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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]

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]

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.

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.

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.

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]

"Gating" is a widely observed phenomenon in biochemistry that describes the transition between the activated (or open) and deactivated (or closed) states of an ion-channel, which makes transport through that channel highly selective. In general, gating is a mechanism that imposes an additional restriction on a transport, as the process ends only when the "gate" is open and continues otherwise. When diffusion occurs in the presence of a constant bias to a gated target, i.e., to a target that switches between an open and a closed state, the dynamics essentially slow down compared to ungated drift-diffusion, resulting in an increase in the mean completion time, ⟨TG⟩ > ⟨T⟩, where T denotes the random time of transport and G indicates gating. In this work, we utilize stochastic resetting as an external protocol to counterbalance the delay due to gating. We consider a particle in the positive semi-infinite space that undergoes drift-diffusion in the presence of a stochastically gated target at the origin and is moreover subjected to rate-limiting resetting dynamics. Calculating the minimal mean completion time ⟨ T r ⋆ G ⟩ rendered by an optimal resetting rate r⋆ for this exactly solvable system, we construct a phase diagram that owns three distinct phases: (i) where resetting can make gated drift-diffusion faster even compared to the original ungated process, ⟨ T r ⋆ G ⟩ < ⟨ T ⟩ < ⟨ T G ⟩ , (ii) where resetting still expedites gated drift-diffusion but not beyond the original ungated process, ⟨ T ⟩ ≤ ⟨ T r ⋆ G ⟩ < ⟨ T G ⟩ , and (iii) where resetting fails to expedite gated drift-diffusion, ⟨ T ⟩ < ⟨ T G ⟩ ≤ ⟨ T r ⋆ G ⟩. We also highlight various non-trivial behaviors of the completion time as the resetting rate, gating parameters, and geometry of the set-up are carefully ramified. Gated drift-diffusion aptly models various stochastic processes such as chemical reactions that exclusively take place in certain activated states of the reactants. Our work predicts the conditions under which stochastic resetting can act as a useful strategy to enhance the rate of such processes without compromising their selectivity. [ABSTRACT FROM AUTHOR]

As biomolecules vibrate and rotate in the terahertz band, the biological effects of terahertz electromagnetic fields have drawn considerable attention from the physiological and medical communities. Ion channels are the basis of biological electrical signals, so studying the effect of terahertz electromagnetic fields on ion channels is significant. In this paper, the effect of a terahertz electromagnetic field with three different frequencies, 6, 15, and 25 THz, on the Kv1.2 potassium ion channel was investigated by molecular dynamics simulations. The results show that an electromagnetic field with a 15 THz frequency can significantly enhance the permeability of the Kv1.2 potassium ion channel, which is 1.7 times higher than without an applied electric field. By analyzing the behavior of water molecules, it is found that the electromagnetic field with the 15 THz frequency shortens the duration of frozen and relaxation processes when potassium ions pass through the channel, increases the proportion of the direct knock-on mode, and, thus, enhances the permeability of the Kv1.2 potassium ion channel. [ABSTRACT FROM AUTHOR]

Ion channels, which are key to physiological regulation and drug discovery, control ion flux across membranes, and their dysregulation leads to various diseases. Ca2+ monitoring is crucial for cellular signaling when performing Ca-based assays in ion channel research; these assays are widely utilized in both academic and pharmaceutical contexts for drug screening and pharmacological profiling. However, existing detection methods are limited by slow detection speeds, low throughput, complex processes, and low analyte viability. In this study, we developed a label-free optical biosensing method using a conical Au/polydimethylsiloxane platform tailored to detect Ca2+ influx in A549-originated nanovesicles facilitated by the transient receptor potential ankyrin 1 (TRPA1) channel. Nanovesicles expressing cellular signaling components mimic TRPA1 signal transduction in cell membranes and improve analyte viability. The conical Au/polydimethylsiloxane sensor converted Ca2+ influx events induced by specific agonist exposure into noticeable changes in relative transmittance under visible light. The optical transmittance change accompanying Ca2+ influx resulted in an enhanced sensing response, high accuracy and reliability, and rapid detection (∼5 s) without immobilization or ligand treatments. In the underlying sensing mechanism, morphological variations in nanovesicles, which depend on Ca2+ influx, induce a considerable light scattering change at an interface between the nanovesicle and Au, revealed by optical simulation. This study provides a foundation for developing biosensors based on light–matter interactions. These sensors are simple and cost-effective with superior performance and diverse functionality. [ABSTRACT FROM AUTHOR]

The current application of gel electrolytes in energy storage fails to meet the demand for higher ion transport and excellent mechanical properties due to the low ionic conductivity and poor mechanical properties. Herein, a novel strategy is proposed to graft oligomer polyetheramine on the surface of MXene to achieve a transformation from solid MXene to MXene nanofluid avoiding oxidation and aggregation of MXene, and then it is introduced to gel electrolytes providing ion transport channels and mechanical properties. The synergistic effect on the core of MXene and the canopy of polyetheramine produce Lewis acid–base interactions on electrolyte ions, which not only promote electrolyte dissociation but also provides ion transport path‐way. The experiment and molecular dynamics simulations show that the ionic diffusion ability of electrolyte ions is enhanced, because the MXene and polyetheramine promote electrolyte dissociation and reduce the electrostatic interference between anions and cations. The specific capacity of the assembled supercapacitor is 114.28 F g−1 at 1 A g−1 current density, and the capacity retention rate is 91.30% after 3000 cycles. This work provides a new insight for fabricating high‐performance devices. [ABSTRACT FROM AUTHOR]

This paper reports the synthesis of a Ni-doped coral-like three-dimensional Mo 2 C nanorod via the pyrolysis of polypyrrole (PPy)-loaded NiMoO 4 ·xH 2 O nanorods for nitrobenzene (NB) detection. The incorporation of Ni species into Mo 2 C enhances dual-atom synergistic catalysis, while the inclusion of PPy as a preferred carbon source improves the composite's active area. The coral-like three-dimensional rod structure not only provides various types of sites for adsorbing reactants but also offers more channels for ion migration and electron transfer, promoting charge transfer and further enhancing its electrical conductivity. The resulting composite demonstrates a wide linear detection range (2.11–1053.61 μM), high sensitivity, low limit of detection (0.64 μM, S/N = 3), and excellent stability and anti-interference performance in NB detection. This novel composite preparation approach offers promising prospects for practical NB detection applications. [ABSTRACT FROM AUTHOR]

Tuberous Sclerosis Complex (TSC) is a lynchpin disorder, as it results in overactive mammalian target of rapamycin (mTOR) signaling, which has been implicated in a multitude of disease states. TSC is an autosomal dominant disease where 90% of affected individuals develop epilepsy. Epilepsy results from aberrant neuronal excitability that leads to recurring seizures. Under neurotypical conditions, the coordinated activity of voltage-gated ion channels keep neurons operating in an optimal range, thus providing network stability. Interestingly, loss or gain of function mutations in voltage-gated potassium, sodium, or calcium channels leads to altered excitability and seizures. To date, little is known about voltage-gated ion channel expression and function in TSC. However, data is beginning to emerge on how mTOR signaling regulates voltage-gated ion channel expression in neurons. Herein, we provide a comprehensive review of the literature describing common seizure types in patients with TSC, and suggest possible parallels between acquired epilepsies with known voltage-gated ion channel dysfunction. Furthermore, we discuss possible links towardmTOR regulation of voltage-gated ion channels expression and channel kinetics and the underlying epileptic manifestations in patients with TSC. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the leading form of dementia, characterized by the accumulation and aggregation of amyloid in brain. Transient receptor potential vanilloid 2 (TRPV2) is an ion channel involved in diverse physiopathological processes, including microglial phagocytosis. Previous studies suggested that cannabidiol (CBD), an activator of TRPV2, improves microglial amyloid-β (Aβ) phagocytosis by TRPV2 modulation. However, the molecular mechanism of TRPV2 in microglial Aβ phagocytosis remains unknown. In this study, we aimed to investigate the involvement of TRPV2 channel in microglial Aβ phagocytosis and the underlying mechanisms. Utilizing human datasets, mouse primary neuron and microglia cultures, and AD model mice, to evaluate TRPV2 expression and microglial Aβ phagocytosis in both in vivo and in vitro. TRPV2 was expressed in cortex, hippocampus, and microglia.Cannabidiol (CBD) could activate and sensitize TRPV2 channel. Short-term CBD (1 week) injection intraperitoneally (i.p.) reduced the expression of neuroinflammation and microglial phagocytic receptors, but long-term CBD (3 week) administration (i.p.) induced neuroinflammation and suppressed the expression of microglial phagocytic receptors in APP/PS1 mice. Furthermore, the hyper-sensitivity of TRPV2 channel was mediated by tyrosine phosphorylation at the molecular sites Tyr(338), Tyr(466), and Tyr(520) by protein tyrosine kinase JAK1, and these sites mutation reduced the microglial Aβ phagocytosis partially dependence on its localization. While TRPV2 was palmitoylated at Cys 277 site and blocking TRPV2 palmitoylation improved microglial Aβ phagocytosis. Moreover, it was demonstrated that TRPV2 palmitoylation was dynamically regulated by ZDHHC21. Overall, our findings elucidated the intricate interplay between TRPV2 channel regulated by tyrosine phosphorylation/dephosphorylation and cysteine palmitoylation/depalmitoylation, which had divergent effects on microglial Aβ phagocytosis. These findings provide valuable insights into the underlying mechanisms linking microglial phagocytosis and TRPV2 sensitivity, and offer potential therapeutic strategies for managing AD. [ABSTRACT FROM AUTHOR]

Post-translational SUMOylation of nuclear and cytosolic proteins maintains homeostasis in eukaryotic cells and orchestrates programmed responses to changes in metabolic demand or extracellular stimuli. In excitable cells, SUMOylation tunes the biophysical properties and trafficking of ion channels. Ion channel SUMOylation status is determined by the opposing enzyme activities of SUMO ligases and deconjugases. Phosphorylation also plays a permissive role in SUMOylation. SUMO deconjugases have been identified for several ion channels, but their corresponding E3 ligases remain unknown. This study shows PIAS3, a.k.a. KChAP, is a bona fide SUMO E3 ligase for Kv4.2 and HCN2 channels in HEK cells, and endogenous Kv4.2 and Kv4.3 channels in cardiomyocytes. PIAS3-mediated SUMOylation at Kv4.2-K579 increases channel surface expression through a rab11a-dependent recycling mechanism. PKA phosphorylation at Kv4.2-S552 reduces the current mediated by Kv4 channels in HEK293 cells, cardiomyocytes, and neurons. This study shows PKA mediated phosphorylation blocks Kv4.2-K579 SUMOylation in HEK cells and cardiomyocytes. Together, these data identify PIAS3 as a key downstream mediator in signaling cascades that control ion channel surface expression. [ABSTRACT FROM AUTHOR]

Classical swine fever virus (CSFV) p7 viroporin plays crucial roles in cellular ion balance and permeabilization. The antiviral drug amantadine effectively inhibits viral replication by blocking the activity of CSFV p7 viroporin. However, little information is available for the binding mode of amantadine with CSFV p7 viroporin, due to the lack of a known polymer structure for CSFV p7. In this study, we employed AlphaFold2 to predict CSFV p7 structures. Subsequently, we conducted a docking study to investigate the binding sites of amantadine to CSFV p7. Computational analysis showed that CSFV p7 forms a pore channel in a hexameric structure. Furthermore, molecular dynamics (MD) simulations and mutant analyses further suggest that CSFV p7 likely exists as a hexamer. Docking studies and MD simulations showed that amantadine interacts with the hydrophibic regions of tetramer and pentamer, as well as with the hydrophobic pore channel of the hexamer. Considering the potential hexameric assembly of CSFV p7, along with docking results, MD simulations, and the characteristics of the gated ion channels, we propose a model of CSFV p7 ion channel based on its hexameric configuration. In this model, residues E21, Y25, and R34 are suggested to selectively recruit and dehydrate ions, while residues L28 and L31 likely act as hydrophobic constrictors, thereby restricting the free movement of water. The binding of amantadine to residues I20, E21, V24 and Y25 effectively blocks ion transport. However, this proposed molecular model requires experimental validation. Our findings give a structural insight into the models of CSFV p7 as an ion channel and provide a molecular explanation for the inhibition effects of amantadine on CSFV p7-mediated ion channel conductance. [ABSTRACT FROM AUTHOR]

Antiseizure medications (ASMs) play a central role in seizure management, however, unpredictability in the response to treatment persists, even among patients with similar seizure manifestations and clinical backgrounds. An objective biomarker capable of reliably predicting the response to ASMs would profoundly impact epilepsy treatment. Presently, clinicians rely on a trial-and-error approach when selecting ASMs, a time-consuming process that can result in delays in receiving alternative non-pharmacological therapies such as a ketogenetic diet, epilepsy surgery, and neuromodulation therapies. Pharmacogenetic studies investigating the correlation between ASMs and genetic variants regarding their mechanistic targets offer promise in predicting the response to treatment. Sodium channel subunit genes have been extensively studied along with other ion channels and receptors as targets, however, the results have been conflicting, possibly due to methodological disparities including inconsistent definitions of drug response, variations in ASM combinations, and diversity of genetic variants/genes studied. Nonetheless, these studies underscore the potential effect of genetic variants on the mechanism of ASMs and consequently the prediction of treatment response. Recent advances in sequencing technology have led to the generation of large genetic datasets, which may be able to enhance the predictive accuracy of the response to ASMs. [ABSTRACT FROM AUTHOR]

P2X receptors, a subfamily of ligand-gated ion channels activated by extracellular ATP, are implicated in various physiopathological processes, including inflammation, pain perception, and immune and respiratory regulations. Structural determinations using crystallography and cryo-EM have revealed that the extracellular three-dimensional architectures of different P2X subtypes across various species are remarkably identical, greatly advancing our understanding of P2X activation mechanisms. However, structural studies yield paradoxical architectures of the intracellular domain (ICD) of different subtypes (e.g., P2X3 and P2X7) at the apo state, and the role of the ICD in P2X functional regulation remains unclear. Here, we propose that the P2X3 receptor's ICD has an apo state conformation similar to the open state but with a less tense architecture, containing allosteric sites that influence P2X3's physiological and pathological roles. Using covalent occupancy, engineered disulfide bonds and voltage-clamp fluorometry, we suggested that the ICD can undergo coordinated motions with the transmembrane domain of P2X3, thereby facilitating channel activation. Additionally, we identified a novel P2X3 enhancer, PSFL77, and uncovered its potential allosteric site located in the 1α3β domain of the ICD. PSFL77 modulated pain perception in P2rx3+/+, but not in P2rx3−/−, mice, indicating that the 1α3β, a "tunable" region implicated in the regulation of P2X3 functions. Thus, when P2X3 is in its apo state, its ICD architecture is fairly ordered rather than an unstructured outward folding, enabling allosteric modulation of the signaling of P2X3 receptors. The intracellular domain (ICD) of ion channels is crucial for the regulation of channel activity and signal transduction. Here the authors show that the P2X3 receptor's ICD can move in coordination with the transmembrane region and facilitate channel activation. [ABSTRACT FROM AUTHOR]

N-methyl-D-aspartate (NMDA) receptors are heterotetrametric ion channels composed of two obligatory GluN1 subunits and two alternative GluN2 or GluN3 subunits, forming GluN1-N2, GluN1-N3, and GluN1-N2-N3 type of NMDA receptors. Extensive research has focused on the functional and structural properties of conventional GluN1–GluN2 NMDA receptors due to their early discovery and high expression levels. However, the knowledge of unconventional GluN1-N3 NMDA receptors remains limited. In this study, we modeled the GluN1-N3A, GluN1-N3B, and GluN1-N3A-N3B NMDA receptors using deep-learned protein-language predication algorithms AlphaFold and RoseTTAFold All-Atom. We then compared these structures with GluN1-N2 and GluN1-N3A receptor cryo-EM structures and found that GluN1-N3 receptors have distinct properties in subunit arrangement, domain swap, and domain interaction. Furthermore, we predicted the agonist- or antagonist-bound structures, highlighting the key molecular–residue interactions. Our findings shed new light on the structural and functional diversity of NMDA receptors and provide a new direction for drug development. This study uses advanced AI algorithms to model GluN1-N3 NMDA receptors, revealing unique structural properties and interactions compared to conventional GluN1-N2 receptors. By highlighting key molecular–residue interactions and predicting ligand-bound structures, our research enhances the understanding of NMDA receptor diversity and offers new insights for targeted drug development. [ABSTRACT FROM AUTHOR]

Spontaneous activity in dorsal root ganglion (DRG) neurons is a key driver of neuropathic pain in patients suffering from this largely untreated disease. While many intracellular signalling mechanisms have been examined in preclinical models that drive spontaneous activity, none have been tested directly on spontaneously active human nociceptors. Using cultured DRG neurons recovered during thoracic vertebrectomy surgeries, we showed that inhibition of mitogen-activated protein kinase interacting kinase (MNK) with tomivosertib (eFT508, 25 nM) reversibly suppresses spontaneous activity in human sensory neurons that are likely nociceptors based on size and action potential characteristics associated with painful dermatomes within minutes of treatment. Tomivosertib treatment also decreased action potential amplitude and produced alterations in the magnitude of after hyperpolarizing currents, suggesting modification of Na+ and K+ channel activity as a consequence of drug treatment. Parallel to the effects on electrophysiology, eFT508 treatment led to a profound loss of eIF4E serine 209 phosphorylation in primary sensory neurons, a specific substrate of MNK, within 2 min of drug treatment. Our results create a compelling case for the future testing of MNK inhibitors in clinical trials for neuropathic pain. [ABSTRACT FROM AUTHOR]

To understand the information processing mechanism of the brain, it is important to decode the bidirectional communication between the brain and organs. For this purpose, computational models were proposed to simulate brain–organ interfaces at different levels of abstraction. Conventional computational models can be modified to understand the bidirectional interactions for further clarification and treatment of morbidity. In this work, a unified model of excitable cells (brain, heart, and pancreatic cells) is proposed that can predict the electrical response with adrenergic features. This enables us to activate the sparsely coupled cardio-neural network to estimate the heart rate variability, one of the key features to identify a healthy heart. The recent advancements in nano- and bioelectronics will make it possible to build and deploy the brain–heart interface as a nanochip in the body to monitor and control the electrophysiological abnormality of the brain and heart by integrating nano-regulators with ion channels for stimulation. [ABSTRACT FROM AUTHOR]

Optimizing the performance of layered double hydroxide (LDH) electrodes by MXene is of significant importance for high-performance asymmetric supercapacitors. In this paper, CoAl-LDH nanosheet-doped s-MXene composites were prepared by a facile hydrothermal method, and two-dimensional layered microstructured CoAl-LDH/s-MXene electrode materials with excellent performance were prepared. The homogeneous growth of CoAl-LDH on s-MXene successfully hinders the agglomeration of CoAl-LDH and provides more layered channels for electron and ion transfer across the electrode material. In addition, CoAl-LDH can effectively suppress the stacking of s-MXene, which increases the electrochemical active site of the material, resulting in an increase in specific capacity. The CoAl-LDH/s-MXene electrode material has a high specific capacity of 1259.9 C g−1 at 1 A g−1, which has outstanding specific capacity and rate capability. The assembled asymmetric CoAl-LDH/s-MXene//AC supercapacitor achieves the desired energy density of 104 and 88 Wh kg−1 at 1500 and 6000 W kg−1. After 5000 laps at 10 A g−1, CoAl-LDH/s-MXene//AC has a capacitance retention rate of 86.6% and a coulomb efficiency of nearly 100%, demonstrating its splendid cycling stability. Therefore, this paper adopts a simple hydrothermal method to prepare CoAl-LDH/s-MXene active material, which provides an effective strategy for constructing supercapacitors with excellent performance. [ABSTRACT FROM AUTHOR]

This article discusses the functional properties of high-affinity K+ transporters (HKTs) in plants, specifically TmHKT1;4-A2 from einkorn and OsHKT2;2 from rice. The researchers used cell-free expression and artificial lipid bilayer membranes to study the transporters at the single-protein level. They found that both TmHKT1;4-A2 and OsHKT2;2 displayed channel-like gating mechanisms and unitary conductances, indicating that they can function as coordinated units. This research provides valuable insights into the mechanisms of salt tolerance in plants and could contribute to the development of crops with improved salt tolerance. [Extracted from the article]

Osteoarthritis (OA) is a highly prevalent joint disease that causes substantial disability, yet effective approaches to disease prevention or to the delay of OA progression are lacking. Emerging evidence has pinpointed ion channels as pivotal mediators in OA pathogenesis and as promising targets for disease-modifying treatments. Preclinical studies have assessed the potential of a variety of ion channel modulators to modify disease pathways involved in cartilage degeneration, synovial inflammation, bone hyperplasia and pain, and to provide symptomatic relief in models of OA. Some of these modulators are currently being evaluated in clinical trials. This review explores the structures and functions of ion channels, including transient receptor potential channels, Piezo channels, voltage-gated sodium channels, voltage-dependent calcium channels, potassium channels, acid-sensing ion channels, chloride channels and the ATP-dependent P2XR channels in the osteoarthritic joint. The discussion spans channel-targeting drug discovery and potential clinical applications, emphasizing opportunities for further research, and underscoring the growing clinical impact of ion channel biology in OA. Ion channels have key functions in chondrocytes, bone cells, immune cells and neurons. Liu and colleagues discuss how these functions might contribute to cartilage degeneration, bone formation inflammation and pain in osteoarthritis, and highlight the therapeutic potential of ion channel modulators. Key points: Ion channels have key functions in the joints and emerge as important contributors to pathogenic processes in osteoarthritis (OA). Dysregulation of mechanical and biochemical stimuli activates ion channels such as TRPV4 and Piezo channels, leading to Ca2+ and Na+ influx, which contributes to cartilage destruction, inflammation and pain in OA. Some ion channels typically associated with peripheral neurons are also expressed in chondrocytes and immune cells, and have a crucial role in the pathophysiology of OA. Exploration of ion channel expression, interactions, and properties in joints, along with development of specific channel agonists and antagonists, has helped to accelerate research on their potential roles in OA. Several ion channel modulators have been recently tested in animal models and patients with OA, with encouraging results. Targeting of ion channels holds promise for the development of new and more effective OA treatment strategies. [ABSTRACT FROM AUTHOR]

Cancer is a pernicious and pressing medical problem; moreover, it is a failure of multicellular morphogenesis that sheds much light on evolutionary developmental biology. Numerous classes of pharmacological agents have been considered as cancer therapeutics and evaluated as potential carcinogenic agents; however, these are spread throughout the primary literature. Here, we briefly review recent work on ion channel drugs as promising anti-cancer treatments and present a systematic review of the known cancer-relevant effects of 109 drugs targeting ion channels. The roles of ion channels in cancer are consistent with the importance of bioelectrical parameters in cell regulation and with the functions of bioelectric signaling in morphogenetic signals that act as cancer suppressors. We find that compounds that are well-known for having targets in the nervous system, such as voltage-gated ion channels, ligand-gated ion channels, proton pumps, and gap junctions are especially relevant to cancer. Our review suggests further opportunities for the repurposing of numerous promising candidates in the field of cancer electroceuticals. [ABSTRACT FROM AUTHOR]

Epithelial Na+ channels (ENaCs) are activated by proteolysis of the α and γ subunits at specific sites flanking embedded inhibitory tracts. To examine the role of α subunit proteolysis in channel activation in vivo, we generated mice lacking the distal furin cleavage site in the α subunit (αF2M mice). On a normal Na+ control diet, no differences in ENaC protein abundance in kidney or distal colon were noted between wild‐type (WT) and αF2M mice. Patch‐clamp analyses revealed similar levels of ENaC activity in kidney tubules, while no physiologically relevant differences in blood chemistry or aldosterone levels were detected. Male αF2M mice did exhibit diminished ENaC activity in the distal colon, as measured by amiloride‐sensitive short‐circuit current (ISC). Following dietary Na+ restriction, WT and αF2M mice had similar natriuretic and colonic ISC responses to amiloride. However, single‐channel activity was significantly lower in kidney tubules from Na+‐restricted αF2M mice compared with WT littermates. ENaC α and γ subunit expression in kidney and distal colon were also enhanced in Na+‐restricted αF2Mvs. WT mice, in association with higher aldosterone levels. These data provide evidence that disrupting α subunit proteolysis impairs ENaC activity in vivo, requiring compensation in response to Na+ restriction. Key points: The epithelial Na+ channel (ENaC) is activated by proteolytic cleavage in vitro, but key questions regarding the role of ENaC proteolysis in terms of whole‐animal physiology remain to be addressed.We studied the in vivo importance of this mechanism by generating a mouse model with a genetic disruption to a key cleavage site in the ENaC's α subunit (αF2M mice).We found that αF2M mice did not exhibit a physiologically relevant phenotype under normal dietary conditions, but have impaired ENaC activation (channel open probability) in the kidney during salt restriction.ENaC function at the organ level was preserved in salt‐restricted αF2M mice, but this was associated with higher aldosterone levels and increased expression of ENaC subunits, suggesting compensation was required to maintain homeostasis.These results provide the first evidence that ENaC α subunit proteolysis is a key regulator of channel activity in vivo. [ABSTRACT FROM AUTHOR]

Transient receptor potential channel canonical 5 (TRPC5) is a non-selective ion channel; ion influx through TRPC5 causes activation of downstream signaling pathways. In addition, TRPC5 has been identified as having a potential role in pathological processes, particularly in diseases caused by cellular cation homeostasis dysregulation, such as bronchial asthma or pulmonary hypertension. However, the expression and distribution of TRPC5 in the human lung remain unclear. To date, TRPC5 has only been detected in a few cell types in the human lung, such as airway, pulmonary venous and arterial smooth muscle cells. The present study therefore aimed to investigate the protein expression of TRPC5 in the human lung and to evaluate its histological distribution. Human lung samples were obtained from six preserved body donors. After processing, both hematoxylin & eosin staining, as well as immunohistochemistry were performed. Microscopic analysis revealed medium to strong immunostaining signals in all lung structures examined, including the pleura, pulmonary arteries and veins, bronchioles, alveolar septa, type 1 and 2 pneumocytes, as well as alveolar macrophages. Current research suggests that TRPC5 may be involved in various pathological processes in the human lung and some pharmacological compounds have already been identified that affect the function of TRPC5. Therefore, TRPC5 may present a novel drug target for therapeutic intervention in various lung diseases. The results of the present study indicate that the TRPC5 protein is expressed in all examined histological structures of the human lung. These findings suggest that TRPC5 may be more important for physiological cell function and pathophysiological cell dysfunction in the lung than is currently known. Further research is needed to explore the role and therapeutic target potential of TRPC5 in the human lung. [ABSTRACT FROM AUTHOR]

Cystic fibrosis (CF) is a life-threatening monogenic disease affecting thousands of people worldwide. Cystic fibrosis transmembrane conductance regulator (CFTR) is an ion channel that facilitates transportation of water and salts across epithelial cell membranes through the conductance of Cl− and other anions. A dysfunctional CFTR due to abnormalities in the cftr gene causes CF, which is believed to be a rare disease in India mainly due to mis/underdiagnosis. Although numerous diagnostic methods and treatment options are available for CF globally, most of these are unaffordable for developing countries like India. Currently, CF symptoms are managed with mucolytics, antibiotics, anti-inflammatory drugs, and various CFTR modulators based on the type of defect. While a definitive cure for CF remains elusive, advancements in stem cell and gene therapies hold promise for permanent cure in the near future. In this review, we discuss the prevalence of CF cases in India, affordable diagnostic methods, and treatment options amenable for developing countries. We further emphasize the scope for the universal newborn screening programme. [ABSTRACT FROM AUTHOR]

Background and Purpose: The voltage‐gated sodium channel isoform NaV1.7 is a high‐interest target for the development of non‐opioid analgesics due to its preferential expression in pain‐sensing neurons. NaV1.7 is also expressed in autonomic neurons, yet its contribution to involuntary visceral reflexes has received limited attention. The small molecule inhibitor ST‐2560 was advanced into pain behaviour and cardiovascular models to understand the pharmacodynamic effects of selective inhibition of NaV1.7. Experimental Approach: Potency of ST‐2560 at NaV1.7 and off‐target ion channels was evaluated by whole‐cell patch‐clamp electrophysiology. Effects on nocifensive reflexes were assessed in non‐human primate (NHP) behavioural models, employing the chemical capsaicin and mechanical stimuli. Cardiovascular parameters were monitored continuously in freely‐moving, telemetered NHPs following administration of vehicle and ST‐2560. Key Results: ST‐2560 is a potent inhibitor (IC50 = 39 nM) of NaV1.7 in primates with ≥1000‐fold selectivity over other isoforms of the human NaV1.x family. Following systemic administration, ST‐2560 (0.1–0.3 mg·kg−1, s.c.) suppressed noxious mechanical‐ and chemical‐evoked reflexes at free plasma concentrations threefold to fivefold above NaV1.7 IC50. ST‐2560 (0.1–1.0 mg·kg−1, s.c.) also produced changes in haemodynamic parameters, most notably a 10‐ to 20‐mmHg reduction in systolic and diastolic arterial blood pressure, at similar exposures. Conclusions and Implications: Acute pharmacological inhibition of NaV1.7 is antinociceptive, but also has the potential to impact the cardiovascular system. Further work is merited to understand the role of NaV1.7 in autonomic ganglia involved in the control of heart rate and blood pressure, and the effect of selective NaV1.7 inhibition on cardiovascular function. [ABSTRACT FROM AUTHOR]

Background and Purpose: Pulpitis is associated with tooth hypersensitivity and results in pulpal damage. Thermosensitive transient receptor potential (TRP) ion channels expressed in the dental pulp may be key transducers of inflammation and nociception. We aimed at investigating the expression and role of thermo‐TRPs in primary human dental pulp cells (hDPCs) in normal and inflammatory conditions. Experimental Approach: Inflammatory conditions were induced in hDPC cultures by applying polyinosinic:polycytidylic acid (poly(I:C)). Gene expression and pro‐inflammatory cytokine release were measured by RT‐qPCR and ELISA. Functions of TRPA1 channels were investigated by monitoring changes in intracellular Ca2+ concentration. Mitochondrial superoxide production was measured using a fluorescent substrate. Cellular viability was assessed by measuring the activity of mitochondrial dehydrogenases and cytoplasmic esterases. TRPA1 activity was modified by agonists, antagonists, and gene silencing. Key Results: Transcripts of TRPV1, TRPV2, TRPV4, TRPC5, and TRPA1 were highly expressed in control hDPCs, whereas TRPV3, TRPM2, and TRPM3 expressions were much lower, and TRPM8 was not detected. Poly(I:C) markedly up‐regulated TRPA1 but not other thermo‐TRPs. TRPA1 agonist‐induced Ca2+ signals were highly potentiated in inflammatory conditions. Poly(I:C)‐treated cells displayed increased Ca2+ responses to H2O2, which was abolished by TRPA1 antagonists. Inflammatory conditions induced oxidative stress, stimulated mitochondrial superoxide production, resulted in mitochondrial damage, and decreased cellular viability of hDPCs. This inflammatory cellular damage was partly prevented by the co‐application of TRPA1 antagonist or TRPA1 silencing. Conclusion and Implications: Pharmacological blockade of TRPA1 channels may be a promising therapeutic approach to alleviate pulpitis and inflammation‐associated pulpal damage. [ABSTRACT FROM AUTHOR]

Psychiatric disorders such as Bipolar disorder, Anxiety, Major depressive disorder, Schizophrenia, Attention-deficit/hyperactivity disorder, as well as neurological disorders such as Migraine, are linked by the evidence of altered calcium homeostasis. The disturbance of intra-cellular calcium homeostasis disrupts the activity of numerous ion channels including transient receptor potential (TRP) channels. TRP channel families comprise non-selective calcium-permeable channels that have been implicated in variety of physiological processes in the brain, as well as in the pathogenesis of psychiatric disorders. Through a comprehensive review of current research and experimentation, this investigation elucidates the role of TRP channels in psychiatric disorders. Furthermore, this review discusses about the exploration of epigenetics and TRP channels in psychiatric disorders. [ABSTRACT FROM AUTHOR]

In addition to insulin-secreting β-cells, other islet endocrine and non-endocrine cells exhibit adaptive changes during pregnancy. The postpartum period and lactation also regulate islet structure and function, including changes that reverse gestational adaptations. Single-cell transcriptomics and other recent studies have identified regulators of gestational and postpartum adaptations, including transcription factors, secreted proteins, and ion channels. Aspects of gestational and postpartum adaptations may be unique and distinct from other compensatory adaptations to metabolic stress. Pancreatic islets, particularly insulin-producing β-cells, are central regulators of glucose homeostasis capable of responding to a variety of metabolic stressors. Pregnancy is a unique physiological stressor, necessitating the islets to adapt to the complex interplay of maternal and fetal–placental factors influencing the metabolic milieu. In this review we highlight studies defining gestational adaptation mechanisms within maternal islets and emerging studies revealing islet adaptations during the early postpartum and lactation periods. These include adaptations in both β and in 'non-β' islet cells. We also discuss insights into how gestational and postpartum adaptation may inform pregnancy-specific and general mechanisms of islet responses to metabolic stress and contribute to investigation of gestational diabetes. [ABSTRACT FROM AUTHOR]

Artificial ion channels that enable high-efficiency ion transport have important implications in nanofluidics and biomedical applications such as drug delivery. Herein, we show a simulation-based chemical design of a biomimetic sodium channel that possesses permeation rate and selectivity potentially higher than those of the state-of-the-art natural vertebrate voltage-gated sodium channels. Importantly, our theoretical findings have undergone empirical testing, aligning well with the Arrhenius law as derived from a diverse range of experimental results. The high-efficiency ion transport is achieved by anchoring the carboxylate functional groups within the channel filter. A key chemical guiding principle underlying the ion channel design is that the freeenergy barrier for the Na+ passage across the channel should be comparable to typical thermal energy at room temperature. With the implementation of the chemical design, we found that the relatively low free-energy barrier can be attributed to the compensation effect of the carboxylate groups to the partially lost oxygen shell of the ion within the ion channel, as well as to the consonant vibration of the ions inside and outside the channel. This mechanistic understanding brings new insight, at the molecular level, into the high-efficiency ion transport across the designed membrane channels. The proof of principle achieved from the simulations will stimulate future experimental confirmation and potential applications of the high-performance artificial channels in nanofluidics and in bioinspired iontronics. [ABSTRACT FROM AUTHOR]

Decidualization describes the transformation of the uterine stroma in response to an implanting embryo, a process critical for supporting the development of the early embryo, for ensuring normal placentation and ultimately for a healthy reproductive outcome. Maternal age has been found to impede the progression of decidualization, heightening the risk of reproductive problems. Here, we set out to comprehensively characterize this deficit by pursuing transcriptomic and epigenomic profiling approaches specifically in the uterine stromal cell (UtSC) compartment of young and aged female mice. We find that UtSCs from aged females are globally far less responsive to the decidualization stimulus triggered by exposure to the steroid hormones estrogen and progesterone. Despite an overall transcriptional hyperactivation of genes that are differentially expressed as a function of maternal age, the hormonally regulated genes specifically fail to be activated in aged UtSCs. Moreover, even in their unstimulated 'ground' state, UtSCs from aged females are epigenetically distinct, as determined by genomic enrichment profiling for the active and repressive histone marks H3K4me3 and H3K9me3, respectively. We find that many hormoneinducible genes exhibit a profound lack of promoter-associated H3K4me3 in aged UtSCs, implying that a significant enrichment of active histone marks prior to gene stimulation is required to enable the elicitation of a rapid transcriptional response. With this combination of criteria, our data highlight specific deficits in epigenetic marking and gene expression of ion channels and vascular markers. These results point to fundamental defects in musclerelated and perivascular niche functions of the uterine stroma with advanced maternal age. [ABSTRACT FROM AUTHOR]

The transport of ions through biological ion channels is regulated not only by their structural characteristics but also by the composition of the phospholipid membrane, which serves as a carrier for nanochannels. Inspired by the modulation of ion currents by lipid membrane composition, exemplified by the activation of the K+ channel of Streptomyces A by anionic lipids, we present a biomimetic nanochannel system based on combining DNA nanotechnology with two-dimensional graphene oxide (GO) nanosheets. By designing multibranched DNA nanowires, we assemble programmable DNA scaffold networks (DSNs) on the GO surface to precisely control membrane composition. Modulating the DSN layers from one to five enhances DNA composition, yielding a maximum 12-fold enhancement in ion current, primarily due to charge effects. Incorporating DNAzymes facilitates reversible modulation of membrane composition, enabling cyclic conversion of ion current. This approach offers a pathway for creating devices with highly efficient, tunable ion transport, applicable in diverse fields like mass transport, environmental protection, biomimetic channels, and biosensors. [ABSTRACT FROM AUTHOR]

ABSTRACT This review paper explores the critical role of vascular ion channels in the regulation of cerebral artery function and examines the impact of Alzheimer's disease (AD) on these processes. Vascular ion channels are fundamental in controlling vascular tone, blood flow, and endothelial function in cerebral arteries. Dysfunction of these channels can lead to impaired cerebral autoregulation, contributing to cerebrovascular pathologies. AD, characterized by the accumulation of amyloid beta (Aβ) plaques and neurofibrillary tangles, has been increasingly linked to vascular abnormalities, including altered vascular ion channel activity. Here, we briefly review the role of vascular ion channels in cerebral blood flow control and neurovascular coupling. We then examine the vascular defects in AD, the current understanding of how AD pathology affects vascular ion channel function, and how these changes may lead to compromised cerebral blood flow and neurodegenerative processes. Finally, we provide future perspectives and conclusions. Understanding this topic is important as ion channels may be potential therapeutic targets for improving cerebrovascular health and mitigating AD progression. [ABSTRACT FROM AUTHOR]

Tetrodotoxin (TTX) is a highly potent and widely distributed ion-channel marine neurotoxin; it has no specific antidote and poses a great risk to human health. Therefore, detecting and quantifying TTX to effectively implement prevention strategies is important for food safety. The development of novel and highly sensitive, highly specific, rapid, and simple techniques for trace TTX detection has attracted widespread attention. This review summarizes the latest advances in the detection and quantitative analysis of TTX, covering detection methods based on biological and cellular sensors, immunoassays and immunosensors, aptamers, and liquid chromatography-mass spectrometry. It further discusses the advantages and applications of various detection technologies developed for TTX and focuses on the frontier areas and development directions of TTX detection, providing relevant information for further investigations. [ABSTRACT FROM AUTHOR]

Neuromodulation is a powerful tool for fundamental studies in neuroscience and potential treatments of neurological disorders. Both photoacoustic (PA) and photothermal (PT) effects are harnessed for non‐genetic high‐precision neural stimulation. Using a fiber‐based device excitable by a nanosecond pulsed laser and a continuous wave laser for PA and PT stimulation, respectively, PA and PT neuromodulation is systematically investigated at the single neuron level. These results show that to achieve the same level of neuron activation recorded by Ca2+ imaging, the laser energy needed for PA stimulation is 1/40 of that needed for PT stimulation. The threshold energy for PA stimulation is found to be further reduced in neurons overexpressing mechano‐sensitive channels, indicating direct involvement of mechano‐sensitive channels in PA stimulation. Electrophysiology study of single neurons upon PA and PT stimulation is performed by patch clamp recordings. Electrophysiological features induced by PA are distinct from those by PT, confirming that PA and PT stimulation operate through different mechanisms. These insights offer a foundation for the rational design of more efficient and safer non‐genetic neural modulation approaches. [ABSTRACT FROM AUTHOR]

Synthetic structures mimicking the transport function of natural ion channel proteins have a wide range of applications, including therapeutic treatments, separation membranes, sensing, and biotechnologies. However, the development of polymer‐based artificial channels has been hampered due to the limitation on available models. In this study, we demonstrate the great potential of bottlebrush polymers as accessible and versatile molecular scaffolds for developing efficient artificial ion channels. Adopting the bottlebrush configuration enhanced ion transport activity of the channels compared to their linear analogs. Matching the structure of lipid bilayers, the bottlebrush channel with a hydrophilic‐hydrophobic‐hydrophilic triblock architecture exhibited the highest activity among the series. Functionalized with urea groups, these channels displayed high anion selectivity. Additionally, we illustrated that the transport properties could be fine‐tuned by modifying the chemistry of ion binding sites. This work not only highlights the importance of polymer topology control in channel design, but also reveals the great potential for further developing bottlebrush channels with customized features and diverse functionalities. [ABSTRACT FROM AUTHOR]

Polyamidoxime (PAO) and its derivatives are widely regarded as promising adsorbents for uranium extraction from seawater. However, their close‐packed structure encapsulates a large number of adsorption sites and slows down the transfer rate of uranyl ions, resulting in a slight uranium adsorption capacity. Herein, PAO polymer chains are synthesized through the molecular coordination template method in the carboxylate covalent organic framework (COF) to obtain a PAO‐inserted COF adsorbent with open ion transport channels. After removing the protons, the COO− groups form in situ electric fields inside the 0.7 nm COF channel. This negatively‐charged framework reduces the electrostatic repulsion among uranium cations, thus realizing ultrahigh utilization of adsorption sites of PAO polymer (81.0%), far exceeding that of classical amidoxime‐based adsorbents (33.7%). After 10 days of contact with natural seawater, COF‐PAO achieved an average capacity of ≈12.26 mg‐U per g for uranium in Bohai (China), satisfying the uranium extraction standard (6.0 mg g−1). This work enumerates a method for the control of the spatial environment of polymer chains, and provides guidance for the design of subsequent high‐efficiency adsorbents. [ABSTRACT FROM AUTHOR]

Ligands such as insulin, epidermal growth factor, platelet-derived growth factor, and nerve growth factor (NGF) initiate signals at the cell membrane by binding to receptor tyrosine kinases (RTKs). Along with G-protein-coupled receptors, RTKs are the main platforms for transducing extracellular signals into intracellular signals. Studying RTK signaling has been a challenge, however, due to the multiple signaling pathways to which RTKs typically are coupled, including MAP/ERK, PLCγ, and Class 1A phosphoinositide 3-kinases (PI3K). The multi-pronged RTK signaling has been a barrier to isolating the effects of any one downstream pathway. Here, we used optogenetic activation of PI3K to decouple its activation from other RTK signaling pathways. In this context, we used genetic code expansion to introduce a click chemistry noncanonical amino acid into the extracellular side of membrane proteins. Applying a cell-impermeant click chemistry fluorophore allowed us to visualize delivery of membrane proteins to the plasma membrane in real time. Using these approaches, we demonstrate that activation of PI3K, without activating other pathways downstream of RTK signaling, is sufficient to traffic the TRPV1 ion channels and insulin receptors to the plasma membrane. [ABSTRACT FROM AUTHOR]

Objective Methods Results Interpretation 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.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.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.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 [ABSTRACT FROM AUTHOR]

Key points Mammalian olfactory sensory neurons (OSNs) generate an odorant‐induced response by sequentially activating two ion channels, which are in their ciliary membranes. First, a cationic, Ca2+‐permeable cyclic nucleotide‐gated channel is opened following odorant stimulation via a G protein‐coupled transduction cascade and an ensuing rise in cAMP. Second, the increase in ciliary Ca2+ opens the excitatory Ca2+‐activated Cl− channel TMEM16B, which carries most of the odorant‐induced receptor current. While the role of TMEM16B in amplifying the response has been well established, it is less understood how this secondary ion channel contributes to response kinetics and action potential generation during single as well as repeated stimulation and, on the other hand, which response properties the cyclic nucleotide‐gated (CNG) channel determines. We first demonstrate that basic membrane properties such as input resistance, resting potential and voltage‐gated currents remained unchanged in OSNs that lack TMEM16B. The CNG channel predominantly determines the response delay and adaptation during odorant exposure, while the absence of the Cl− channels shortens both the time the response requires to reach its maximum and the time to terminate after odorant stimulation. This faster response termination in Tmem16b knockout OSNs allows them, somewhat counterintuitively despite the large reduction in receptor current, to fire action potentials more reliably when stimulated repeatedly in rapid succession, a phenomenon that occurs both in isolated OSNs and in OSNs within epithelial slices. Thus, while the two olfactory ion channels act in concert to generate the overall response, each one controls specific aspects of the odorant‐induced response. Mammalian olfactory sensory neurons (OSNs) generate odorant‐induced responses by activating two ion channels sequentially in their ciliary membranes: a Na+, Ca2⁺‐permeable cyclic nucleotide‐gated (CNG) channel and the Ca2⁺‐activated Cl⁻ channel TMEM16B. The CNG channel controls response delay and adaptation during odorant exposure, while TMEM16B amplifies the response and influences the time required for the response to reach its peak and terminate. OSNs lacking TMEM16B display faster response termination, allowing them to fire action potentials more reliably during rapid repeated stimulation. The CNG and TMEM16B channels have distinct and complementary roles in shaping the kinetics and reliability of odorant‐induced responses in OSNs. [ABSTRACT FROM AUTHOR]

Osteoporosis, a systemic skeletal disorder marked by diminished bone mass and compromised bone microarchitecture, is becoming increasingly prevalent due to an aging population. The underlying pathophysiology of osteoporosis is attributed to an imbalance between osteoclast-mediated bone resorption and osteoblast-mediated bone formation. Osteoclasts play a crucial role in the development of osteoporosis through various molecular pathways, including the RANK/RANKL/OPG signaling axis, cytokines, and integrins. Notably, the calcium signaling pathway is pivotal in regulating osteoclast activation and function, influencing bone resorption activity. Disruption in calcium signaling can lead to increased osteoclast-mediated bone resorption, contributing to the progression of osteoporosis. Emerging research indicates that calciumpermeable channels on the cellular membrane play a critical role in bone metabolism by modulating these intracellular calcium pathways. Here, we provide an overview of current literature on the regulation of plasma membrane calcium channels in relation to bone metabolism with particular emphasis on their dysregulation during the progression of osteoporosis. Targeting these calcium channels may represent a potential therapeutic strategy for treating osteoporosis. [ABSTRACT FROM AUTHOR]

Water splitting is an important approach to hydrogen production. But the efficiency of the process is always controlled by the oxygen evolution reaction process. In this study, a three-dimensional nickel–molybdenum binary nanoarray microstructure electrocatalyst is successfully synthesized. It is grown uniformly on Ni foam using a hydrothermal method. Attributed to their unique nanostructure and controllable nature, the Ni-Mo-based nanoarray samples show superior reactivity and durability in oxygen evolution reactions. The series of Ni-Mo-based electrocatalysts presents a competitive overpotential of 296 mV at 10 mA·cm−2 for an OER in 1.0 M KOH, corresponding with a low Tafel slope of 121 mV dec−1. The three-dimensional nanostructure has a large double-layer capacitance and plenty of channels for ion transfer, which demonstrates more active sites and improved charge transmission. This study provides a valuable reference for the development of non-precious catalysts for water splitting. [ABSTRACT FROM AUTHOR]

Simple Summary: It is of great significance to explore the synergistic mechanisms of the brain and muscle in Eriocheir sinensis in response to environmental stress. In the present study, proteomics, metabolomics, and combination analyses of the cerebral ganglion and muscle of Eriocheir sinensis under alkalinity stress were performed. The results indicated that the cerebral ganglion and muscle played a significant synergistic regulatory role in alkalinity adaptation. This study provides a theoretical reference for further research on the mechanisms of the regulation of the growth and development of E. sinensis in saline–alkaline environments. The cerebral ganglion and muscle are important regulatory tissues in Eriocheir sinensis. Therefore, it is of great significance to explore their synergistic roles in this organism's anti-stress response. In this study, proteomics, metabolomics, and combination analyses of the cerebral ganglion and muscle of E. sinensis under alkalinity stress were performed. The cerebral ganglion and muscle played a significant synergistic regulatory role in alkalinity adaptation. The key regulatory pathways involved were amino acid metabolism, energy metabolism, signal transduction, and the organismal system. They also played a modulatory role in the TCA cycle, nerve signal transduction, immune response, homeostasis maintenance, and ion channel function. In conclusion, the present study provides a theoretical reference for further research on the mechanisms regulating the growth and development of E. sinensis in saline–alkaline environments. In addition, it provides theoretical guidelines for promoting the vigorous development of the E. sinensis breeding industry in saline–alkaline environments in the future. [ABSTRACT FROM AUTHOR]

The lysosomal Ca2+ channel TRPML1 was found to be responsible for gastric acid secretion in murine gastric parietal cells by inducing the trafficking of H+/K+-ATPase containing tubulovesicles to the apical membrane. Therefore, we hypothesized a similar role of TRPML1 in regulating proton secretion in the immortalized human parietal cell line HGT-1. The primary focus was to investigate the involvement of TRPML1 in proton secretion using the known synthetic agonists ML-SA1 and ML-SA5 and the antagonist ML-SI3 and, furthermore, to identify food-derived compounds that target the channel. Proton secretion stimulated by ML-SA1 was reduced by 122.2 ± 22.7% by the antagonist ML-SI3. The steroid hormone 17β-estradiol, present in animal-derived foods, diminished the proton secretory effect of ML-SA1 by 63.4 ± 14.5%. We also demonstrated a reduction in the proton secretory effects of ML-SA1 and ML-SA5 on TRPML1 knock-down cells. The food-derived compounds sulforaphane and trehalose promoted proton secretion in HGT-1 cells but may act independently of TRPML1. Also, histamine- and caffeine-induced proton secretion were affected by neither the TRPML1 antagonist ML-SI3 nor the TRPML1 knock-down. In summary, the results obtained suggest that the activation of TRPML1 promotes proton secretion in HGT-1 cells, but the channel may not participate in canonical signaling pathways. [ABSTRACT FROM AUTHOR]

This comprehensive review critically examines the current state of research on the biological effects of millimeter-wave (MMW) therapy and its potential implications for disease treatment. By investigating both the thermal and non-thermal impacts of MMWs, we elucidate cellular-level alterations, including changes in ion channels and signaling pathways. Our analysis encompasses MMW's therapeutic prospects in oncology, such as inducing apoptosis, managing pain, and modulating immunity through cytokine regulation and immune cell activation. By employing a rigorous methodology involving an extensive database search and stringent inclusion criteria, we emphasize the need for standardized protocols to enhance the reliability of future research. Although MMWs exhibit promising therapeutic potential, our findings highlight the urgent need for further elucidation of non-thermal mechanisms and rigorous safety assessments, considering the intricate nature of MMW interactions and inconsistent study outcomes. This review underscores the importance of focused research on the biological mechanisms of MMWs and the identification of optimal frequencies to fully harness their therapeutic capabilities. However, we acknowledge the challenges of variable study quality and the necessity for advanced quality control measures to ensure the reproducibility and comparability of future investigations. In conclusion, while MMW therapy holds promise as a novel therapeutic modality, further research is imperative to unravel its complex biological effects, establish safety profiles, and optimize treatment protocols before widespread clinical application. [ABSTRACT FROM AUTHOR]