 4 NPs in the lipidic hexagonal structure using SAXS and cryo-TEM methods. Additionally, we thoroughly investigated the conductive characteristics of freestanding films of lipidic hexagonal mesophases, both with and without gramicidin potassium channels, utilizing a range of electrochemical techniques, including impedance spectroscopy, normal pulse voltammetry, and chronoamperometry. Findings: Our research reveals a state-of-the-art breakthrough in enhancing ion transport in lyotropic liquid crystals as matrices for integral proteins and peptides. We demonstrate the remarkable efficacy of membranes composed of hexagonal lipid mesophases embedded with K+ transporting peptides. This enhancement is achieved through doping with hFe 3 O 4 NPs and exposure to a magnetic field. We investigate the intricate interplay between the conductive properties of the lipidic hexagonal structure, hFe 3 O 4 NPs, gramicidin incorporation, and the influence of Ca2+ on K+ channels. Furthermore, our study unveils a new direction in ion channel studies and biomimetic membrane investigations, presenting a versatile model for biomimetic membranes with unprecedented ion transport capabilities under an appropriately oriented magnetic field. These findings hold promise for advancing membrane technology and various biotechnological and biomedical applications of membrane proteins. [ABSTRACT FROM AUTHOR]

Myofascial orofacial pain, traditionally viewed as a nociceptive pain condition, also exhibits characteristics consistent with nociplastic pain—pain arising from altered nociception without clear evidence of tissue damage. Evidence supporting myofascial orofacial pain as nociplastic pain includes clinical observations of central sensitisation in patients, even in the absence of visible inflammation. Sensitisation is characterised by heightened responsiveness of nociceptive neurons to normal stimuli or activation by normally subthreshold stimuli, either in the peripheral or central nervous system. It is linked to maladaptive neuroplastic changes, including increased functional potentiation and altered expression of neuronal ion channels, receptors and neurotransmitters. This mini-review presents insights from existing evidence regarding altered nociception and its relation to changes in the expression of neuronal ion channels in myofascial orofacial pain. Increased expression of transient receptor potential (TRP) vanilloid 1 channels (TRPV1), TRPV4, TRP ankyrin 1 channels (TRPA1), Piezo2 channels, P2X3 purinergic receptors, N-Methyl-D-Aspartate (NMDA) receptors and voltage-gated calcium channels in the trigeminal ganglion of rodents has been observed in association with myofascial orofacial pain. This evidence highlights the role of neuronal ion channels in the pathophysiology of myofascial orofacial pain and supports the involvement of nociplastic mechanisms. [ABSTRACT FROM AUTHOR]

Background and Purpose Experimental Approach Key Results Conclusion and Implications Mutations in both KCNQ1 and KCNE1, which together form the cardiac IKs current, are associated with inherited conditions such as long and short QT syndromes. Mefenamic acid, a non‐steroidal anti‐inflammatory drug, is an IKs potentiator and may be utilised as an archetype to design therapeutically useful IKs agonists. However, here we show that mefenamic acid can also act as an IKs inhibitor, and our data reveal its dual effects on KCNQ1/KCNE1 channels.Effects of mefenamic acid on wild type (WT) and mutant KCNQ1/KCNE1 channels expressed in tsA201 cells were studied using whole cell patch clamp. Molecular dynamics simulations were used to determine trajectory clustering.Mefenamic acid inhibits WT IKs at high concentrations while preserving some attributes of current potentiation. Inhibitory actions of mefenamic acid are unmasked at lower drug concentrations by KCNE1 and KCNQ1 mutations in the mefenamic acid binding pocket, at the extracellular end of KCNE1 and in the KCNQ1 S6 helix. Mefenamic acid does not inhibit KCNQ1 in the absence of KCNE1 but inhibits IKs current in a concentration‐dependent manner in the mutant channels. Inhibition involves modulation of pore kinetics and/or voltage sensor domain‐pore coupling in WT and in the KCNE1 E43C mutant.This work highlights the importance of structural motifs at the extracellular inter‐subunit interface of KCNQ1 and KCNE1 channels, and their interactions, in determining the nature of drug effects on the IKs channel complex and has important implications for treating patients with specific long QT mutations. [ABSTRACT FROM AUTHOR]

Extracting lithium resources from seawater and brine can promote the development of the new energy materials industry. The electrochemical method is green and efficient. Iron phosphate (FePO4) crystal, with its 1D ion channel, holds significant potential as a primary lithium extraction electrode material. Li+ encounters a substantial concentration disadvantage in brines, and the co‐intercalation of Na+ diminishes Li+ selectivity. To address this issue, this work enhances the energy barrier for Na+ insertion through prelithiation strategies applied to the 1D channels of FePO4 crystal, thereby improving Li+ selectivity, and further investigating the prelithiation effect with particle size and morphology control. The results indicate that the Li(4C‐40%)FePO4// Activated carbon(AC) system enhances selectivity of lithium. The Li(4C‐40%)FePO4 with size diameter of 2500 nm demonstrates an energy consumption of 0.79 Wh mol−1 and a purity of 97.94% for lithium extraction at a unit lithium extraction of 5.93 mmol g−1 in simulated brine. Li(4C‐40%)FePO4‐nanoplates demonstrate the most optimal lithium extraction performance among the three morphologies due to their lamellar structure's short ion diffusion path in the [010] channel, favoring Li+ diffusion. The diffusion energy barriers of Li+ and Na+ are calculated using Density Functional Theory (DFT) before and after prelithiation, showing good agreement with experimental results. [ABSTRACT FROM AUTHOR]

Action potential generation underlies some of the most consequential dynamical systems on Earth, from brains to hearts. It is therefore interesting to develop synthetic cell-free systems, based on the same molecular mechanisms, which may allow for the exploration of parameter regions and phenomena not attainable, or not apparent, in the live cell. We previously constructed such a synthetic system, based on biological components, which fires action potentials. We call it "Artificial Axon". The system is minimal in that it relies on a single ion channel species for its dynamics. Here we characterize the Artificial Axon as a dynamical system in time, using a simplified Hodgkin-Huxley model adapted to our experimental context. We construct a phase diagram in parameter space identifying regions corresponding to different temporal behavior, such as Action Potential (AP) trains, single shot APs, or damped oscillations. The main new result is the finding that our system with a single ion channel species, with inactivation, is dynamically equivalent to the system of two channel species without inactivation (the Morris-Lecar system), which exists in nature. We discuss the transitions and bifurcations occurring crossing phase boundaries in the phase diagram, and obtain criteria for the channels' properties necessary to obtain the desired dynamical behavior. In the second part of the paper we present new experimental results obtained with a system of two AAs connected by excitatory and/or inhibitory electronic "synapses". We discuss the feasibility of constructing an autonomous oscillator with this system. [ABSTRACT FROM AUTHOR]

In the current era of rapid development in the new energy vehicle industry, graphite (Gr) has gained significant attention as the primary anode material for commercial lithium‐ion batteries due to its exceptional reversibility in lithium‐ion insertion/extraction and abundant availability. In this study, a multifunctional ferroelectric Bi12TiO20@C (BIT@C) modified interlayer between Gr and polymer electrolyte (PE) is fabricated. This approach established a channel and homogeneous ion‐conducting network that facilitated lithium‐ion intercalation into Gr at the interface while suppressing erratic lithium precipitation, thereby stabilizing the structure of Gr. The uniform electric field generated by BIT intercalation enabled homogeneous intercalation/deintercalation of lithium ions, effectively preventing the structural collapse of the Gr anode. Assembled LIBs exhibited reduced polarization and enhanced electrochemical properties attributed to facile charge transfer at the interface. The results revealed that Gr│carbon‐BIT@C‐lithium bistrifluoromethane sulfonimide (LiTFSI)/silicon dioxide (SiO2)/poly allyl acetoacetate (PAAA)/poly(vinylidene fluoride‐hexafluoropropylene) (P(VDF‐HFP))/polyvinylidene fluoride (PVDF)│LiFePO4 (LFP) batteries achieved an initial discharge specific capacity of 120.4 mAh g−1 with stable performance over 1200 cycles at 2 C and room temperature (RT), maintaining a Coulombic efficiency of 99.5% after 1200 cycles. The ferroelectric‐modified interface addressed challenges associated with ion transport at the electrode‐electrolyte interface. [ABSTRACT FROM AUTHOR]

Electrospun is a unique technique for the fabrication of multiscale structured nanofibers (MSNFs), which can be used as functional units for improving the performance of lithium‐based batteries. This review systematically examines how MSNFs, including core–shell, hollow porous, multichannel, wire‐in‐tube, tube‐in‐tube, and hierarchical nanofibers, effectively improve battery performance as components in lithium‐based batteries. The application of aforementioned MSNFs and their chemical modification contributes to the development of lithium‐based batteries with high energy density and enhanced safety when used as electrodes, separators, and electrolytes. Specifically, MSNFs are used to derive electrodes and electrolytes that improve electron/ion transfer rates, increase the utilization ratio of active materials, suppress dendrite growth, and mitigate volume expansion, enabling fast and stable electrochemical reactions at the electrodes. Additionally, MSNFs‐derived separators, which feature more ion transport channels, exceptional mechanical properties, and the capability to inhibit thermal runaway, are also discussed. Finally, the challenges and prospective pathways for electrospun technology in the application of lithium‐based batteries are reviewed. [ABSTRACT FROM AUTHOR]

Biomass derived carbon is considered as a promising carbon because it contains abundant channel and pore structure and is not easy to degrade. Double transition metal oxides show abundant valence states, good biocompatibility, conductivity, high stability and satisfactory catalytic properties. In addition, a large number of waste biomass such as the fruit peel could cause the waste of resources and environmental pollution. Therefore, we used waste grape skins as a carbon source for assembly with double transition metal oxides. After calcination at high temperature, N-doped biomass-derived carbon loaded with double transition metal oxide composite was formed. The waste grape skins carbon substrate with large pores and large specific surface area provides more channels for ion migration and electron transport, promotes charge transfer, and further improves the ability to reduce NB. The material shows excellent electro-catalytic activity for nitrobenzene (NB), the limit of detection (LOD) is as low as 0.143 μM, the linear response range is wide (0.47–1798.71 μM), the sensitivity is high, the reproducibility, the selectivity and the stability are good. In addition, the sensing assembled from this material has achieved a recovery rate of 97–102.6 % in testing the NB content in actual water sample. This work provides a new idea for the detection of NB, and also finds a greener and more meaningful treatment method for waste biomass. [ABSTRACT FROM AUTHOR]

The endothelial cells of the blood circulation are exposed to hemodynamic forces, such as cyclic strain, hydrostatic forces, and shear stress caused by the blood fluid's frictional force. Endothelial cells perceive mechanical forces via mechanosensors and thus elicit physiological reactions such as alterations in vessel width. The mechanosensors considered comprise ion channels, structures linked to the plasma membrane, cytoskeletal spectrin scaffold, mechanoreceptors, and junctional proteins. This review focuses on endothelial mechanosensors and how they alter the vascular functions of endothelial cells. The current state of knowledge on the dysregulation of endothelial mechanosensitivity in disease is briefly presented. The interplay in mechanical perception between endothelial cells and vascular smooth muscle cells is briefly outlined. Finally, future research avenues are highlighted, which are necessary to overcome existing limitations. [ABSTRACT FROM AUTHOR]

The channels commonly responsible for maintaining cell resting membrane potentials are referred to as K2P (two-P-domain K+ subunit) channels. These K+ ion channels generally remain open but can be modulated by their local environment. These channels are classified based on pharmacology, pH sensitivity, mechanical stretch, and ionic permeability. Little is known about the physiological nature of these K2P channels in invertebrates. Acidic conditions depolarize neurons and muscle fibers, which may be caused by K2P channels given that one subtype can be blocked by acidic conditions. Doxapram is used clinically as a respiratory aid known to block acid-sensitive K2P channels; thus, the effects of doxapram on the muscle fibers and synaptic transmission in larval Drosophila and crawfish were monitored. A dose-dependent response was observed via depolarization of the larval Drosophila muscle and an increase in evoked synaptic transmission, but doxapram blocked the production of action potentials in the crawfish motor neuron and had a minor effect on the resting membrane potential of the crawfish muscle. This indicates that the nerve and muscle tissues in larval Drosophila and crawfish likely express different K2P channel subtypes. Since these organisms serve as physiological models for neurobiology and physiology, it would be of interest to further investigate what types of K2P channel are expressed in these tissues. (212 words) [ABSTRACT FROM AUTHOR]

The intestines are in a constant state of motion and self-renewal. The mechanical breakdown of food facilitates intestinal movement and aids digestion. It is believed that mechanical stimulation, triggered by changes in osmotic pressure within the intestines, plays a crucial role in regulating gastrointestinal motility. While TRPs and PIEZO1/2 have been identified as mechanosensitive ion channels involved in this process, there still exist numerous unidentified channels with similar properties. In this study, we demonstrate that the TMEM63B expressed in intestinal stem cells contributes to the regulation of intestinal motility and digestion. The deletion of TMEM63B in intestinal stem cells not only decelerates intestinal motility and impairs digestion but also attenuates the proliferation of intestinal stem cells and exacerbates DSS-induced colitis in mice. Collectively, our findings unveil the pivotal role of TMEM63B in governing optimal digestive function and modulating intestinal motility. [ABSTRACT FROM AUTHOR]

Developmental and Epileptic Encephalopathies (DEEs) represent a clinically and genetically heterogeneous group of rare and severe epilepsies. DEEs commonly begin early in infancy with frequent seizures of various types associated with intellectual disability and leading to a neurodevelopmental delay or regression. Disease-causing genomic variants have been identified in numerous genes and are implicated in over 100 types of DEEs. In this context, genes encoding voltage-gated ion channels (VGCs) play a significant role, and part of the large phenotypic variability observed in DEE patients carrying VGC mutations could be explained by the presence of genetic modifier alleles that can compensate for these mutations. This review will focus on the current knowledge of the compensatory effect of DEE-associated voltage-gated ion channels and their therapeutic implications in DEE. We will enter into detailed considerations regarding the sodium channels SCN1A, SCN2A, and SCN8A; the potassium channels KCNA1, KCNQ2, and KCNT1; and the calcium channels CACNA1A and CACNA1G. [ABSTRACT FROM AUTHOR]

CD4+ T cells play a central role in orchestrating the immune response in asthma, with dysregulated ion channel profiles and altered metabolic signatures contributing to disease progression and severity. An important classification of asthma is based on the presence of T-helper cell type 2 (Th2) inflammation, dividing patients into Th2-high and Th2-low endotypes. These distinct endotypes have implications for disease severity, treatment response, and prognosis. By elucidating how ion channels and energy metabolism control Th cells in asthma, this review contributes to the pathophysiological understanding and the prospective development of personalized therapeutic treatment strategies for patients suffering from distinct asthma endotypes. [ABSTRACT FROM AUTHOR]

Voltage-gated ion channels are key players in neuronal excitability, synaptic transmission, and neuronal synchrony and represent one of the major sources of abnormal function of neuronal circuits occurring during epilepsy. Epilepsy does not result solely from the imbalance between excitatory and inhibitory ion channels; loss of function in excitatory channels or gain of function in inhibitory channels is also reported in epileptic encephalopathies. Synaptic inhibition triggers focal epilepsies, possibly through the facilitation of excitatory synaptic transmission due to the deinactivation of axonal sodium channels. Neural synchrony and its transmission within neural microcircuits is controlled by voltage-gated ion channels located in the axon, the dendrites, and the cell body. New molecules targeting excitatory and inhibitory ion channels need to be identified and tested in in vitro and in vivo models of epileptic encephalopathies. Epileptic encephalopathies are generally considered to be functional disruptions in the balance between neural excitation and inhibition. Excitatory and inhibitory voltage-gated ion channels are key targets of antiepileptic drugs, playing a critical role in regulating neuronal excitation and synaptic transmission. Recent research has highlighted the significance of ion channels in various aspects of epilepsy, including presynaptic neurotransmitter release, intrinsic neuronal excitability, and neural synchrony. Genetic alterations in excitatory and inhibitory ion channels within principal neurons and in inhibitory interneurons have also been identified as key contributors to the development of epilepsies. We review these recent studies and shed light on the bidirectional relationship between epilepsy and neuronal excitability and the latest advancements in pharmacological therapeutics targeting ion channels for epilepsy treatment. [ABSTRACT FROM AUTHOR]

Uncovering the effects of radical injection into responsive organic molecules is a long-sought goal, and the single-molecule junctions provide a unique way to investigate molecular conductance evolution during the radical injection. We can modulate the main channel conductance by using electronic injection from off-site neutral radicals acting as gating terminals. Two families of cyclopentadienone derivatives were synthesized, featuring the inter-pyridyl main conductance channel and the inter-radical paths that are linear (FCF) or cross conjugated (PCP). Using a scanning tunneling microscope break junction technique, we find that the injection of mono-and diradicals in the PCP system unexpectedly decreases the conductance regarding the closed-shell analog, while that of FCF systems increases. Through-bond and through-space conductance mechanisms are found in the FCF and PCP series, respectively, and jointly modulate the overall charge transmission. This off-site injection concept offers a promising approach for developing molecular devices by manipulating electrical conductance in single-molecule junctions. [ABSTRACT FROM AUTHOR]

Complex integral membrane proteins, which are embedded in the cell surface lipid bilayer by multiple transmembrane spanning polypeptides, encompass families of proteins that are important target classes for drug discovery. These protein families include G protein-coupled receptors, ion channels, transporters, enzymes, and adhesion molecules. The high specificity of monoclonal antibodies and the ability to engineer their properties offers a significant opportunity to selectively bind these target proteins, allowing direct modulation of pharmacology or enabling other mechanisms of action such as cell killing. Isolation of antibodies that bind these types of membrane proteins and exhibit the desired pharmacological function has, however, remained challenging due to technical issues in preparing membrane protein antigens suitable for enabling and driving antibody drug discovery strategies. In this article, we review progress and emerging themes in defining discovery strategies for a generation of antibodies that target these complex membrane protein antigens. We also comment on how this field may develop with the emerging implementation of computational techniques, artificial intelligence, and machine learning. [ABSTRACT FROM AUTHOR]

Historically, studies show that female patients with cystic fibrosis (CF) have worse pulmonary outcomes than male patients, including decreased life expectancy. It is unknown whether this disparity persists in the new era of highly effective modulator therapies. Ivacaftor has been available in the United States for > 10 years, allowing for the opportunity to understand the impact this therapy may have on sex disparities in CF. We hypothesized that female patients will continue to show worse outcomes because we suspect that the disparity is not driven solely by ion channel dysfunction. Does a difference in outcomes between male and female patients persist after the initiation of ivacaftor in people with CF? We conducted a retrospective cohort study using the CF Foundation Patient Registry comparing changes in pulmonary exacerbation rate, lung function (FEV 1 % predicted), and presence of Pseudomonas aeruginosa among male patients vs female patients before and after initiation of treatment with the highly effective modulator ivacaftor. The cohort comprised 1,900 people with CF who were treated with ivacaftor between 2010 and 2017; 928 patients (48.84%) were male and 972 patients (51.16%) were female with a mean age of 33.09 years. Male patients showed a significant decrease in pulmonary exacerbations after ivacaftor treatment (from 0.38 to 0.34; adjusted rate ratio, 0.89; P =.028), whereas female patients did not (from 0.48 to 0.45; adjusted rate ratio, 0.95; P =.174). FEV 1 % predicted similarly decreased in both male and female patients before vs after ivacaftor treatment. P aeruginosa prevalence decreased to a similar extent in both male and female patients after ivacaftor treatment. Our findings demonstrate that sex disparities in CF persist in those treated with ivacaftor because of differences in pulmonary exacerbations. More research is needed to determine the specific pathophysiologic drivers of this disparity. [ABSTRACT FROM AUTHOR]

Chronic neuropathic pain is a debilitating pain syndrome caused by damage to the nervous system that is poorly served by current medications. Given these problems, clinical studies have pursued extracts of the plant Cannabis sativa as alternative treatments for this condition. The vast majority of these studies have examined cannabinoids which contain the psychoactive constituent delta‐9‐tetrahydrocannabinol (THC). While there have been some positive findings, meta‐analyses of this clinical work indicates that this effectiveness is limited and hampered by side‐effects. This review focuses on how recent preclinical studies have predicted the clinical limitations of THC‐containing cannabis extracts, and importantly, point to how they might be improved. This work highlights the importance of targeting channels and receptors other than cannabinoid CB1 receptors which mediate many of the side‐effects of cannabis. [ABSTRACT FROM AUTHOR]

Chronic pelvic pain (CPP) is the primary symptom of endometriosis patients, but adequate treatments are lacking. Modulation of ion channels expressed by sensory nerves innervating the viscera has shown promise for the treatment of irritable bowel syndrome and overactive bladder. However, similar approaches for endometriosis‐associated CPP remain underdeveloped. Here, we examined the role of the voltage‐gated sodium (NaV) channel NaV1.7 in (i) the sensitivity of vagina‐innervating sensory afferents and investigated whether (ii) NaV1.7 inhibition reduces nociceptive signals from the vagina and (iii) ameliorates endometriosis‐associated CPP. The mechanical responsiveness of vagina‐innervating sensory afferents was assessed with ex vivo single‐unit recording preparations. Pain evoked by vaginal distension (VD) was quantified by the visceromotor response (VMR) in vivo. In control mice, pharmacological activation of NaV1.7 with OD1 sensitised vagina‐innervating pelvic afferents to mechanical stimuli. Using a syngeneic mouse model of endometriosis, we established that endometriosis sensitised vagina‐innervating pelvic afferents to mechanical stimuli. The highly selective NaV1.7 inhibitor Tsp1a revealed that this afferent hypersensitivity occurred in a NaV1.7‐dependent manner. Moreover, in vivo intra‐vaginal treatment with Tsp1a reduced the exaggerated VMRs to VD which is characteristic of mice with endometriosis. Conversely, Tsp1a did not alter ex vivo afferent mechanosensitivity nor in vivo VMRs to VD in Sham control mice. Collectively, these findings suggest that NaV1.7 plays a crucial role in endometriosis‐induced vaginal hyperalgesia. Importantly, NaV1.7 inhibition selectively alleviated endometriosis‐associated CPP without the loss of normal sensation, suggesting that selective targeting of NaV1.7 could improve the quality of life of women with endometriosis. [ABSTRACT FROM AUTHOR]

Neuronal information processing depends on converting membrane depolarizations into compartmentalized biochemical signals that can modify neuronal activity and structure. However, our understanding of how neurons translate electrical signals into specific biochemical responses remains limited, especially in the soma where gene expression and ion channel function are crucial for neuronal activity. Here, I emphasize the importance of physically compartmentalizing action potential‐triggered biochemical reactions within the soma. Emerging evidence suggests that somatic endoplasmic reticulum–plasma membrane (ER‐PM) junctions are specialized organelles that coordinate electrical and biochemical signaling. The juxtaposition of ion channels and signaling proteins at a prominent subset of these sites enables compartmentalized calcium and cAMP‐dependent protein kinase (PKA) signaling. I explore the hypothesis that these PKA‐containing ER‐PM junctions serve as critical sites for translating membrane depolarizations into PKA signals and identify key gaps in knowledge of the assembly, regulation, and neurobiological functions of this somatic signaling system. [ABSTRACT FROM AUTHOR]

Objective: Developmental and epileptic encephalopathies (DEEs) can result from dominant, gain of function variants of neuronal ion channels. More than 450 de novo missense variants of the sodium channel gene SCN8A have been identified in individuals with DEE. Methods: We studied a mouse model carrying the patient Scn8a variant p.Asn1768Asp. An AAV‐PHP.eB virus carrying an allele‐specific single guide RNA (sgRNA) was administered by intracerebroventricular injection. Cas9 was provided by an inherited transgene. Results: Allele‐specific disruption of the reading frame of the pathogenic transcript generated out‐of‐frame indels in 1/4 to 1/3 of transcripts throughout the brain. This editing efficiency was sufficient to rescue lethality and seizures. Neuronal hyperexcitability was reduced in cells expressing the virus. Interpretation: The data demonstrate efficient allele‐specific editing of a dominant missense variant and support the feasibility of allele‐specific therapy for DEE epilepsy. ANN NEUROL 2024;96:958–969 [ABSTRACT FROM AUTHOR]

Cannabidiol (CBD), the main nonpsychoactive cannabinoid of cannabis, holds promise for nonaddictive treatment of pain. Although preclinical studies have been encouraging, well-controlled human trials have been largely unsuccessful. To investigate this dichotomy and better understand the actions of CBD, we used high-content calcium imaging with automated liquid handling and observed broad inhibition of neuronal activation by a host of ionotropic and metabotropic receptors, including transient receptor potential (Trp) and purinergic receptors, as well as mediators of intracellular calcium cycling. To assess the effect of CBD on overall nociceptor electrical activity, we combined the light-activated ion channel channelrhodposin in TRPV1-positive nociceptors and a red-shifted calcium indicator and found that 1 µM CBD profoundly increased the optical threshold for calcium flux activation. Experiments using traditional whole-cell patch-clamp showed increase of nociceptor activation threshold at submicromolar concentrations, but with unusually slow kinetics, as well as block of voltage-activated currents. To address a more integrated capacity of CBD to influence nociceptor sensitization, a process implicated in multiple pain states, we found that sub micromolar concentrations of CBD inhibited sensitization by the chemotherapeutic drug vincristine. Taken together, these results demonstrate that CBD can reduce neuronal activity evoked by a strikingly wide range of stimuli implicated in pain signaling. The extensive effects underscore the need for further studies at substantially lower drug concentrations, which are more likely to reflect physiologically relevant mechanisms. The slow kinetics and block raise biophysical questions regarding the lipophilic properties of CBD and its action on channels and receptors within membranes. [ABSTRACT FROM AUTHOR]

Millions of people worldwide are affected by neurodegenerative diseases and cognitive impairment, which includes dementia, while there are only symptomatic treatments available for this syndrome at present. However, several important prospective drug targets have been identified in recent years that can potentially arrest or even reverse the progression of neurodegenerative diseases. Their natural or synthetic ligands are currently in the experimental stage of drug development. In vitro and preclinical (e.g. using animal models) studies confirm their therapeutic potential, but clinical trials often fail or produce conflicting results. Here, we first review the complexity and typology of dementia, followed by the discussion of currently available treatments, and, finally, some novel molecular and cellular approaches to this problem. [ABSTRACT FROM AUTHOR]

Neuropathic pain (NPP) is a refractory pain syndrome, caused by damage or disease of the somatosensory nervous system and characterized by spontaneous pain, hyperalgesia, abnormal pain and sensory abnormality. Non-coding RNAs (ncRNAs), including microRNA (miRNA), long non-coding RNA (lncRNA), circular RNA (circRNA) and Piwi interacting RNA (piRNA), play a notable role in initiation and maintenance of NPP. In this review, we summarize the role of ncRNAs in NPP and their underlaying mechanism. Generally, ncRNAs are interacted with mRNA, protein or DNA to regulate the molecules and signals assciated with neuroinflammation, ion channels, neurotrophic factors and others, and then involved in the occurrence and development of NPP. Therefore, this review not only contributes to deepen our understanding of the pathophysiological mechanism of NPP, but also provides theoretical basis for the development of new therapy strategies for this disorder. [ABSTRACT FROM AUTHOR]

Transient receptor potential canonical 3 (TRPC3) protein belongs to the TRP family of nonselective cation channels. Its activation occurs by signaling through a G protein‐coupled receptor (GPCR) and a phospholipase C‐dependent (PLC) pathway. Perturbations in the expression of TRPC3 are associated with a plethora of pathophysiological conditions responsible for disorders of the cardiovascular, immune, and central nervous systems. The recently solved cryo‐EM structure of TRPC3 provides detailed inputs about the underlying mechanistic aspects of the channel, which in turn enables more efficient ways of designing small‐molecule modulators. Pharmacologically targeting TRPC3 in animal models has demonstrated great efficacy in treating diseases including cancers, neurological disorders, and cardiovascular diseases. Despite extensive scientific evidence supporting some strong correlations between the expression and activity of TRPC3 and various pathophysiological conditions, therapeutic strategies based on its pharmacological modulations have not led to clinical trials. The development of small‐molecule TRPC3 modulators with high safety, sufficient brain penetration, and acceptable drug‐like profiles remains in progress. Determining the pathological mechanisms for TRPC3 involvement in human diseases and understanding the requirements for a drug‐like TRPC3 modulator will be valuable in advancing small‐molecule therapeutics to future clinical trials. In this review, we provide an overview of the origin and activation mechanism of TRPC3 channels, diseases associated with irregularities in their expression, and new development in small‐molecule modulators as potential therapeutic interventions for treating TRPC3 channelopathies. [ABSTRACT FROM AUTHOR]

Zinc hydroxide [Zn(OH)2] is a multifaceted substance with significant potential in diverse domains such as energy storage, catalysis, and environmental cleanup. Zn(OH)2 is appropriate for pseudocapacitor applications because of its strong electrochemical activity, cost-effectiveness, and environmentally favorable features. In this investigation, we have effectively synthesized nanoflakes of zinc hydroxide [Zn(OH)2] as electrode material on stainless steel substrates for supercapacitor applications using the successive ionic layer adsorption and reaction (SILAR) technique. The performance of the electrode material is enhanced by nanoflakes, which encourage electrolyte diffusion and provide more channels for ion migration. Optical absorption analysis unveiled a direct band transition, showcasing a band gap of 3.35 eV. The synthesized material underwent characterization through scanning electron microscopy (SEM) and X-ray diffraction (XRD), confirming their well-defined morphology and crystalline structure with uniform distribution. The cyclic voltammetry as well as galvanostatic charge–discharge experiments were performed in a three-electrode configuration using a 1 M KOH aqueous electrolyte. The electrochemical results demonstrated that the Zn(OH)2 nanoflakes thin film electrode revealed a remarkable specific capacitance of 123 F g−1 at a current density of 1 A g−1. Additionally, it displayed an extended cycling lifespan, retaining 72% of its original capacitance even afterward undergoing 5000 cycles at a scan rate of 100 mV s−1. [ABSTRACT FROM AUTHOR]

Venoms are complex mixtures produced by animals and consist of hundreds of components including small molecules, peptides, and enzymes selected for effectiveness and efficacy over millions of years of evolution. With the development of venomics, which combines genomics, transcriptomics, and proteomics to study animal venoms and their effects deeply, researchers have identified molecules that selectively and effectively act against membrane targets, such as ion channels and G protein-coupled receptors. Due to their remarkable physico-chemical properties, these molecules represent a credible source of new lead compounds. Today, not less than 11 approved venom-derived drugs are on the market. In this review, we aimed to highlight the advances in the use of venom peptides in the treatment of diseases such as neurological disorders, cardiovascular diseases, or cancer. We report on the origin and activity of the peptides already approved and provide a comprehensive overview of those still in development. [ABSTRACT FROM AUTHOR]

Cryo-EM particle identification from micrographs ("picking") is challenging due to the low signal-to-noise ratio and lack of ground truth for particle locations. State-of-the-art computational algorithms ("pickers") identify different particle sets, complicating the selection of the best-suited picker for a protein of interest. Here, we present REliable PIcking by Consensus (REPIC), a computational approach to identifying particles common to the output of multiple pickers. We frame consensus particle picking as a graph problem, which REPIC solves using integer linear programming. REPIC picks high-quality particles even when the best picker is not known a priori or a protein is difficult-to-pick (e.g., NOMPC ion channel). Reconstructions using consensus particles without particle filtering achieve resolutions comparable to those from particles picked by experts. Our results show that REPIC requires minimal (often no) manual intervention, and considerably reduces the burden on cryo-EM users for picker selection and particle picking. Availability: https://github.com/ccameron/REPIC. Cryo-EM particle picking is difficult due to noise and no ground truth. Here, a computational method for finding consensus particles from different picking algorithms is presented. This method identifies high-quality particles with minimal user input. [ABSTRACT FROM AUTHOR]

Priority 1: critical WHO pathogen Acinetobacter baumannii depends on ATP synthesis and ATP:ADP homeostasis and its bifunctional F1FO‐ATP synthase. While synthesizing ATP, it regulates ATP cleavage by its inhibitory ε subunit to prevent wasteful ATP consumption. We determined cryo‐electron microscopy structures of the ATPase active A. baumannii F1‐αßγεΔ134–139 mutant in four distinct conformational states, revealing four transition states and structural transformation of the ε's C‐terminal domain, forming the switch of an ATP hydrolysis off‐ and an ATP synthesis on‐state based. These alterations go in concert with altered motions and interactions in the catalytic‐ and rotary subunits of this engine. These A. baumannii interacting sites provide novel pathogen‐specific targets for inhibitors, with the aim of ATP depletion and/or ATP synthesis and growth inhibition. Furthermore, the presented diversity to other bacterial F‐ATP synthases extends the view of structural elements regulating such a catalyst. [ABSTRACT FROM AUTHOR]

In polarized cells, the precise regulation of protein transport to and from the plasma membrane is crucial to maintain cellular function. Dysregulation of intracellular protein transport in neurons can lead to neurodegenerative diseases such as Retinitis Pigmentosa, Alzheimer's and Parkinson's disease. Here we used the light-dependent transport of the TRPL (transient receptor potential-like) ion channel in Drosophila photoreceptor cells to study the role of Rab proteins in TRPL recycling. TRPL is located in the rhabdomeric membrane of dark-adapted flies, but it is transported out of the rhabdomere upon light exposure and localizes at the Endoplasmatic Reticulum within 12 h. Upon subsequent dark adaptation, TRPL is recycled back to the rhabdomeric membrane within 90 min. To screen for Rab proteins involved in TRPL recycling, we established a tissue specific (ts) CRISPR/Cas9-mediated knock-out of individual Rab genes in Drosophila photoreceptors and assessed TRPL localization using an eGFP tagged TRPL protein in the intact eyes of these mutants. We observed severe TRPL recycling defects in the knockouts of Rab3, Rab4, Rab7, Rab32, and RabX2. Using immunohistochemistry, we further showed that Rab3 and RabX2 each play a significant role in TRPL recycling and also influence TRPL transport. We localized Rab3 to the late endosome in Drosophila photoreceptors and observed disruption of TRPL transport to the ER in Rab3 knock-out mutants. TRPL transport from the ER to the rhabdomere ensues from the trans-Golgi where RabX2 is located. We observed accumulated TRPL at the trans-Golgi in RabX2 knock-out mutants. In summary, our study reveals the requirement of specific Rab proteins for different steps of TRPL transport in photoreceptor cells and provides evidence for a unique retrograde recycling pathway of TRPL from the ER via the trans-Golgi. [ABSTRACT FROM AUTHOR]

Persistent inflammation is a major contributor in the development of various inflammatory diseases like atherosclerosis. Our study investigates how transient receptor potential vanilloid 4 (TRPV4), a mechanosensitive ion channel, interacts with microRNA-146a (miR-146a), within the context of inflammation and atherosclerosis. Micro-RNAs play a critical role in controlling gene expression, and miR-146a is notable for its anti-inflammatory actions. TRPV4 is activated by diverse soluble and mechanical stimuli, and often associated with inflammatory responses in various diseases. Here, we find that TRPV4 negatively regulates miR146a expression in macrophages, especially following stimulation by lipopolysaccharides or alterations in matrix stiffness. We show that in atherosclerosis, a condition characterized by matrix stiffening, TRPV4 decreases miR-146a expression in aortic tissue macrophages. We find that TRPV4’s impact on miR-146a is independent of activation of NFkB, Stat1, P38, and AKT, but is rather mediated through a mechanism involving histone deacetylation instead of DNA methylation at the miR-146a promoter site. Furthermore, we show that N-terminal residues 1 to 130 in TRPV4 is essential in suppression of miR-146a expression in LPS-stimulated macrophages. Altogether, this study identifies a regulatory mechanism of miR-146a expression by TRPV4 which may open new potential therapeutic strategies for managing inflammatory diseases. [ABSTRACT FROM AUTHOR]

Calcium homeostasis modulators (CALHMs) are the most recently discovered members of the large‐pore channel family. They mediate the conductance of ions and larger molecules, such as ATP, and play critical roles in pathways related to Alzheimer's disease, neuroinflammation, neuromodulation, taste perception and innate immune responses. Since the inaugural report on CALHM1 in 2008, significant breakthroughs have revealed their biological roles, ion and ATP channel functions, and structures, positioning the field for further advancements. In this review, we discuss the overall progress and recent developments in understanding the biological roles, functions and molecular structures of CALHM proteins. [ABSTRACT FROM AUTHOR]

An iterative design process of polymer fabric from point to line and plane, inspired by the fabric craft, has been rationally designed to improve the electrochemical performance of organic electrode materials (OEMs) in rechargeable metal–organic batteries (MOBs). The evolution from point to line and plane of OEM improves its structure stability, kinetics, and utilization of active sites, benefitting the construction of high-performance MOBs. [Display omitted] Organic electrode materials (OEMs) have attracted significant attention for use in aqueous zinc-ion batteries (AZIBs) because of their abundant resources and flexible designability. However, the development of high-performance OEMs is strongly hindered by their high solubility, poor conductivity, sluggish ion diffusion kinetics, and difficult coordination toward Zn2+. Herein, inspired by fabric crafts, we have designed a robust polymer fabric through the iterative evolution of the building blocks from point to line and plane. The evolution from point to line could not only improve the structural stability and electrical conductivity but also adjust the active site arrangement to enable the storage of Zn2+. In addition to further boosting the aforementioned properties, the evolution from line to plane could also facilitate the construction of noninterference channels for ion migration. Accordingly, the poly(1,4,5,8-naphthalenetetracarboxylic dianhydride/2,3,5,6-tetraaminocyclohexa-2,5-diene-1,4-dione) (PNT) polymer fabric has the most enhanced structural stability, optimized active site arrangement, improved electrical conductivity, and suitable ion channels, resulting in a record-high capacity retention of 96% at a high mass loading of 56.9 mg cm−2 and a stable cycle life of more than 20,000 cycles at 150 C (1 C=200 mA g−1) in AZIBs. In addition, PNT exhibits universality for a wide range of ions in organic electrolyte systems, such as Li/Na/K-ion batteries. Our iterative design of polymer fabric cathode has laid the foundation for the development of advanced OEMs to promote the performance of metal-ion batteries. [ABSTRACT FROM AUTHOR]

Reverse electrodialysis (RED) technology, relying on ion‐selective permeability membranes (ISPM), offers a direct means of harnessing osmotic energy from the salinity difference between seawater and freshwater. Critical technical challenges include limitations in ISPM's immobile charge carriers, transmembrane ionic internal resistance, and durability in water. Drawing inspiration from the subunit structure of the epithelial sodium channel (ENaC), an ISPM assembled using a supramolecular engineering strategy is introduced. This innovative approach enables the synergistic action of multiple molecular building blocks to mimic the distribution of ENaC subunit structures, strategically planning the placement of immobile charge carriers on nanofluidic channels. The design incorporates nano‐confined oxygen‐rich functionalized MXene (O‐MXene) and high‐strength polymer backbone aramid fibers to construct 3D nanofluidic channels with a high surface charge density. Enhanced by a bonding network of sodium carboxymethylcellulose, the ISPM achieved an exceptional output power density of 21.7 W m−2 and 46.0% energy conversion efficiency in a RED half‐cell system using natural seawater and river water, surpassing current technologies. This research not only advances RED technology but also provides biomimetic customization concepts for ISPM design across various applications, including flow batteries, fuel cells, and related fields. [ABSTRACT FROM AUTHOR]

Thermogenetics is a promising neuromodulation technique based on the use of heat-sensitive ion channels. However, on the way to its clinical application, a number of questions have to be addressed. First, to avoid immune response in future human applications, human ion channels should be studied as thermogenetic actuators. Second, heating levels necessary to activate these channels in vivo in brain tissue should be studied and cytotoxicity of these temperatures addressed. Third, the possibility and safety of chronic neuromodulation has to be demonstrated. In this study, we present a comprehensive framework for thermogenetic neuromodulation in vivo using the thermosensitive human ion channel hTRPV1. By targeting hTRPV1 expression to excitatory neurons of the mouse brain and activating them within a non-harmful temperature range with a fiber-coupled infrared laser, we not only induced neuronal firing and stimulated locomotion in mice, but also demonstrated that thermogenetics can be employed for repeated neuromodulation without causing evident brain tissue injury. Our results lay the foundation for the use of thermogenetic neuromodulation in brain research and therapy of neuropathologies. [ABSTRACT FROM AUTHOR]

Triple negative breast cancer (TNBC) is known for its heterogeneous nature and aggressive onset, limited unresponsiveness to hormone therapies and immunotherapy as well as high likelihood of metastasis and recurrence. Since no targeted standard treatment options are available for TNBC, novel and effective therapeutic targets are urgently needed. Ion channels have emerged as possible novel therapeutic candidates for cancer therapy. We previously showed that GABAA β3 subunit are expressed at higher levels in TNBC cell lines than non-tumorigenic MCF10A cells. GABAA β3 subunit knockdown causes cell cycle arrest in TNBC cell lines via decreased cyclin D1 and increased p21 expression. However, it is not known if the upregulated GABAAR express at the cell-surface in TNBC and mediate Cl- flux. Cl- ions are known to play a role in cell-cycle progression in other cancers such as gastric cancer. Here, using surface biotinylation and (N-(Ethoxycarbonylmethyl)-6-Methoxyquinolinium Bromide) MQAE-dye based fluorescence quenching, we show that upregulated GABAAR are on the cell-surface in TNBC cell lines and mediate significantly higher chloride (Cl-) flux as compared to non-tumorigenic MCF10A cells. Moreover, this GABAAR mediated Cl- flux can be modulated by pharmacological agents and is decreased in TNBC cells with GABAA β3 subunit knockdown. Further, treatment of TNBC cells with bicuculline, a GABAAR antagonist reduced cell viability in TNBC cells Overall, these results point to an unexplored role of GABAAR mediated Cl- flux in TNBC. [ABSTRACT FROM AUTHOR]

Serotonin, a monoamine neurotransmitter, is important in both the central nervous system (CNS) and the peripheral nervous system. Malfunction of serotonin signaling leads to various disorders. We studied serotonin signaling from serotonergic neurons inside the ventral nerve cord of Drosophila melanogaster. Serotonergic neurons and stimulated release were visualized and achieved with mCherry and channelrhodopsin‐2 (an optogenetically transfected ion channel), respectively, and two electrochemical techniques quantified serotonin release and vesicular content. Mean vesicular serotonin content released during exocytosis from these neurons was 84 %, considerably higher than reported in previous studies regarding octopamine (4.5 %) and glutamate release (31 %). Serotonin content within all vesicles is uniformly changed when serotonin concentration is inhibited or enhanced. However, serotonin release exhibits two Gaussian distributions: higher frequency of small release events, and similar or slightly higher frequency of large events, resulting in differential release fractions ranging from partial (13–18 %) to full (100 %) release after treatment with agents to either enhance or diminish release. This is the first example of consistent full exocytotic release events we have observed in any system. We suggest one pool of vesicles can release significantly diverse fractions of transmitter load during exocytosis, a potentially novel pathway to regulate exocytosis and neuronal signaling. [ABSTRACT FROM AUTHOR]