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To locate and fertilize the egg, sperm probe the varying microenvironment prevailing at different stages during their journey across the female genital tract. To this end, they are equipped with a unique repertoire of mostly sperm-specific proteins. In particular, the flagellar Ca2+ channel CatSper has come into focus as a polymodal sensor used by human sperm to register ligands released into the female genital tract. Here, we provide the first comprehensive study on the pharmacology of the sperm-specific human Slo3 channel, shedding light on its modulation by reproductive fluids and their constituents. Weshow that seminal fluid and contained prostaglandins and Zn2+ do not affect the channel, whereas human Slo3 is inhibited in a non-genomic fashion by diverse steroids as well as by albumin, which are released into the oviduct along with the egg. This indicates that not only CatSper but also Slo3 harbours promiscuous ligandbinding sites that can accommodate structurally diverse molecules, suggesting that Slo3 is involved in chemosensory signalling in human sperm. [ABSTRACT FROM AUTHOR]

Neurological disorders such as Alzheimer's, Parkinson's, amyotrophic lateral sclerosis, and schizophrenia are associated with altered neuronal excitability, resulting from dysfunctions in the molecular architecture and physiological regulation of ion channels and synaptic transmission. Ion channels and synapses are regarded as suitable therapeutic targets in modern pharmacology. Cannabinoids have received great attention as an original therapeutic approach for their effects on human health due to their ability to modulate the neurotransmitter release through interaction with the endocannabinoid system. In our study, we explored the effect of cannabinol (CBN) through next-generation sequencing analysis of NSC-34 cell physiology. Our findings revealed that CBN strongly influences the ontologies related to ion channels and synapse activity at all doses tested. Specifically, the genes coding for calcium and potassium voltage-gated channel subunits, and the glutamatergic and GABAergic receptors (Cacna1b, Cacna1h, Cacng8, Kcnc3, Kcnd1, Kcnd2, Kcnj4, Grik5, Grik1, Slc17a7, Gabra5), were up-regulated. Conversely, the genes involved into serotoninergic and cholinergic pathways (Htr3a, Htr3b, Htr1b, Chrna3, Chrnb2, Chrnb4), were down-regulated. These findings highlight the influence of CBN in the expression of genes involved into ion influx and synaptic transmission. [ABSTRACT FROM AUTHOR]

As atrial fibrillation (AF) progresses from initial paroxysmal episodes to the persistent phase, maintaining sinus rhythm for an extended period through pharmacotherapy and catheter ablation becomes difficult. A major cause of the deteriorated treatment outcome is the atrial structural and electrophysiological heterogeneity, which AF itself can exacerbate. This heterogeneity exists or manifests in various dimensions, including anatomically segmental structural features, the distribution of histological fibrosis and the autonomic nervous system, sarcolemmal ion channels, and electrophysiological properties. All these types of heterogeneity are closely related to the development of AF. Recognizing the heterogeneity provides a valuable approach to comprehending the underlying mechanisms in the complex excitatory patterns of AF and the determining factors that govern the seemingly chaotic propagation. Furthermore, substrate modification based on heterogeneity is a potential therapeutic strategy. This review aims to consolidate the current knowledge on structural and electrophysiological atrial heterogeneity and its relation to the pathogenesis of AF, drawing insights from clinical studies, animal and cell experiments, molecular basis, and computer-based approaches, to advance our understanding of the pathophysiology and management of AF. [ABSTRACT FROM AUTHOR]

Infections caused by methicillin-resistant Staphylococcus aureus (MRSA) are a major public health burden. Emerging antibiotic resistance has heightened the need for new treatment approaches for MRSA infection such as developing novel antimicrobial agents and enhancing the host's defense response. The thermo-ion channels Transient Receptor Potential (TRP-) A1 and V1 have been identified as modulators of S. aureus quorum sensing in cell culture models. However, their effects on in vivo infection control are unknown. In this study, we investigated the therapeutic effect of natural TRP ion channel inhibitors on MRSA skin infection in mice. While deletion of TRPV1 did not affect lesion size or inflammatory markers, TRPA1−/− mice demonstrated significantly reduced infection severity and abscess size. Treatment with natural inhibitors of TRPA1 with or without blockade of TRPV1 also reduced abscess size. Tissue transcriptomic data coupled with immunohistochemistry revealed that TRPA1 inhibition impacted heat shock protein expression (HSP), modulated the HIF-1a and MAPK pathways, and reduced IL4 expression. Additionally, metabolomics data showed an impact on purine and glycosaminoglycan pathways. Multi-omic integration of transcriptomic and metabolic data revealed that diacylglycerol metabolism was the likely bridge between metabolic and immunological impacts. Our findings suggest that TRPA1 antagonism could provide a promising and cost-effective therapeutic approach for reducing the severity of MRSA infection, and presents a novel underlying molecular mechanism. [ABSTRACT FROM AUTHOR]

With increasing numbers of patients worldwide diagnosed with diabetes mellitus, renal disease, and iatrogenic immune deficiencies, an increased understanding of the role of electrolyte interactions in mitigating pathogen virulence is necessary. The levels of divalent cations affect host susceptibility and pathogen survival in persons with relative immune insufficiency. For instance, when host cellular levels of calcium are high compared to magnesium, this relationship contributes to insulin resistance and triples the risk of clinical tuberculosis. The movement of divalent cations within intracellular spaces contributes to the host defense, causing apoptosis or autophagy of the pathogen. The control of divalent cation flow is dependent in part upon the mammalian natural resistance-associated macrophage protein (NRAMP) in the host. Survival of pathogens such as M tuberculosis within the bronchoalveolar macrophage is also dependent upon NRAMP. Pathogens evolve mutations to control the movement of calcium through external and internal channels. The host NRAMP as a metal transporter competes for divalent cations with the pathogen NRAMP in M tuberculosis (whether in latent, dormant, or active phase). This review paper summarizes mechanisms of pathogen offense and patient defense using inflow and efflux through divalent cation channels under the influence of parathyroid hormone vitamin D and calcitonin. [ABSTRACT FROM AUTHOR]

Macrophages (MΦ) play pivotal roles in tissue homeostasis and repair. Their mechanical environment has been identified as a key modulator of various cell functions, and MΦ mechanosensitivity is likely to be critical – in particular in a rhythmically contracting organ such as the heart. Cultured MΦ, differentiated in vitro from bone marrow (MΦBM), form a popular research model. This study explores the activity of mechanosensitive ion channels (MSC) in murine MΦBM and compares it to MSC activity in MΦ enzymatically isolated from cardiac tissue (tissue‐resident MΦ; MΦTR). We show that MΦBM and MΦTR have stretch‐induced currents, indicating the presence of functional MSC in their plasma membrane. The current profiles in MΦBM and in MΦTR show characteristics of cation non‐selective MSC such as Piezo1 or transient receptor potential channels. While Piezo1 ion channel activity is detectable in the plasma membrane of MΦBM using the patch‐clamp technique, or by measuring cytosolic calcium concentration upon perfusion with the Piezo1 channel agonist Yoda1, no Piezo1 channel activity was observed in MΦTR. The selective transient receptor potential vanilloid 4 (TRPV4) channel agonist GSK1016790A induces calcium entry in MΦTR and in MΦBM. In MΦ isolated from left‐ventricular scar tissue 28 days after cryoablation, stretch‐induced current characteristics are not significantly different compared to non‐injured control tissue, even though scarred ventricular tissue is expected to be mechanically remodelled and to contain an altered composition of pre‐existing cardiac and circulation‐recruited MΦ. Our data suggest that the in vitro differentiation protocols used to obtain MΦBM generate cells that differ from MΦ recruited from the circulation during tissue repair in vivo. Further investigations are needed to explore MSC identity in lineage‐traced MΦ in scar tissue, and to compare mechanosensitivity of circulating monocytes with that of MΦBM. Key points: Bone marrow‐derived (MΦBM) and tissue resident (MΦTR) macrophages have stretch‐induced currents, indicating expression of functional mechanosensitive channels (MSC) in their plasma membrane.Stretch‐activated current profiles show characteristics of cation non‐selective MSC; and mRNA coding for MSC, including Piezo1 and TRPV4, is expressed in murine MΦBM and in MΦTR.Calcium entry upon pharmacological activation of TRPV4 confirms functionality of the channel in MΦTR and in MΦBM.Piezo1 ion channel activity is detected in the plasma membrane of MΦBM but not in MΦTR, suggesting that MΦBM may not be a good model to study the mechanotransduction of MΦTR.Stretch‐induced currents, Piezo1 mRNA expression and response to pharmacological activation are not significantly changed in cardiac MΦ 28 days after cryoinjury compared to sham operated mice. [ABSTRACT FROM AUTHOR]

Cardiac electrophysiology and mechanics are strongly interconnected. Their interaction is, among others, mediated by mechano‐electric feedback through stretch‐activated ion channels (SACs). The electrophysiological changes induced by SACs may contribute to arrhythmogenesis, but the precise SAC‐induced electrophysiological changes remain incompletely understood. Here, we provide a systematic characterization of stretch effects through three distinguished SACs on cardiac electrophysiology using computational modelling. We implemented potassium‐selective, calcium‐selective and non‐selective SACs in the Tomek–Rodriguez–O'Hara–Rudy model of human ventricular electrophysiology. The model was calibrated to experimental data from isolated cardiomyocytes undergoing stretch, considering inter‐species differences, and disease‐related remodelling of SACs. SAC‐mediated effects on the action potential (AP) were analysed by varying stretch amplitude, application timing and/or duration. Afterdepolarizations of different amplitudes were observed with transient 10‐ms stretch stimuli of 15–18% applied during phase 4, while stretch ≥18% during phase 4 elicited triggered APs. Longer stimuli shifted the threshold of AP trigger during phase 4 to lower amplitudes, while shorter stimuli increased it. Continuous stretch provoked electrophysiological remodelling. Furthermore, stretch shortened duration or changed morphology of a subsequent electrically evoked AP, and, if applied during a vulnerable time window with sufficient amplitude, prevented its occurrence because of stretch‐induced modulation of sodium and L‐type calcium channel gating. These effects were more pronounced with disease‐related SAC remodelling due to increased stretch sensitivity of diseased hearts. We showed that SACs may induce afterdepolarizations and triggered activities, and prevent subsequent AP generation or change its morphology. These effects depend on cardiomyocyte stretch characteristics and disease‐related SACs remodelling and may contribute to cardiac arrhythmogenesis. Key points: The interplay between cardiac electrophysiology and mechanics is mediated by mechano‐electric feedback through stretch‐activated ion channels (SACs). These channels may be pro‐arrhythmic, but their precise effect on electrophysiology remains unclear.Here we present a systematic in silico characterization of stretch effects through three SACs by implementing inter‐species differences as well as disease‐related remodelling of SACs in a novel computational model of human ventricular cardiomyocyte electrophysiology.Our simulations showed that, at the cellular level, SACs may provoke electrophysiological remodelling, afterdepolarizations, triggered activities, change the morphology or shorten subsequent electrically evoked action potentials. The model further suggests that a vulnerable window exists in which stretch prevents the following electrically triggered beat occurrence.The pro‐arrhythmic effects of stretch strongly depend on disease‐related SAC remodelling as well as on stretch characteristics, such as amplitude, time of application and duration. Our study helps in understanding the role of stretch in cardiac arrhythmogenesis and revealing the underlying cellular mechanisms. [ABSTRACT FROM AUTHOR]

Modeled after biological neurons, neuristors are emerging hardware that generate recurring voltage spikes in response to electrical stimulation. This type of excitability can enable transistor‐free spiking neural networks for efficient signal processing and computing. Yet, most neuristors consist of circuits containing numerous devices, thus complicating fabrication and increasing size, power usage, and cost. In contrast, it is shown that a single, 5nm‐thick lipid membrane functionalized with voltage‐activated peptides functions as a two‐terminal, ultra‐low power (fW‐pW) artificial neuristor in response to supplied current. Specifically, the biomolecular membrane generates stochastic voltage oscillations (10–150 mV) in response to direct currents (|5–40| pA), and is capable of generating two distinct types of action potentials fast (≈1–50 ms) and slow (≈1–2 s) spikes via distinct physical mechanisms. This discovery showcases the inherent multifunctionality and modularity of engineered biomembranes, and it contributes to an expanding suite of ionic and biomolecular devices designed with synapse and neuron functionalities for emerging computing architectures. [ABSTRACT FROM AUTHOR]

Transmembrane channel-like (TMC) proteins are a highly conserved ion channel family consisting of eight members (TMC1–TMC8) in mammals. TMC1/2 are components of the mechanotransduction channel in hair cells, and mutations of TMC1/2 cause deafness in humans and mice. However, the physiological roles of other TMC proteins remain largely unknown. Here, we show that Tmc7 is specifically expressed in the testis and that it is required for acrosome biogenesis during spermatogenesis. Tmc7−/− mice exhibited abnormal sperm head, disorganized mitochondrial sheaths, and reduced number of elongating spermatids, similar to human oligo-asthenoteratozoospermia. We further demonstrate that TMC7 is colocalized with GM130 at the cis-Golgi region in round spermatids. TMC7 deficiency leads to aberrant Golgi morphology and impaired fusion of Golgi-derived vesicles to the developing acrosome. Moreover, upon loss of TMC7 intracellular ion homeostasis is impaired and ROS levels are increased, which in turn causes Golgi and endoplasmic reticulum stress. Taken together, these results suggest that TMC7 is required to maintain pH and ion homeostasis, which is needed for acrosome biogenesis. Our findings unveil a novel role for TMC7 in acrosome biogenesis during spermiogenesis. [ABSTRACT FROM AUTHOR]

As the key component of various energy storage and conversion devices, proton exchange membranes (PEMs) have been attracting significant interest. However, their further development is limited by the high cost of perfluorosulfonic acid polymers and the poor stability of acid‐dopped non‐fluorinated polymers. Recently, a new group of PEMs has been developed by hybridizing polyoxometalates (POMs), a group of super acidic sub‐nanoscale metal oxide clusters, with polymers. POMs can serve simultaneously as both proton sponges and stabilizing agents, and their complexation with polymers can further improve polymers' mechanical performance and processability. Enormous efforts have been focused on studying supramolecular complexation or covalent grafting of POMs with various polymers to optimize PEMs in terms of cost, mechanical properties and stabilities. This concept summarizes recent advances in this emerging field and outlines the design strategies and application perspectives employed for using POM‐polymer hybrid materials as PEMs. [ABSTRACT FROM AUTHOR]

Cellulose‐based solid electrolyte possesses the characteristics of low cost, high strength, and sustainability, and has great potential in the field of solid‐state lithium metal batteries. However, the large hydrogen bonds between cellulose molecules make the molecular chains tightly arranged, and hinder the ion conduction, seriously limiting its further development. Herein, an ion‐conducting molecular grafting strategy is proposed for the fabrication of cellulose acetate quasi‐solid composite electrolyte (CLA‐CN‐LATP QCE) with a superior ionic conductivity of 1.25 × 10−3 S cm−1 at room temperature. Benefited from grafted functional molecules, the assembled symmetrical battery exhibits low polarization voltage and highly stable lithium stripping/plating cycling of more than 1200 h at 0.1 mA cm−2 current density. Moreover, it endows LFP|CLA‐CN‐LATP QCE|Li battery with excellent long‐cycle stability of 1500 cycles at 0.5 C and 25 °C and superior capacity retention of 92.1%. Importantly, this work provides an effective strategy for further opening the ion transport channel between cellulose molecular chains and improving the interface properties of electrolytes and electrodes. [ABSTRACT FROM AUTHOR]

Transition metal oxides ion diffusion channels have been developed for ammonium-ion batteries (AIBs). However, the influence of microstructural features of diffusion channels on the storage and diffusion behavior of NH4+ is not fully unveiled. In this study, by using MnCo2O4 spinel as a model electrode, the asymmetric ion diffusion channels of MnCo2O4 have been regulated through bond length optimization strategy and investigate the effect of channel size on the diffusion process of NH4+. In addition, the reducing channel size significantly decreases NH4+ adsorption energy, thereby accelerating hydrogen bond formation/fracture kinetics and NH4+ reversible diffusion within 3D asymmetric channels. The optimized MnCo2O4 with oxygen vacancies/carbon nanotubes composite exhibits impressive specific capacity (219.2 mAh g-1 at 0.1 A g-1) and long-cycle stability. The full cell with 3,4,9,10-perylenetetracarboxylic diimide anode demonstrates a remarkable energy density of 52.3 Wh kg-1 and maintains 91.9% capacity after 500 cycles. This finding provides a unique approach for the development of cathode materials in AIBs. [ABSTRACT FROM AUTHOR]

Human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) have gained traction as a powerful model in cardiac disease and therapeutics research, since iPSCs are self-renewing and can be derived from healthy and diseased patients without invasive surgery. However, current iPSC-CM differentiation methods produce cardiomyocytes with immature, fetal-like electrophysiological phenotypes, and the variety of maturation protocols in the literature results in phenotypic differences between labs. Heterogeneity of iPSC donor genetic backgrounds contributes to additional phenotypic variability. Several mathematical models of iPSC-CM electrophysiology have been developed to help to predict cell responses, but these models individually do not capture the phenotypic variability observed in iPSC-CMs. Here, we tackle these limitations by developing a computational pipeline to calibrate cell preparation-specific iPSC-CM electrophysiological parameters. We used the genetic algorithm (GA), a heuristic parameter calibration method, to tune ion channel parameters in a mathematical model of iPSC-CM physiology. To systematically optimize an experimental protocol that generates sufficient data for parameter calibration, we created in silico datasets by simulating various protocols applied to a population of models with known conductance variations, and then fitted parameters to those datasets. We found that calibrating to voltage and calcium transient data under 3 varied experimental conditions, including electrical pacing combined with ion channel blockade and changing buffer ion concentrations, improved model parameter estimates and model predictions of unseen channel block responses. This observation also held when the fitted data were normalized, suggesting that normalized fluorescence recordings, which are more accessible and higher throughput than patch clamp recordings, could sufficiently inform conductance parameters. Therefore, this computational pipeline can be applied to different iPSC-CM preparations to determine cell line-specific ion channel properties and understand the mechanisms behind variability in perturbation responses. Author summary: Many drug treatments or environmental factors can trigger cardiac arrhythmias, which are dangerous and often unpredictable. Human cardiomyocytes derived from donor stem cells have proven to be a promising model for studying these events, but variability in donor genetic background and cell maturation methods, as well as overall immaturity of stem cell-derived cardiomyocytes relative to the adult heart, have hindered reproducibility and reliability of these studies. Mathematical models of these cells can aid in understanding the underlying electrophysiological contributors to this variability, but determining these models' parameters for multiple cell preparations is challenging. In this study, we tackle these limitations by developing a computational method to simultaneously estimate multiple model parameters using data from imaging-based experiments, which can be easily scaled to rapidly characterize multiple cell lines. This method can generate many personalized models of individual cell preparations, improving drug response predictions and revealing specific differences in electrophysiological properties that contribute to variability in cardiac maturity and arrhythmia susceptibility. [ABSTRACT FROM AUTHOR]

This article explores the concept of paraptosis, a type of programmed cell death that is different from apoptosis and necrosis. It discusses the mechanisms of paraptosis and highlights the potential of natural products to induce paraptosis in cancer cells, offering an alternative to traditional cancer therapies. The article also mentions the potential of paraptosis in enhancing tumor immunogenicity and triggering immune responses against cancer cells. Clinical trials are being conducted to test the efficacy and safety of paraptosis in cancer treatment, although challenges such as the lack of rigorous clinical trials and difficulties in large-scale isolation and standardization of natural products exist. Overall, the article provides valuable insights into the field of paraptosis and its potential applications in cancer therapy. [Extracted from the article]

While natural channels respond to external stimuli to regulate ion concentration across cell membranes, creating a synthetic version remains challenging. Here, we present a photo‐responsive uncaging technique within an artificial ion channel system, which activates the ion transport process from a transport‐inactive o‐nitrobenzyl‐based caged system. From the comparative ion transport screening, 1 b emerged as the most active transporter. Interestingly, its bis(o‐nitrobenzyl) derivative, i.e., protransporter 1 b′ was inefficient in transporting ions. Detailed transport studies indicated that compound 1 b is an anion selective transporter with a prominent selectivity towards chloride ions by following the antiport mechanism. Compound 1 b′ did not form an ion channel, but after the o‐nitrobenzyl groups were photocleaved, it released 1 b, forming a transmembrane ion channel. The channel exhibited an average diameter of 6.5±0.2 Å and a permeability ratio of PCl-/PK+=7.3±1.5 ${{P}_{{Cl}^{-}}/{P}_{{K}^{+}}=7.3\pm 1.5}$ . The geometry‐optimization of protransporter 1 b′ indicated significant non‐planarity, corroborating its inefficient self‐assembly. In contrast, the crystal structure of 1 b demonstrates strong self‐assembly via the formation of an intermolecular H‐bond. Geometry optimization studies revealed the plausible self‐assembled channel model and the interactions between the channel and chloride ion. [ABSTRACT FROM AUTHOR]

Cystic fibrosis transmembrane conductance regulator (CFTR) protein is an ion channel found in numerous epithelia and controls the flow of water and salt across the epithelium. The aim of our study to find natural compounds that can improve lung function for people with cystic fibrosis (CF) caused by the p.Gly628Arg (rs397508316) mutation of CFTR protein. The sequence of CFTR protein as a target structure was retrieved from UniProt and PDB database. The ligands that included Armepavine, Osthole, Curcumin, Plumbagine, Quercetin, and one Trikafta (R*) reference drug were screened out from PubChem database. Autodock vina software carried out docking, and binding energies between the drug and the target were included using docking-score. The following tools examined binding energy, interaction, stability, toxicity, and visualize protein-ligand complexes. The compounds having binding energies of −6.4, −5.1, −6.6, −5.1, and − 6.5 kcal/mol for Armepavine, Osthole, Curcumin, Plumbagine, Quercetin, and R*-drug, respectively with mutated CFTR (Gly628Arg) structure were chosen as the most promising ligands. The ligands bind to the mutated CFTR protein structure active sites in hydrophobic bonds, hydrogen bonds, and electrostatic interactions. According to ADMET analyses, the ligands Armepavine and Quercetin also displayed good pharmacokinetic and toxicity characteristics. An MD simulation for 200 ns was also established to ensure that Armepavine and Quercetin ligands attached to the target protein favorably and dynamically, and that protein-ligand complex stability was maintained. It is concluded that Armepavine and Quercetin have stronger capacity to inhibit the effect of mutated CFTR protein through improved trafficking and restoration of original function. [ABSTRACT FROM AUTHOR]

Background Objective Results Conclusion Changes in K+ channel expression/function are associated with disruption of vascular reactivity in several pathological conditions, including hypertension, diabetes, and atherosclerosis. Gasotransmitters achieve part of their effects in the organism by regulating ion channels, especially K+ channels. Their involvement in hydrogen sulfide (H2S)‐mediated vasorelaxation is still unclear, and data about human vessels are limited.To determine the role of K+ channel subtypes in the vasorelaxant mechanism of H2S donor, sodium‐hydrosulfide (NaHS), on isolated human internal mammary artery (HIMA).NaHS (1 × 10−6–3 × 10−3 mol/L) induced a concentration‐dependent relaxation of HIMA pre‐contracted by phenylephrine and high K+. Among K+ channel blockers, iberiotoxin, glibenclamide, 4‐aminopyridine (4‐AP), and margatoxin significantly inhibited NaHS‐induced relaxation of phenylephrine‐contracted HIMA (P < 0.01), whereas in the presence of apamin/1‐[(2‐chlorophenyl) diphenylmethyl]‐1H‐pyrazole (TRAM‐34) combination, the HIMA relaxation was partially reduced (P < 0.05). The effect of NaHS was antagonized by NO pathway inhibitors, L‐NAME and KT5823, and by cyclo‐oxygenase inhibitor, indomethacin (P < 0.01). Under conditions of blocked NO/prostacyclin synthesis and release, apamin/TRAM‐34 and glibenclamide caused further decrease in NaHS‐induced vasorelaxation (P < 0.01), while iberiotoxin, 4‐AP, and margatoxin were without additional effect (P > 0.05). In the presence of nifedipine, NaHS induced partial relaxation of HIMA (P < 0.01).Our results demonstrated that H2S donor, NaHS, induced concentration‐dependent relaxation of isolated HIMA. Vasorelaxant mechanisms of H2S included direct or indirect opening of different K+ channel subtypes, KATP, BKCa, SKCa/IKCa, and KV (subtype KV1.3), in addition to NO pathway activation and interference with extracellular Ca2+ influx. [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]

Gliomas are highly malignant brain tumours that remain refractory to treatment. Treatment is typically surgical intervention followed by concomitant temozolomide and radiotherapy; however patient prognosis remains poor. Voltage gated ion channels have emerged as novel targets in cancer therapy and inhibition of a potassium selective subtype (hERG, Kv11.1) has demonstrated antitumour activity. Unfortunately blockade of hERG has been limited by cardiotoxicity, however hERG channel agonists have produced similar chemotherapeutic benefit without significant side effects. In this study, electrophysiological recordings suggest the presence of hERG channels in the anaplastic astrocytoma cell line SMA-560, and treatment with the hERG channel agonist NS1643, resulted in a significant reduction in the proliferation of SMA-560 cells. In addition, NS1643 treatment also resulted in a reduction of the secretion of matrix metalloproteinase-9 and SMA-560 cell migration. When combined with temozolomide, an additive impact was observed, suggesting that NS1643 may be a suitable adjuvant to temozolomide and limit the invasiveness of glioma. [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]

The inward rectifier potassium channel Kir2.1 (KCNJ2) is an important regulator of resting membrane potential in both excitable and non-excitable cells. The functions of Kir2.1 channels are dependent on their lipid environment, including the availability of PI(4,5)P2, secondary anionic lipids, cholesterol and long-chain fatty acids acyl coenzyme A (LC-CoA). Endocannabinoids are a class of lipids that are naturally expressed in a variety of cells, including cardiac, neuronal, and immune cells. While these lipids are identified as ligands for cannabinoid receptors there is a growing body of evidence that they can directly regulate the function of numerous ion channels independently of CBRs. Here we examine the effects of a panel of endocannabinoids on Kir2.1 function and demonstrate that a subset of endocannabinoids can alter Kir2.1 conductance to varying degrees independently of CBRs. Using computational and Surface plasmon resonance analysis, endocannabinoid regulation of Kir2.1 channels appears to be the result of altered membrane properties, rather than through direct protein-lipid interactions. Furthermore, differences in endocannabinoid effects on Kir4.1 and Kir7.1 channels, indicating that endocannabinoid regulation is not conserved among Kir family members. These findings may have broader implications on the function of cardiac, neuronal and/or immune cells. [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]

Metropolitan Mexico City (MMC) children and young adults exhibit overlapping Alzheimer and Parkinsons' diseases (AD, PD) and TAR DNA-binding protein 43 pathology with magnetic ultrafine particulate matter (UFPM) and industrial nanoparticles (NPs). We studied magnetophoresis, electron microscopy and energy-dispersive X-ray spectrometry in 203 brain samples from 14 children, 27 adults, and 27 ALS cases/controls. Saturation isothermal remanent magnetization (SIRM), capturing magnetically unstable FeNPs ~ 20nm, was higher in caudate, thalamus, hippocampus, putamen, and motor regions with subcortical vs. cortical higher SIRM in MMC = 40y. Motion behavior was associated with magnetic exposures 25-100 mT and children exhibited IRM saturated curves at 50-300 mT associated to change in NPs position and/or orientation in situ. Targeted magnetic profiles moving under AC/AD magnetic fields could distinguish ALS vs. controls. Motor neuron magnetic NPs accumulation potentially interferes with action potentials, ion channels, nuclear pores and enhances the membrane insertion process when coated with lipopolysaccharides. TEM and EDX showed 7-20 nm NP Fe, Ti, Co, Ni, V, Hg, W, Al, Zn, Ag, Si, S, Br, Ce, La, and Pr in abnormal neural and vascular organelles. Brain accumulation of magnetic unstable particles start in childhood and cytotoxic, hyperthermia, free radical formation, and NPs motion associated to 30-50 μT (DC magnetic fields) are critical given ubiquitous electric and magnetic fields exposures could induce motion behavior and neural damage. Magnetic UFPM/NPs are a fatal brain cargo in children's brains, and a preventable AD, PD, FTLD, ALS environmental threat. Billions of people are at risk. We are clearly poisoning ourselves. [ABSTRACT FROM AUTHOR]

ρ-type γ-aminobutyric acid-A (GABAA) receptors are widely distributed in the retina and brain, and are potential drug targets for the treatment of visual, sleep and cognitive disorders. Endogenous neuroactive steroids including β-estradiol and pregnenolone sulfate negatively modulate the function of ρ1 GABAA receptors, but their inhibitory mechanisms are not clear. By combining five cryo-EM structures with electrophysiology and molecular dynamics simulations, we characterize binding sites and negative modulation mechanisms of β-estradiol and pregnenolone sulfate at the human ρ1 GABAA receptor. β-estradiol binds in a pocket at the interface between extracellular and transmembrane domains, apparently specific to the ρ subfamily, and disturbs allosteric conformational transitions linking GABA binding to pore opening. In contrast, pregnenolone sulfate binds inside the pore to block ion permeation, with a preference for activated structures. These results illuminate contrasting mechanisms of ρ1 inhibition by two different neuroactive steroids, with potential implications for subtype-specific gating and pharmacological design. Neurological processes from vision to cognition rely on precise control of ion channels, particularly GABAA receptors. Here, the authors report structures of a ρ1 GABAA receptor with naturally occurring steroids, revealing their specific interactions and suggesting approaches to understand and develop drugs. [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]

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]

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]

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]

Positive allosteric modulators (PAMs) are of great interest to compensate for the lack of NMDA receptor function in the CNS in dementia. Known PAMs increase the amplitude of whole-cell ionic currents carried by NMDA receptors, but do not affect their calcium-calmodulin dependent desensitization. We studied the possibility of modulating NMDA receptor desensitization by the recently synthesized PAM GNE-9278, which has a unique binding site on the transmembrane domain. Experiments were performed on native NMDA receptors expressed in rat cortical neurons in primary tissue culture. Using the method of "patch-clamp" recording of transmembrane currents, a comparative study of the effect on NMDA receptor desensitization of three substances potentiating NMDA receptor currents was carried out: GNE-9278 (10 µM), dithiothreitol (1 mM) and copper ions (5 µM). These substances increased the amplitude of currents evoked by 100 µM NMDA, but only GNE-9278 reduced the difference between equilibrium and peak current amplitudes by 15%. In addition, GNE-9278 doubled the time constant of the decline from peak to equilibrium state thus attenuating NMDA receptor desensitization. Because GNE-9278 did not alter the effective concentration of extracellular calcium to induce desensitization, its effect probably does not interfere with receptor-calmodulin interaction. Analysis of the shape of the currents within the kinetic model showed that GNE-9278 reduced two kinetic parameters: the channel closure rate, which determines the open state time, and the rates of receptor entry into and exit from the desensitized state, which determines the probability of the open state of the channel. Modulation of calcium-dependent NMDA receptor desensitization places GNE-9278 apart from other known PAMs, which is likely determined by the GNE-9278 binding site in the pre-M1 segment of the GluN1 subunit. [ABSTRACT FROM AUTHOR]

Exploring special anode materials with high capacity, stable structure, and extreme temperature feasibility remains a great challenge in secondary sodium based energy systems. Here, a bimetallic Cu‐Fe selenide nanosheet with refined nanostructure providing confined internal ion transport channels are reported, in which the structure improves the pseudocapacitance and reduces the charge transfer resistance for making a significant contribution to accelerating the reaction dynamics. The CuFeSe2 nanosheets have a high initial specific capacity of 480.4 mAh g−1 at 0.25 A g−1, showing impressively excellent rate performance and ultralong cycling life over 1000 cycles with 261.1 mAh g−1 at 2.5 A g−1. Meanwhile, it exhibits a good sodium storage performance at extreme temperatures from −20 °C to 50 °C, supporting at least 500 cycles. Besides, the CuFeSe2||Na3V2(PO4)3/C full cell delivers a high specific capacity of 168.5 mAh g−1 at 0.5 A g−1 and excellent feasibility for over 600 cycles long cycling. Additionally, the Na+ storage mechanisms are further revealed by ex situ X‐ray diffraction (XRD) and in situ transmission electron microscopy (TEM) techniques. A feasible channelized structural design strategy is provided that inspires new instruction into the development of novel materials with high structural stability and low volume expansion rate toward the application of other secondary batteries. [ABSTRACT FROM AUTHOR]

Disuse osteoporosis (OP) is a state of bone loss due to lack of mechanical stimuli, probably induced by prolonged bed rest, neurological diseases, as well as microgravity. Currently the precise treatment strategies of disuse OP remain largely unexplored. Piezo1, a mechanosensitive calcium (Ca2+) ion channel, is a key force sensor mediating mechanotransduction and it is demonstrated to regulate bone homeostasis and osteogenesis in response to mechanical forces. Using structure‐based drug design, a novel small‐molecule Piezo1 agonist, MCB‐22‐174, which can effectively activate Piezo1 and initiate Ca2+ influx, is developed and is more potent than the canonical Piezo1 agonist, Yoda1. Moreover, MCB‐22‐174 is found as a safe Piezo1 agonist without any signs of serious toxicity. Mechanistically, Piezo1 activation promotes the proliferation of bone marrow mesenchymal stem cells by activating the Ca2+‐related extracellular signal‐related kinases and calcium–calmodulin (CaM)‐dependent protein kinase II (CaMKII) pathway. Importantly, MCB‐22‐174 could effectively promote osteogenesis and attenuate disuse OP in vivo. Overall, the findings provide a promising therapeutic strategy for disuse OP by chemical activation of Piezo1. [ABSTRACT FROM AUTHOR]

Poly(3,4‐ethylenedioxythiophene):polystyrene sulfonate (PEDOT:PSS), a conductive polymer, has gained popularity as the channel layer in organic electrochemical transistors (OECTs) due to its high conductivity and straightforward processing. However, difficulties arise in controlling its conductivity through gate voltage, presenting a challenge. To address this issue, aromatic amidine base, diazabicyclo[4.3.0]non‐5‐ene (DBN), is used to stabilize the doping state of the PEDOT chain through a reliable chemical de‐doping process. Furthermore, the addition of the proton‐penetrable material Nafion to the PEDOT:PSS channel layer induces phase separation between the substances. By utilizing a solution containing both PEDOT:PSS and Nafion as the channel layer of OECTs, the efficiency of ion movement into the channel from the electrolyte is enhanced, resulting in improved OECT performance. The inclusion of Nafion in the OECTs' channel layer modifies ion movement dynamics, allowing for the adjustment of synaptic properties such as pulse‐paired facilitation, memory level, short‐term plasticity, and long‐term plasticity. This research aims to introduce new possibilities in the field of neuromorphic computing and contribute to biomimetic technology through the enhancement of electronic component performance. [ABSTRACT FROM AUTHOR]

Polycystic kidney disease (PKD), a disease characterized by the enlargement of the kidney through cystic growth is the fourth leading cause of end-stage kidney disease world-wide. Transient receptor potential Vanilloid 4 (TRPV4), a calcium-permeable TRP, channel participates in kidney cell physiology and since TRPV4 forms complexes with another channel whose malfunction is associated to PKD, TRPP2 (or PKD2), we sought to determine whether patients with PKD, exhibit previously unknown mutations in TRPV4. Here, we report the presence of mutations in the TRPV4 gene in patients diagnosed with PKD and determine that they produce gain-of-function (GOF). Mutations in the sequence of the TRPV4 gene have been associated to a broad spectrum of neuropathies and skeletal dysplasias but not PKD, and their biophysical effects on channel function have not been elucidated. We identified and examined the functional behavior of a novel E6K mutant and of the previously known S94L and A217S mutant TRVP4 channels. The A217S mutation has been associated to mixed neuropathy and/or skeletal dysplasia phenotypes, however, the PKD carriers of these variants had not been diagnosed with these reported clinical manifestations. The presence of certain mutations in TRPV4 may influence the progression and severity of PKD through GOF mechanisms. PKD patients carrying TRVP4 mutations are putatively more likely to require dialysis or renal transplant as compared to those without these mutations. Graphical Abstract Abstract graph showing a schematic representation of a wild-type TRPV4 channel compared to the increased activity of a mutant TRPV4 channel carrying one of the two TRPV4 mutations located in the amino-terminal domain and found in a patient cohort diagnosed with polycystic kidney disease.Abstract graph showing a schematic representation of a wild-type TRPV4 channel compared to the increased activity of a mutant TRPV4 channel carrying one of the two TRPV4 mutations located in the amino-terminal domain and found in a patient cohort diagnosed with polycystic kidney disease. [ABSTRACT FROM AUTHOR]

Mechanosensitive ion channels, particularly Piezo channels, are widely expressed in various tissues. However, their role in immune cells remains underexplored. Therefore, this study aimed to investigate the functional role of Piezo1 in the human eosinophil cell line AML14.3D10. We detected Piezo1 mRNA expression, but not Piezo2 expression, in these cells, confirming the presence of the Piezo1 protein. Activation of Piezo1 with Yoda1, its specific agonist, resulted in a significant calcium influx, which was inhibited by the Piezo1-specific inhibitor Dooku1, as well as other nonspecific inhibitors (Ruthenium Red, Gd3+, and GsMTx-4). Further analysis revealed that Piezo1 activation modulated the expression and secretion of both pro-inflammatory and anti-inflammatory cytokines in AML14.3D10 cells. Notably, supernatants from Piezo1-activated AML14.3D10 cells enhanced capsaicin and ATP-induced calcium responses in the dorsal root ganglion neurons of mice. These findings elucidate the physiological role of Piezo1 in AML14.3D10 cells and suggest that factors secreted by these cells can modulate the activity of transient receptor potential 1 (TRPV1) and purinergic receptors, which are associated with pain and itch signaling. The results of this study significantly advance our understanding of the function of Piezo1 channels in the immune and sensory nervous systems. [ABSTRACT FROM AUTHOR]

Simple Summary: The factors that influence electrical potential across the cell membrane are important because they affect cellular properties that, in turn, allow tissues, organs, and whole organism to function; as such, it is important to understand them. The distribution and movement of certain ions (i.e., Na+, K+, Ca2+) determine this electrical potential as they move across the membrane through channels and transport processes, some of which are impeded by the presence of other ions. As a particularly apt example: free Ca2+ ions are known to block open Na+ channels. This study illustrated that raising the Ca2+ ion concentration on one side of the membrane led to a larger membrane potential, and this is suggested herein to be caused by blockage of a leaky Na+ channel. If more such channels are present in the membrane, the effects of altering Ca2+ concentration have less impact. Regulating membrane potential is key to cellular function. For many animal cells, resting membrane potential is predominantly driven by a family of K2P (two-pore domain) potassium channels. These channels are commonly referred to as leak channels, as their presence results in the membrane being permeable to K+ ions. These channels, along with various pumps and exchangers, keep the cell resting membrane potential (Rp) relatively close to potassium's equilibrium potential (EK); however, in many cells, the resting membrane potential is more depolarized than the EK due to a small Na+ ion leak. Raising [Ca2+]O (extracellular Ca2+ concentration) can result in hyperpolarization of the membrane potential from the resting state. The mechanism for this hyperpolarization likely lies in the blockage of a Na+ leak channel (NALCN) and/or voltage-gated Na+ channels. The effects may also be connected to calcium-activated potassium channels. Using Drosophila melanogaster, we here illustrate that changing [Ca2+]O from 0.5 to 3 mM hyperpolarizes the muscle. Replacing NaCl with LiCl or choline chloride still led to hyperpolarization when increasing [Ca2+]O. Replacing CaCl2 with BaCl2 results in depolarization. K2P channel overexpression in the larval muscle greatly reduces the effects of [Ca2+]O on cell membrane potential, likely because potential is heavily driven by the EK in these muscles. These experiments provide an understanding of the mechanisms behind neuronal hypo-excitability during hypercalcemia, as well as the effects of altered expression of K2P channels on membrane potential. [ABSTRACT FROM AUTHOR]

Aim: Most of the subarachnoid hemorrhage (SAH) patients experienced the symptom of severe headache caused by intracranial hypertension. Piezo1 is a mechanosensitive ion channel protein. This study aimed to investigate the effect of Piezo1 on neurons in response to intracranial hypertension. Methods: The SAH rat model was performed by the modified endovascular perforation method. Piezo1 inhibitor GsMTx4 was administered intraperitoneally after SAH induction. To investigate the underlying mechanism, the selective Piezo1 agonist Yoda1, Piezo1 shRNA, and MY‐875 were administered via intracerebroventricular injection before SAH induction. In vitro, we designed a pressurizing device to exclusively explore the effect of Piezo1 activation on primary neurons. Neurons were pretreated with Piezo1 inhibition followed by intracranial hypertension treatment, and then apoptosis‐related proteins were detected. Results: Piezo1 inhibition significantly attenuated neuronal apoptosis and improved the outcome of neurological deficits in rats after SAH. The Hippo pathway agonist MY‐875 reversed the anti‐apoptotic effects of Piezo1 knockdown. In vitro, intracranial hypertension mimicked by the pressurizing device induced Piezo1 expression, resulting in Hippo pathway activation and neuronal apoptosis. The Hippo pathway inhibitor Xmu‐mp‐1 attenuated Yoda1‐induced neuronal apoptosis. In addition, the combination of hypertension and oxyhemoglobin treatment exacerbated neuronal apoptosis. Conclusions: Intracranial hypertension induced Piezo1 expression, neuronal apoptosis, and the Hippo pathway activation; the Hippo signaling pathway is involved in Piezo1 activation‐induced neuronal apoptosis in respond to intracranial hypertension. Primary neurons treated with intracranial hypertension and oxyhemoglobin together can better characterize the circumstance of SAH in vivo, which is contributed to construct an ideal in vitro SAH model. [ABSTRACT FROM AUTHOR]

Scorpions, an ancient group of venomous invertebrates, have existed for over 430 million years. Their toxins, important for predation and defense, exhibit a variety of biological and pharmacological activities. Research on scorpion toxins has spanned decades. Notably, the toxin genes of Mesobuthus martensii (Scorpiones: Buthidae), a well-known Chinese herbal medicine, have been described at genomic and proteomic levels. However, previous studies primarily focused on the toxin genes expressed in the venom glands, overlooking their expression in multiple tissues. This study analyzed transcriptomes from 14 tissues of M. martensii. Gene annotation revealed 83 toxin and toxin-like genes, including those affecting sodium, potassium, calcium, and chloride ion channels. Approximately 70% of toxin genes were highly expressed in the vesicle; additionally, some exhibited low or no expression in the vesicle while showing high expression in other tissues. Beyond the vesicle, high expression levels of toxin genes were observed in metasoma segments II-V, blood, lateral eyes, chelicerae, legs, pedipalp chelae, femurs, and patellae. This expression pattern suggests that toxin genes are recruited from multiple tissues and may help prevent intraspecific harm during courtship and competition for prey. These findings inspire further research into the evolutionary recruitment process of scorpion toxins. [ABSTRACT FROM AUTHOR]

Pain management remains a major challenge in medicine, highlighting the need for the development of new therapeutic agents. The transient receptor potential ankyrin 1 (TRPA1) and vanilloid 1 (TRPV1) are ion channels that play key roles in pain perception. Targeting both TRPA1 and TRPV1 simultaneously with dual antagonists offers a promising approach to pain relief. In this study, we investigated a series of hybrid analogs of TRPA1 and TRPV1 antagonists to discover novel therapeutic agents for pain. Among these compounds synthesized by a condensation reaction forming 1,2,4-oxadiazole between the A- and C-regions, compound 50 exhibited substantial dual-acting antagonism to TRPA1 and TRPV1 with IC50 values of 1.42, 2.84, 2.13, and 5.02 μM for hTRPA1, mTRPA1, hTRPV1, and rTRPV1, respectively. In the formalin test, compound 50 demonstrated dose-dependent analgesic activity with an ED50 of 85.9 mg/kg in phase 1 and 21.6 mg/kg in phase 2, respectively, and was able to inhibit pain behavior completely at a dose of 100 mg/kg. This study presents the discovery and characterization of a novel dual TRPA1/TRPV1 antagonist, highlighting its potential as a therapeutic agent for pain management. [ABSTRACT FROM AUTHOR]

Irritable bowel syndrome (IBS) is a gastrointestinal (GI) disease accompanied by changes in bowel habits without any specific cause. Gintonin is a newly isolated glycoprotein from ginseng that is a lysophosphatidic acid (LPA) receptor ligand. To investigate the efficacy and mechanisms of action of gintonin in IBS, we developed a zymosan-induced IBS murine model. In addition, electrophysiological experiments were conducted to confirm the relevance of various ion channels. In mice, gintonin restored colon length and weight to normal and decreased stool scores, whilst food intake remained constant. Colon mucosal thickness and inflammation-related tumor necrosis factor-α levels were decreased by gintonin, along with a reduction in pain-related behaviors. In addition, the fecal microbiota from gintonin-treated mice had relatively more Lactobacillaceae and Lachnospiraceae and less Bacteroidaceae than microbiota from the control mice. Moreover, gintonin inhibited transient receptor potential vanilloid (TRPV) 1 and TRPV4 associated with visceral hypersensitivity and voltage-gated Na+ 1.5 channels associated with GI function. These results suggest that gintonin may be one of the effective components in the treatment of IBS. [ABSTRACT FROM AUTHOR]

To investigate the effects of water flow on fish body color, the number of melanophore and gene expression in zebrafish skin were investigated under water flow culture with two different flow rates 0. 010 m/s (low flow rate) and 0. 022 m/s (high flow rate). The results showed that compared with low flow rate, the number of skin melanophore increased significantly after 3 months of culturing zebrafish under higher flow rate, especially in the caudal region of the body of the fish, the expression levels of the skin melanophore marker genes kita, mitfa and tyrp1a were significantly increased as well. Meanwhile, the relative expression level of the xanthophore marker gene csf1ra was significantly decreased, and there was no significant change in the iridophore marker gene pnp4a, indicating that the high flow rate water induced the formation of melanophore and inhibited the formation of xanthophore. The RT-qPCR results showed that the expression of melanophore formation inhibitor gene asip1 was significantly decreased in the skin of zebrafish in the high-flow group compared with that in the low-flow group; the melanocortin receptor gene mc1r and the amelanocortinogen gene pomca, which are related to melanophore formation, were not significantly changed; and the retinoid dehydrogenase genes raldh2 and raldh3, which are related to retinoic acid synthesis, were significantly downregulated; water flow stimulation upregulated the transient receptor channel protein gene trpv4 and the piezoelectric mechanosensitive channel protein gene piezo2, whereas there was no significant change in piezo1. The above results indicate that the high flow rate water flow induces melanophore formation in zebrafish, possibly as a result of reduced asip1 expression mediated by water flow stimulation through the skin mechanosensitive proteins Trpv4 and Piezo2. Asip1 regulates fat accumulation in addition to melanophore formation, and indeed zebrafish body fullness reduces significantly in the high water flow group compared with low flow rate group. GO enrichment analysiss showed differentially expressed genes was mainly enriched to entries for triglyceride catabolism, HDL particles, lipid binding, etc and differentially expressed genes was significantly enriched in the following KEGG pathways: aminoglycan and nucleotide sugar metabolism, PPAR signaling pathway, linoleic acid metabolism, and arachidonic acid metabolism, etc. RT-qPCR showed the fatty acid peroxidase 2 gene fads2, which is associated with lipid metabolism, was significantly up-regulated, and there was no significant difference in the leptin gene lep, indicating that water flow may affect fat degradation through Asip1 affecting Fads2. In conclusion, this study for the first time reported the effect of water flow on fish body color and proposed a preliminary signaling regulatory pathway, which provides a preliminary theoretical basis for understanding the effect of water flow culture on fish body color and fullness. [ABSTRACT FROM AUTHOR]

Complex systems are neither fully determined nor completely random. Biological complex systems, including single neurons, manifest intermediate regimes of randomness that recruit integration of specific combinations of functionally specialized subsystems. Such emergence of biological function provides the substrate for the expression of degeneracy, the ability of disparate combinations of subsystems to yield similar function. Here, we present evidence for the expression of degeneracy in morphologically realistic models of dentate gyrus granule cells (GCs) through functional integration of disparate ion-channel combinations. We performed a 45-parameter randomized search spanning 16 active and passive ion channels, each biophysically constrained by their gating kinetics and localization profiles, to search for valid GC models. Valid models were those that satisfied 17 sub- and suprathreshold cellular-scale electrophysiological measurements from rat GCs. A vast majority (>99%) of the 15,000 random models were not electrophysiologically valid, demonstrating that arbitrarily random ion-channel combinations would not yield GC functions. The 141 valid models (0.94% of 15,000) manifested heterogeneities in and cross-dependencies across local and propagating electrophysiological measurements, which matched with their respective biological counterparts. Importantly, these valid models were widespread throughout the parametric space and manifested weak cross-dependencies across different parameters. These observations together showed that GC physiology could neither be obtained by entirely random ion-channel combinations nor is there an entirely determined single parametric combination that satisfied all constraints. The complexity, the heterogeneities in measurement and parametric spaces, and degeneracy associated with GC physiology should be rigorously accounted for while assessing GCs and their robustness under physiological and pathological conditions. NEW & NOTEWORTHY: A recent study from our laboratory had demonstrated pronounced heterogeneities in a set of 17 electrophysiological measurements obtained from a large population of rat hippocampal granule cells. Here, we demonstrate the manifestation of ion-channel degeneracy in a heterogeneous population of morphologically realistic conductance-based granule cell models that were validated against these measurements and their cross-dependencies. Our analyses show that single neurons are complex entities whose functions emerge through intricate interactions among several functionally specialized subsystems. [ABSTRACT FROM AUTHOR]

Spermatozoon volume regulation is an essential determinant of male fertility competence in mammals and oviparous fishes. In mammals, aquaporin water channels (AQP3, -7 and -8) have been suggested to play a role in spermatozoon cell volume regulatory responses in the hypotonic female oviduct. In contrast, the ejaculated spermatozoa of marine teleosts, such as the gilthead seabream (Sparus aurata), experience a high hypertonic shock in seawater, initially resulting in an Aqp1aa-mediated water efflux, cell shrinkage and the activation of motility. Further regulatory recovery of cell volume in post-activated spermatozoa is mediated by Aqp4a in cooperation with the Trpv4 Ca2+ channel and other ion channels and transporters. Using a paralog-specific antibody, here, we show that seabream spermatozoa also express the aquaglyceroporin AQP3 ortholog Aqp3a, which is highly accumulated in the mid posterior region of the spermatozoon flagella, in a similar pattern to that described in mouse and human sperm. To investigate the role of Aqp3a in seabream sperm motility, we used a recently developed AQP3 antagonist (DFP00173), as well as the seabream Aqp3a-specific antibody (α-SaAqp3a), both of which specifically inhibit Aqp3a-mediated water conductance when the channel was heterologously expressed in Xenopus laevis oocytes. Inhibition with either DFP00173 or α-SaAqp3a did not affect sperm motility activation but did impair the spermatozoon motion kinetics at 30 s post activation in a dose-dependent manner. Interestingly, in close resemblance to the phenotypes of AQP3-deficient murine sperm, electron microscopy image analysis revealed that both Aqp3a inhibitors induce abnormal sperm tail morphologies, including swelling and angulation of the tail, with complete coiling of the flagella in some cases. These findings suggest a conserved role of Aqp3a as an osmosensor that regulates cell volume in fish spermatozoa under a high hypertonic stress, thereby controlling the efflux of water and/or solutes in the post-activated spermatozoon. [ABSTRACT FROM AUTHOR]

Just over thirty years is the span of a generation. It is also the time that has passed since the discovery of the gene responsible for cystic fibrosis. Today, it is safe to say that this discovery has revolutionized our understanding, research perspectives, and management of this disease, which was, thirty years ago, a pediatric condition with a grim prognosis. The aim of this review is to present the advances that science and medicine have brought to our understanding of the pathophysiology of the disease and its management, which in many ways, epitomizes modern molecular genetic research. Since the discovery of the cystic fibrosis transmembrane conductance regulator (CFTR) gene in 1989, modeling the CFTR protein, deciphering its function as an ion channel, and identifying its molecular partners have led to numerous therapeutic advances. The most significant advancement in this field has been the discovery of protein modulators that can target its membrane localization and chloride channel activity. However, further progress is needed to ensure that all patients can benefit from a therapy tailored to their mutations, with the primary challenge being the development of treatments for mutations leading to a complete absence of the protein. The present review delves into the history of the multifaceted world of CF, covering main historical facts, current landscape, clinical management, emerging therapies, patient perspectives, and the importance of ongoing research, bridging science and medicine in the fight against the disease. [ABSTRACT FROM AUTHOR]

Transient receptor potential (TRP) channels, first identified in Drosophila in 1969, are multifunctional ion channels expressed in various cell types. Structurally, TRP channels consist of six membrane segments and are classified into seven subfamilies. Transient receptor potential ankyrin 1 (TRPA1), the first member of the TRPA family, is a calcium ion affinity non-selective cation channel involved in sensory transduction and responds to odors, tastes, and chemicals. It also regulates temperature and responses to stimuli. Recent studies have linked TRPA1 to several disorders, including chronic pain, inflammatory diseases, allergies, and respiratory problems, owing to its activation by environmental toxins. Mutations in TRPA1 can affect the sensory nerves and microvasculature, potentially causing nerve pain and vascular problems. Understanding the function of TRPA1 is important for the development of treatments for these diseases. Recent developments in nanomedicines that target various ion channels, including TRPA1, have had a significant impact on disease treatment, providing innovative alternatives to traditional disease treatments by overcoming various adverse effects. [ABSTRACT FROM AUTHOR]

Piezo proteins have been identified as mechanosensitive ion channels involved in mechanotransduction. Several ion channel dysfunctions may be associated with diseases (including deafness and pain); thus, studying them is critical to understand their role in mechanosensitive disorders and to establish new therapeutic strategies. The current study investigated for the first time the expression patterns of Piezo proteins in zebrafish octavolateralis mechanosensory organs. Piezo 1 and 2 were immunoreactive in the sensory epithelia of the lateral line system and the inner ear. Piezo 1 (28.7 ± 1.55 cells) and Piezo 2 (28.8 ± 3.31 cells) immunopositive neuromast cells were identified based on their ultrastructural features, and their overlapping immunoreactivity to the s100p specific marker (28.6 ± 1.62 cells), as sensory cells. These findings are in favor of Piezo proteins' potential role in sensory cell activation, while their expression on mantle cells reflects their implication in the maintenance and regeneration of the neuromast during cell turnover. In the inner ear, Piezo proteins' colocalization with BDNF introduces their potential implication in neuronal plasticity and regenerative events, typical of zebrafish mechanosensory epithelia. Assessing these proteins in zebrafish could open up new scenarios for the roles of these important ionic membrane channels, for example in treating impairments of sensory systems. [ABSTRACT FROM AUTHOR]

As a better alternative to lithium-ion batteries (LIBs), lithium–sulfur batteries (LSBs) stand out because of their multi-electron redox reactions and high theoretical specific capacity (1675 mA h g−1). However, the long-term stability of LSBs and their commercialization are significantly compromised by the inherently irreversible transition of soluble lithium polysulfides (LiPS) into solid short-chain S species (Li2S2 and Li2S) and the resulting substantial density change in S. To address these issues, we used activated carbon cloth (ACC) coated with Ni12P5 as a porous, conductive, and scalable sulfur host material for LSBs. ACC has the benefit of high electrical conductivity, high surface area, and a three-dimensional (3D) porous architecture, allowing for ion transport channels and void spaces for the volume expansion of S upon lithiation. Ni12P5 accelerates the breakdown of Li2S to increase the efficiency of active materials and trap soluble polysulfides. The highly effective Ni12P5 electrocatalyst supported on ACC drastically reduced the severity of the LiPS shuttle, affected the abundance of adsorption–diffusion–conversion interfaces, and demonstrated outstanding performance. Our cells achieved near theoretical capacity (>1611 mA h g−1) during initial cycling and superior capacity retention (87%) for >250 cycles following stabilization with a 0.05% decay rate per cycle at 0.2 C. [ABSTRACT FROM AUTHOR]

Rare-earth elements (REEs) are critical to modern industry but difficult to separate due to their subtle and monotonic changes in physicochemical properties. MoS2-based two-dimensional (2D) materials offer novel opportunities for enhancing REE separation, exhibiting a distinct volcano-shaped transport performance distribution that peaks at Sm3+. However, the specific contributions of thermodynamic and kinetic factors to ion transport within 2D confinement remain unclear. In this study, we conducted a series of non-equilibrium all-atom molecular dynamics (MD) simulations to explore the effects of interlayer spacing and external pressure on the transport of lanthanide ions in Å-scale acetate functionalized 2D MoS2 (MoS2-COOH) channels. We examined ion entry and permeation rates, water flux, dehydration, and binding modes. The simulation results reveal that the transport trends of lanthanide ions are jointly driven by the dehydration degree and the relative-binding strengths of ions to water and to the acetate within the 2D channels. Notably, the dehydration pattern of lanthanide ions during permeation is closely linked to kinetic factors. Overall, this study provides a detailed atomistic understanding of the mechanisms underlying lanthanide ion transport under confinement. These findings point to the significant potential for tuning confinement and chemical functionalization within Å-scale channels for more efficient REE separation. [ABSTRACT FROM AUTHOR]