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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]

Although phytochemicals are plant-derived toxins that are primarily produced as a form of defense against insects or microbes, several lines of study have demonstrated that the phytochemical, quercetin, has several beneficial biological actions for human health, including antioxidant and inflammatory effects without side effects. Quercetin is a flavonoid that is widely found in fruits and vegetables. Since recent studies have demonstrated that quercetin can modulate neuronal excitability in the nervous system, including nociceptive sensory transmission via mechanoreceptors and voltage-gated ion channels, and inhibit the cyclooxygenase-2-cascade, it is possible that quercetin could be a complementary alternative medicine candidate; specifically, a therapeutic agent against nociceptive and pathological pain. The focus of this review is to elucidate the neurophysiological mechanisms underlying the modulatory effects of quercetin on nociceptive neuronal activity under nociceptive and pathological conditions, without inducing side effects. Based on the results of our previous research on trigeminal pain, we have confirmed in vivo that the phytochemical, quercetin, demonstrates (i) a local anesthetic effect on nociceptive pain, (ii) a local anesthetic effect on pain related to acute inflammation, and (iii) an anti-inflammatory effect on chronic pain. In addition, we discuss the contribution of quercetin to the relief of nociceptive and inflammatory pain and its potential clinical application. [ABSTRACT FROM AUTHOR]

Migraines are a common type of headache affecting around 15% of the population. The signalling pathways leading to migraines have not been fully understood, but neuronal voltage-gated ion channels, such as KCNG4, have been linked to this pathology. KCNG4 (Kv6.4) is a silent member of the superfamily of voltage-gated potassium (Kv) channels, which expresses in heterotetramers with members of the KCNB (Kv2) family. The genetic variant Kv6.4-L360P has previously been linked to migraines, but their mode of action remains unknown. Here, we characterized the molecular characteristics of Kv6.4-L360P when co-expressed with Kv2.1. We found that Kv6.4-L360P almost completely abolishes Kv2 currents, and we propose that this mechanism in the trigeminal system, linked to the initiation of migraine, leads to the pathology. [ABSTRACT FROM AUTHOR]

Introduction: Cytotoxic cerebral edema is a serious complication associated with cerebral ischemic stroke and is widely treated using the hypertonic dehydrant. Here, we propose, for the first time, the decrease of intracellular osmosis as a treatment strategy for alleviating cytotoxic cerebral edema. Methods: We established a fluorescence resonance energy transfer-based intermediate filament tension probe for the study and in situ evaluation of osmotic gradients, which were examined in real-time in living cells from primary cultures as well as cell lines. The MCAO rat model was used to confirm our therapy of cerebral edema. Results: Depolymerization of microfilaments/microtubules and the production of NLRP3 inflammasome resulted in an abundance of protein nanoparticles (PNs) in the glutamate-induced swelling of astrocytes. PNs induced changes in membrane potential and intracellular second messengers, thereby contributing to hyper-osmosis and the resultant astrocyte swelling via the activation of voltage-dependent nonselective ion channels. Therefore, multiple inhibitors of PNs, sodium and chloride ion channels were screened as compound combinations, based on a decrease in cell osmosis and astrocyte swelling, which was followed by further confirmation of the effectiveness of the compound combination against alleviated cerebral edema after ischemia. Discussion: The present study proposes new pathological mechanisms underlying "electrophysiology-biochemical signal-osmotic tension," which are responsible for cascade regulation in cerebral edema. It also explores various compound combinations as a potential treatment strategy for cerebral edema, which act by multi-targeting intracellular PNs and voltage-dependent nonselective ion flux to reduce astrocyte osmosis. [ABSTRACT FROM AUTHOR]

Sea anemones are an important source of bioactive compounds with potential pharmacological applications. Their toxins are produced and stored in organelles called nematocysts and act on specific targets, including voltage-gated ion channels. To date, sea anemone toxins have demonstrated effects on voltage-gated sodium and potassium channels, facilitating investigations into the structure and function of these proteins. In this study, we evaluated the effect of Bunodeopsis globulifera sea anemone crude extract, and of a low molecular weight fraction, on voltage-gated sodium and calcium channels within the murine nervous system. Notably, the crude extract led to a significant reduction in total sodium current, while also triggering calcium-dependent glutamate release. Furthermore, the low molecular weight fraction, in particular, enhanced total calcium currents and current density. These findings underscore the existence of sea anemone toxins with diverse mechanisms of action beyond those previously documented. [ABSTRACT FROM AUTHOR]

Drug studies targeting neuronal ion channels are crucial to understand neuronal function and develop therapies for neurological diseases. The traditional method to study neuronal ion‐channel activities heavily relies on the whole‐cell patch clamp as the industry standard. However, this technique is both technically challenging and labour‐intensive, while involving the complexity of keeping cells alive with low throughput. Therefore, the shortcomings are limiting the efficiency of ion‐channel‐related neuroscience research and drug testing. Here, this work reports a new system of integrating neuron membranes with organic microelectrode arrays (OMEAs) for ion‐channel‐related drug studies. This work demonstrates that the supported lipid bilayers (SLBs) derived from both neuron‐like (neuroblastoma) cells and primary neurons are integrated with OMEAs for the first time. The increased expression of voltage‐gated calcium (CaV) ion channels on differentiated SH‐SY5Y SLBs compared to non‐differentiated ones is sensed electrically. Also, dose‐response of the CaV ion‐channel blocking effect on primary cortical neuronal SLBs from rats is monitored. The dose range causing ion channel blocking is comparable to literature. This system overcomes the major challenges from traditional methods (e.g., patch clamp) and showcases an easy‐to‐test, rapid, ultra‐sensitive, cell‐free, and high‐throughput platform to monitor dose‐dependent ion‐channel blocking effects on native neuronal membranes. [ABSTRACT FROM AUTHOR]

The transcription factor Sox10 is an important determinant of oligodendroglial identity and influences oligodendroglial development and characteristics at various stages. Starting from RNA-seq data, we here show that the expression of several voltage-gated ion channels with known expression and important function in oligodendroglial cells depends upon Sox10. These include the Nav1.1, Cav2.2, Kv1.1, and Kir4.1 channels. For each of the four encoding genes, we found at least one regulatory region that is activated by Sox10 in vitro and at the same time bound by Sox10 in vivo. Cell-specific deletion of Sox10 in oligodendroglial cells furthermore led to a strong downregulation of all four ion channels in a mouse model and thus in vivo. Our study provides a clear functional link between voltage-gated ion channels and the transcriptional regulatory network in oligodendroglial cells. Furthermore, our study argues that Sox10 exerts at least some of its functions in oligodendrocyte progenitor cells, in myelinating oligodendrocytes, or throughout lineage development via these ion channels. By doing so, we present one way in which oligodendroglial development and properties can be linked to neuronal activity to ensure crosstalk between cell types during the development and function of the central nervous system. [ABSTRACT FROM AUTHOR]

Cardiac electromechanics is a coupled multiphysics and multiscale problem. Of great interest to medicine and pharmacology is how the heart responds to changes in ion channel dynamics within the myocyte that are either caused by disease or by the administration of drugs. A successful model of cardiac mechanical response must therefore incorporate a first-principles description of electrophysiology of the cardiac myocyte including intracellular calcium dynamics, transmembrane ionic currents and action potential (AP) formation at the cellular level. This article reviews the evolution of electrophysiological models of cardiac ventricular myocytes in terms of coupled differential equations whose state variables include ion channel gating parameters, intracellular ionic concentrations and the membrane voltage. The myocytes are connected through gap junctions forming fibers, which in turn connect to form cardiac tissues. The electromechanical response of cardiac tissues is coupled through intracellular calcium dynamics and stretch induced/ modulated currents, and can be solved using suitable discretization schemes under appropriate initial and boundary conditions. We discuss in detail the single-cell dynamics of the ORd model of human ventricular myocytes and describe the propagation of AP in periodically paced 1D fibers and 2D tissues. The origin of tissue-level diseased conditions in altered subcellular dynamics are discussed. [ABSTRACT FROM AUTHOR]

The development of cationic polymers as alternative materials to antibiotics necessitates addressing the challenge of balancing their antimicrobial activity and toxicity. Here we propose a precise switching strategy inspired by biomimetic voltage-gated ion channels, enabling controlled activation and inhibition of cationic antimicrobial functions through protein conformational transitions in diverse physiological environments. Following thermodynamic studies on the specific recognition between mannose end groups on polycations and concanavalin A (ConA), we synthesized a type of ConA-polycation nanoparticle. The nanoparticle was inhibited under neutral conditions, with cationic moieties shielded by ConA's β -sheet. This shielding suppresses their antimicrobial activity, thereby ensuring satisfactory biocompatibility. In mildly acidic environments, however, the transition of a portion of ConA to an α -helix conformation exposed cations at the particle periphery, activating antibacterial functionality. Compared to inhibited nanoparticles, those in the activated state exhibited a 32–256 times reduction in the minimum bactericidal concentration against bacteria and fungi (2–16 µg/mL). In a murine acute pulmonary infection model, intravenous administration of inhibited nanoparticles effectively reduced bacterial counts by 4-log within 12 h. The biomimetic design, regulating cationic antimicrobial functionality through the alteration in protein secondary structure, significantly retards bacterial resistance development, holding great promise for intelligent antimicrobial materials. Cationic antimicrobial polymers exhibit advantages distinct from antibiotics due to their lower propensity for resistance development. However, the presence of cationic moieties also poses a threat to healthy cells and tissues, significantly constraining their potential for clinical applications. To address this challenge, we propose a biomimetic strategy that mimics voltage-gated ion channels to activate the antimicrobial functionality of cations selectively in bacterial environments through the conformational transitions of proteins between β –sheets and α –helices. In healthy tissues, the antimicrobial functionality is inhibited, ensuring satisfactory biocompatibility. Antimicrobial cationic materials capable of intelligent switching between an activated state and an inhibited state in response to environmental changes offer an effective strategy to prevent the development of resistance and mitigate potential side effects. [Display omitted] [ABSTRACT FROM AUTHOR]

Background and purpose: Pulmonary arterial hypertension (PAH) is a progressive disease in which chronic membrane potential (Em) depolarisation of the pulmonary arterial smooth muscle cells (PASMCs) causes calcium overload, a key pathological alteration. Under resting conditions, the negative Em is mainly set by two pore domain potassium (K2P) channels, of which the TASK‐1 has been extensively investigated. Experimental Approach: Ion channel currents and membrane potential of primary cultured human(h) PASMCs were measured using the voltage‐ and current clamp methods. Intracellular [Ca2+] was monitored using fluorescent microscopy. Pulmonary BP and vascular tone measurements were also performed ex vivo using a rat PAH model. Key Results: TREK‐1 was the most abundantly expressed K2P in hPASMCs of healthy donors and idiopathic(I) PAH patients. Background K+‐current was similar in hPASMCs for both groups and significantly enhanced by the TREK activator ML‐335. In donor hPASMCs, siRNA silencing or pharmacological inhibition of TREK‐1 caused depolarisation, reminiscent of the electrophysiological phenotype of idiopathic PAH. ML‐335 hyperpolarised donor hPASMCs and normalised the Em of IPAH hPASMCs. A close link was found between TREK‐1 activity and intracellular Ca2+‐signalling using a channel activator, ML‐335, and an inhibitor, spadin. In the rat, ML‐335 relaxed isolated pre‐constricted pulmonary arteries and significantly decreased pulmonary arterial pressure in the isolated perfused lung. Conclusions and Implications: These data suggest that TREK‐1is a key factor in Em setting and Ca2+ homeostasis of hPASMC, and therefore, essential for maintenance of a low resting pulmonary vascular tone. Thus TREK‐1 may represent a new therapeutic target for PAH. [ABSTRACT FROM AUTHOR]

As human skin comes into contact with the tiny hairs or setae of the oak processionary caterpillar, Thaumetopoea processionea, a silent yet intense chemical confrontation occurs. The result is a mix of issues: skin rashes and an intense itching that typically lasts days and weeks after the contact. This discomfort poses a significant health threat not only to humans but also to animals. In Western Europe, the alarming increase in outbreaks extends beyond areas near infested trees due to the dispersion of the setae. Predictions indicate a sustained rise in outbreaks, fueled by global changes favoring the caterpillar's survival and distribution. Currently, the absence of an efficient treatment persists due to significant gaps in our comprehension of the pathophysiology associated with this envenomation. Here, we explored the interaction between the venom extract derived from the setae of T. processionea and voltage- and ligand-gated ion channels and receptors. By conducting electrophysiological analyses, we discovered ex vivo evidence highlighting the significant role of TPTX1-Tp1, a peptide toxin from T. processionea, in modulating TRPV1. TPTX1-Tp1 is a secapin-like peptide and demonstrates a unique ability to modulate TRPV1 channels in the presence of capsaicin, leading to cell depolarization, itch and inflammatory responses. This discovery opens new avenues for developing a topical medication, suggesting the incorporation of a TRPV1 blocker as a potential solution for the local effects caused by T. processionea. [ABSTRACT FROM AUTHOR]

Insulin-like growth factor-1 (IGF-1) is a polypeptide hormone with a ubiquitous distribution in numerous tissues and with various functions in both neuronal and non-neuronal cells. IGF-1 provides trophic support for many neurons of both the central and peripheral nervous systems. In the central nervous system (CNS), IGF-1R signaling regulates brain development, increases neuronal firing and modulates synaptic transmission. IGF-1 and IGF-IR are not only expressed in CNS neurons but also in sensory dorsal root ganglion (DRG) nociceptive neurons that convey pain signals. DRG nociceptive neurons express a variety of receptors and ion channels that are essential players of neuronal excitability, notably the ligand-gated cation channel TRPV1 and the voltage-gated M-type K+ channel, which, respectively, triggers and dampens sensory neuron excitability. Although many lines of evidence suggest that IGF-IR signaling contributes to pain sensitivity, its possible modulation of TRPV1 and M-type K+ channel remains largely unexplored. In this study, we examined the impact of IGF-1R signaling on DRG neuron excitability and its modulation of TRPV1 and M-type K+ channel activities in cultured rat DRG neurons. Acute application of IGF-1 to DRG neurons triggered hyper-excitability by inducing spontaneous firing or by increasing the frequency of spikes evoked by depolarizing current injection. These effects were prevented by the IGF-1R antagonist NVP-AEW541 and by the PI3Kinase blocker wortmannin. Surprisingly, acute exposure to IGF-1 profoundly inhibited both the TRPV1 current and the spike burst evoked by capsaicin. The Src kinase inhibitor PP2 potently depressed the capsaicin-evoked spike burst but did not alter the IGF-1 inhibition of the hyperexcitability triggered by capsaicin. Chronic IGF-1 treatment (24 h) reduced the spike firing evoked by depolarizing current injection and upregulated the M-current density. In contrast, chronic IGF-1 markedly increased the spike burst evoked by capsaicin. In all, our data suggest that IGF-1 exerts complex effects on DRG neuron excitability as revealed by its dual and opposite actions upon acute and chronic exposures. [ABSTRACT FROM AUTHOR]

Ion channels play a pivotal role in regulating cellular excitability and signal transduction processes. Among the various ion channels, G-protein-coupled inwardly rectifying potassium (GIRK) channels serve as key mediators of neurotransmission and cellular responses to extracellular signals. GIRK channels are members of the larger family of inwardly-rectifying potassium (Kir) channels. Typically, GIRK channels are activated via the direct binding of G-protein βγ subunits upon the activation of G-protein-coupled receptors (GPCRs). GIRK channel activation requires the presence of the lipid signaling molecule, phosphatidylinositol 4,5-bisphosphate (PIP2). GIRK channels are also modulated by endogenous proteins and other molecules, including RGS proteins, cholesterol, and SNX27 as well as exogenous compounds, such as alcohol. In the last decade or so, several groups have developed novel drugs and small molecules, such as ML297, GAT1508 and GiGA1, that activate GIRK channels in a G-protein independent manner. Here, we aim to provide a comprehensive overview focusing on the direct modulation of GIRK channels by G-proteins, PIP2, cholesterol, and novel modulatory compounds. These studies offer valuable insights into the underlying molecular mechanisms of channel function, and have potential implications for both basic research and therapeutic development. [ABSTRACT FROM AUTHOR]

Hyperpolarization and cyclic nucleotide (HCN) activated ion channels are critical for the automaticity of action potentials in pacemaking and rhythmic electrical circuits in the human body. Unlike most voltage-gated ion channels, the HCN and related plant ion channels activate upon membrane hyperpolarization. Although functional studies have identified residues in the interface between the voltage-sensing and pore domain as crucial for inverted electromechanical coupling, the structural mechanisms for this unusual voltage-dependence remain unclear. Here, we present cryo-electron microscopy structures of human HCN1 corresponding to Closed, Open, and a putative Intermediate state. Our structures reveal that the downward motion of the gating charges past the charge transfer center is accompanied by concomitant unwinding of the inner end of the S4 and S5 helices, disrupting the tight gating interface observed in the Closed state structure. This helix-coil transition at the intracellular gating interface accompanies a concerted iris-like dilation of the pore helices and underlies the reversed voltage dependence of HCN channels. HCN ion channels activate upon hyperpolarization, in contrast to other members of the voltage-gated ion channel superfamily. Here, authors reveal the structural basis of inverted voltage-dependence by solving the structures of this channel in Closed, Open and Intermediate conformations. [ABSTRACT FROM AUTHOR]

Utilizing trio whole-exome sequencing and a gene matching approach, we identified a cohort of 18 male individuals from 17 families with hemizygous variants in KCND1 , including two de novo missense variants, three maternally inherited protein-truncating variants, and 12 maternally inherited missense variants. Affected subjects present with a neurodevelopmental disorder characterized by diverse neurological abnormalities, mostly delays in different developmental domains, but also distinct neuropsychiatric signs and epilepsy. Heterozygous carrier mothers are clinically unaffected. KCND1 encodes the α-subunit of Kv4.1 voltage-gated potassium channels. All variant-associated amino acid substitutions affect either the cytoplasmic N- or C-terminus of the channel protein except for two occurring in transmembrane segments 1 and 4. Kv4.1 channels were functionally characterized in the absence and presence of auxiliary β subunits. Variant-specific alterations of biophysical channel properties were diverse and varied in magnitude. Genetic data analysis in combination with our functional assessment shows that Kv4.1 channel dysfunction is involved in the pathogenesis of an X-linked neurodevelopmental disorder frequently associated with a variable neuropsychiatric clinical phenotype. Hemizygous variants of KCND1 lead to alterations in the biophysical properties of the encoded ion channel, implicating dysfunction of Kv4.1 voltage-gated potassium channels in the etiology of an X-linked neurodevelopmental disorder with variable expressivity. [ABSTRACT FROM AUTHOR]

Voltage-gated ion channels (VGICs) respond to changes in membrane potential (Vm) and typically exhibit fast kinetic properties. They play an important role in signal detection and propagation in excitable tissues. In contrast, the role of VGICs in non-excitable tissues like epithelia is less studied and less clear. Studies in epithelia of vertebrates and invertebrates demonstrate wide expression of VGICs in epithelia of animals. Recently, VGICs have emerged as regulators of ion transport in the Malpighian tubules (MTs) and other osmoregulatory organs of insects. This mini-review aims to concisely summarize which VGICs have been implicated in the regulation of ion transport in the osmoregulatory epithelia of insects to date, and highlight select groups for further study. We have also speculated on the roles VGICs may potentially play in regulating processes connected directly to ion transport in insects (e.g., acid-base balance, desiccation, thermal tolerance). This review is not meant to be exhaustive but should rather serve as a thought-provoking collection of select existing highlights on VGICs, and to emphasize how understudied this mechanism of ion transport regulation is in insect epithelia. [ABSTRACT FROM AUTHOR]

Voltage‐clamp fluorometry (VCF) enables the study of voltage‐sensitive proteins through fluorescent labeling accompanied by ionic current measurements for voltage‐gated ion channels. The heterogeneity of the fluorescent signal represents a significant challenge in VCF. The VCF signal depends on where the cysteine mutation is incorporated, making it difficult to compare data among different mutations and different studies and standardize their interpretation. We have recently shown that the VCF signal originates from quenching amino acids in the vicinity of the attached fluorophores, together with the effect of the lipid microenvironment. Based on these, we performed experiments to test the hypothesis that the VCF signal could be altered by amphiphilic quenching molecules in the cell membrane. Here we show that a phenylalanine‐conjugated flavonoid (4‐oxo‐2‐phenyl‐4H‐chromene‐7‐yl)‐phenylalanine, (later Oxophench) has potent effects on the VCF signals of the Ciona intestinalis HV1 (CiHv1) proton channel. Using spectrofluorimetry, we showed that Oxophench quenches TAMRA (5(6)‐carboxytetramethylrhodamine‐(methane thiosulfonate)) fluorescence. Moreover, Oxophench reduces the baseline fluorescence in oocytes and incorporates into the cell membrane while reducing the membrane fluidity of HEK293 cells. Our model calculations confirmed that Oxophench, a potent membrane‐bound quencher, modifies the VCF signal during conformational changes. These results support our previously published model of VCF signal generation and point out that a change in the VCF signal may not necessarily indicate an altered conformational transition of the investigated protein. [ABSTRACT FROM AUTHOR]

This paper presents an in-depth analysis of an excitable membrane of a biological system by proposing a novel approach that the cells of the excitable membrane can be modeled as the networks of memristors. We provide compelling evidence from the Chay neuron model that the state-independent mixed ion channel is a nonlinear resistor, while the state-dependent voltage-sensitive potassium ion channel and calcium-sensitive potassium ion channel function as generic memristors from the perspective of electrical circuit theory. The mechanisms that give rise to periodic oscillation, aperiodic (chaotic) oscillation, spikes, and bursting in an excitable cell are also analyzed via a small-signal model, a pole-zero diagram of admittance functions, local activity, the edge of chaos, and the Hopf bifurcation theorem. It is also proved that the zeros of the admittance functions are equivalent to the eigen values of the Jacobian matrix, and the presence of the positive real parts of the eigen values between the two bifurcation points lead to the generation of complicated electrical signals in an excitable membrane. The innovative concepts outlined in this paper pave the way for a deeper understanding of the dynamic behavior of excitable cells, offering potent tools for simulating and exploring the fundamental characteristics of biological neurons. [ABSTRACT FROM AUTHOR]

S-amlodipine (S-AM) is a commonly prescribed antihypertensive drug for patients with hypertension, and it is used for an extended duration in most hypertensive patients. However, it remains unclear whether long-term exposure to non-antibiotic drug S-amlodipine induces bacterial antibiotic resistance. To investigate the potential impact of S-AM on bacterial antibiotic resistance, we conducted a 60-day in vitro evolution experiment in which intestinal pathogen K. pneumoniae was exposed to 2 mg⋅L-1 S-AM. We determined the resistance of the evolved strains to six antibiotics through antibiotic susceptibility testing. Furthermore, we delved into the potential resistance mechanisms of K. pneumoniae via genome sequencing, fluorescence quantitative PCR, and bioinformatics analysis. This study observed that the mutation frequency of K. pneumoniae increased from 10-7 to 1.5 x 10-1 under S-AM stress, and the intracellular reactive oxygen species (ROS) levels of the evolved strains significantly increased compared to that of the control strains. Additionally, the evolved strains exhibited heightened resistance to polymyxin, kanamycin, chloramphenicol, erythromycin, and moxifloxacin. Whole genome sequencing analysis results showed the presence of three non-synonymous single nucleotide polymorphism (SNP) mutation sites, one synonymous SNP mutation site, two intergenic SNPs, and one intergenic insertion site in the evolved strains. These non-synonymous gene mutations include the HAMP domain-containing histidine kinase crrB gene, sensor domain-containing diguanylate cyclase, and type 3 fimbria adhesin subunit mrkD gene. Notably, the mutated crrB gene, in collaboration with the crrA gene, enhanced the modification of the lipid A component of the cell membrane lipopoly-saccharide (LPS) in the evolved strains. This modification increased the positive charge on the bacterial cell membrane surface, hindering polymyxin-cell interactions and contributing to increased polymyxin resistance in K. pneumoniae. Fluorescence quantitative PCR results revealed that exposure to S-AM enhanced the mRNA expressions of two-component regulatory system genes (e.g., crrAB, phoPQ, pmrAB, and pmrDFIK), multidrug efflux pump genes (e.g., emrD and oqxAB), and the intrinsic resistance gene aadA2, which might be responsible for increased bacterial resistance to multiple antibiotics. In summary, this study is the first to demonstrate that S-AM stress triggers multiple antibiotic resistance in K. pneumoniae and elucidates the underlying molecular mechanisms, serving as an early warning for potential health risks associated with long-term medication in hypertensive patients. It lays a foundation for further exploration of antibiotic resistance in diverse intestinal bacteria under prolonged S-AM stress. [ABSTRACT FROM AUTHOR]

Voltage-gated ion channels are essential for membrane potential maintenance, homeostasis, electrical signal production and controlling the Ca2+ flow through the membrane. Among all ion channels, the key regulators of neuronal excitability are the voltage-gated potassium channels (KV), the largest family of K+ channels. Due to the ROS high levels in the aging brain, K+ channels might be affected by oxidative agents and be key in aging and neurodegeneration processes. This review provides new insight about channelopathies in the most studied neurodegenerative disorders, such as Alzheimer Disease, Parkinson's Disease, Huntington Disease or Spinocerebellar Ataxia. The main affected KV channels in these neurodegenerative diseases are the KV1, KV2.1, KV3, KV4 and KV7. Moreover, in order to prevent or repair the development of these neurodegenerative diseases, previous KV channel modulators have been proposed as therapeutic targets. [ABSTRACT FROM AUTHOR]

Mitochondrial dysfunction contributes to the development of secondary brain injury (SBI) following intracerebral hemorrhage (ICH) and represents a promising therapeutic target. Celastrol, the primary active component of Tripterygium wilfordii, is a natural product that exhibits mitochondrial and neuronal protection in various cell types. This study aims to investigate the neuroprotective effects of celastrol against ICH‐induced SBI and explore its underlying mechanisms. Celastrol improves neurobehavioral and cognitive abilities in mice with autologous blood‐induced ICH, reduces neuronal death in vivo and in vitro, and promotes mitochondrial function recovery in neurons. Single‐cell nuclear sequencing reveals that the cyclic adenosine monophosphate (cAMP)/cAMP‐activated exchange protein‐1 (EPAC‐1) signaling pathways are impacted by celastrol. Celastrol binds to cNMP (a domain of EPAC‐1) to inhibit its interaction with voltage‐dependent anion‐selective channel protein 1 (VDAC1) and blocks the opening of mitochondrial permeability transition pores. After neuron‐specific knockout of EPAC1, the neuroprotective effects of celastrol are diminished. In summary, this study demonstrates that celastrol, through its interaction with EPAC‐1, ameliorates mitochondrial dysfunction in neurons, thus potentially improving SBI induced by ICH. These findings suggest that targeting EPAC‐1 with celastrol can be a promising therapeutic approach for treating ICH‐induced SBI. [ABSTRACT FROM AUTHOR]

The electric potential stimulation of biological structures in aqueous environments is well-known to be a result of the gating of voltage-gated ion channels. Such voltage-gated ion channels are ubiquitous in the membranes of a wide variety of cells and they play central roles in a wide variety of sensing mechanisms and neuronal functions in biological systems. Experimental studies of ion-channel gating are frequently conducted using path-clamp techniques by placing a cumbersome external electrode in the vicinity of the extracellular side of the ion channel. Recently, it has been demonstrated that laser-induced polarization of nanoscale quantum dots can produce voltage sufficient to gate voltage-gated ion channels. This study specifically focuses on a new method of gating voltage-gated ion channels using 2D structures made of materials exhibiting large naturally occurring spontaneous polarizations, thereby eliminating the need for an external electrode or an illuminating laser. The work presents the use of self-polarizing semiconductor flakes, namely, 2H-SiC, ZnO, and GaN, to produce electric potential that is sufficient to gate voltage-gated ion channels when existing in proximity to it. [ABSTRACT FROM AUTHOR]

The human voltage-gated sodium channel Nav1.7 is a widely proven target for analgesic drug studies. ProTx2, a 30-residue polypeptide from Peruvian green tarantula venom, shows high specificity to activity against human Nav1.7, suggesting its potential to become a non-addictive analgesic. However, its high sensitivity to human Nav1.4 raises concerns about muscle side effects. Here, we engineered three mutants (R13A, R13D, and K27Y) of ProTx2 to evaluate their pharmacological activities toward Nav1.7 and Nav1.4. It is demonstrated that the mutant R13D maintained the analgesic effect in mice while dramatically reducing its muscle toxicity compared with ProTx2. The main reason is the formation of a strong electrostatic interaction between R13D and the negatively charged amino acid residues in DII/S3-S4 of Nav1.7, which is absent in Nav1.4. This study advances our understanding and insights on peptide toxins, paving the way for safer, effective non-addictive analgesic development. [ABSTRACT FROM AUTHOR]

Soil salinity is a major environmental constraint affecting the sustainability and profitability of agricultural production systems. Salinity stress tolerance has been present in wild crop relatives but then lost, or significantly weakened, during their domestication. Given the genetic and physiological complexity of salinity tolerance traits, agronomical solutions may be a suitable alternative to crop breeding for improved salinity stress tolerance. One of them is optimizing fertilization practices to assist plants in dealing with elevated salt levels in the soil. In this review, we analyse the causal relationship between the availability of boron (an essential metalloid micronutrient) and plant's adaptive responses to salinity stress at the whole‐plant, cellular, and molecular levels, and a possibility of using boron for salt stress mitigation. The topics covered include the impact of salinity and the role of boron in cell wall remodelling, plasma membrane integrity, hormonal signalling, and operation of various membrane transporters mediating plant ionic and water homeostasis. Of specific interest is the role of boron in the regulation of H+‐ATPase activity whose operation is essential for the control of a broad range of voltage‐gated ion channels. The complex relationship between boron availability and expression patterns and the operation of aquaporins is also discussed. [ABSTRACT FROM AUTHOR]

Acid-sensing ion channel 1a (ASIC1a) is a proton-activated channel that is expressed ubiquitously throughout the central nervous system and in various types of immune cells. Its role in spinal cord injury (SCI) is controversial; inhibition of ASIC1a has been reported to improve SCI pathology in vivo, but conversely, gene ablation increased kainite-mediated excitotoxic cell death in vitro. Here, we re-examined the role of ASIC1a in a mouse model of SCI. First, we observed functional outcomes up to 42 days post-operation (DPO) in SCI mice with a selective genetic ablation of ASIC1a. Mice lacking ASIC1a had significantly worsened locomotor ability and increased lesion size compared with mice possessing the ASIC1a gene. Next, we explored pharmacological antagonism of this ion channel by administering the potent ASIC1a inhibitor, Hi1a. Consistent with a role for ASIC1a to attenuate excitotoxicity, accelerated neuronal cell loss was found at the lesion site in SCI mice treated with Hi1a, but there were no differences in locomotor recovery. Moreover, ASIC1a inhibition did not cause significant alterations to neutrophil migration, microglial density, or blood–spinal cord barrier integrity. [ABSTRACT FROM AUTHOR]

Spreading depolarization (SD) is an electrochemical wave of neuronal depolarization mediated by extracellular K+ and glutamate, interacting with voltage-gated and ligandgated ion channels. SD is increasingly recognized as a major cause of injury progression in stroke and brain trauma, where the mechanisms of SD-induced neuronal injury are intimately linked to energetic status and metabolic impairment. Here, I review the established working model of SD initiation and propagation. Then, I summarize the historical and recent evidence for the metabolic impact of SD, transitioning from a descriptive to a mechanistic working model of metabolic signaling and its potential to promote neuronal survival and resilience. I quantify the energetic cost of restoring ionic gradients eroded during SD, and the extent to which ion pumping impacts high-energy phosphate pools and the energy charge of affected tissue. I link energy deficits to adaptive increases in the utilization of glucose and O2, and the resulting accumulation of lactic acid and CO2 downstream of catabolic metabolic activity. Finally, I discuss the neuromodulatory and vasoactive paracrine signaling mediated by adenosine and acidosis, highlighting these metabolites' potential to protect vulnerable tissue in the context of high-frequency SD clusters. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer is a leading cause of death worldwide. The costs involved in cancer diagnosis and treatment are extraordinary. Important steps that can be taken that would reduce costs include earlier cancer diagnosis for which significant headway is being made through biomarker identification in bodily fluids and imaging. Other important steps will be to identify treatment approaches that do not 'break the bank' and affect a patient's wellbeing. Herein, we aim to highlight the potential of phytochemicals as a cost-effective approach to aid in the treatment of cancer. We focus on phytochemicals that target ion channels, as molecules that mediate critical communication of a cell with its environment. Ultimately, we posit that phytochemicals targeting ion channels can be employed to aid cancer treatment. Modern chemotherapies offer a broad approach to cancer treatment but eliminate both cancer and non-cancer cells indiscriminately and, thus, are associated with a host of side effects. Advances in precision oncology have brought about new targeted therapeutics, albeit mostly limited to a subset of patients with an actionable mutation. They too come with side effects and, ultimately, 'self-resistance' to the treatment. There is recent interest in the modulation of ion channels, transmembrane proteins that regulate the flow of electrically charged molecules in and out of cells, as an approach to aid treatment of cancer. Phytochemicals have been shown to act on ion channels with high specificity regardless of the tumor's genetic profile. This paper explores the use of phytochemicals in cancer symptom management and treatment. [ABSTRACT FROM AUTHOR]

This article explores a method for predicting the pathogenicity of genetic variants in ion channel-encoding genes. By analyzing the distance of amino acids from the central axis of the ion channel pore, researchers can determine the likelihood of a variant being pathogenic. However, this approach may not be effective for all ion channels, particularly ligand-gated channels. The authors suggest a protein-specific approach that considers the activation pathway instead of the pore axis. They demonstrate this approach using GABAA receptors as an example. The study found that the distance to the activation pathway was a better predictor of pathogenicity than the distance to the pore axis. The researchers also proposed a two-step method that combines the distance to the activation pathway and the channel gate for more accurate predictions. The study was funded by the Australian National Health & Medical Research Council and The Lundbeck Foundation. [Extracted from the article]

Background Information: Two pore channels (TPCs) are voltage‐gated ion channel superfamily members that release Ca2+ from acidic intracellular stores and are ubiquitously present in both animals and plants. Starvation initiates multicellular development in Dictyostelium discoideum. Increased intracellular calcium levels bias Dictyostelium cells towards the stalk pathway and thus we decided to analyze the role of TPC2 in development, differentiation, and autophagy. Results: We showed TPC2 protein localizes in lysosome‐like acidic vesicles and the in situ data showed stalk cell biasness. Deletion of tpc2 showed defective and delayed development with formation of multi‐tipped structures attached to a common base, while tpc2OE cells showed faster development with numerous small‐sized aggregates and wiry fruiting bodies. The tpc2OE cells showed higher intracellular cAMP levels as compared to the tpc2− cells while pinocytosis was found to be higher in the tpc2− cells. Also, TPC2 regulates cell‐substrate adhesion and cellular morphology. Under nutrient starvation, deletion of tpc2 reduced autophagic flux as compared to Ax2. During chimera formation, tpc2− cells showed a bias towards the prestalk/stalk region while tpc2OE cells showed a bias towards the prespore/spore region. tpc2 deficient strain exhibits aberrant cell‐type patterning and loss of distinct boundary between the prestalk/prespore regions. Conclusion: TPC2 is required for effective development and differentiation in Dictyostelium and supports autophagic cell death and cell‐type patterning. Significance: Decreased calcium due to deletion of tpc2 inhibit autophagic flux. [ABSTRACT FROM AUTHOR]

In this report we present seven lines of bioinformatic evidence supporting the conclusion that the Pentameric Ligand-gated Ion Channel (pLIC) Family is a member of the Voltage-gated Ion Channel (VIC) Superfamily. In our approach, we used the Transporter Classification Database (TCDB) as a reference and applied a series of bioinformatic methods to search for similarities between the pLIC family and members of the VIC superfamily. These include: (1) sequence similarity, (2) compatibility of topology and hydropathy profiles, (3) shared domains, (4) conserved motifs, (5) similarity of Hidden Markov Model profiles between families, (6) common 3D structural folds, and (7) clustering analysis of all families. Furthermore, sequence and structural comparisons as well as the identification of a 3-TMS repeat unit in the VIC superfamily suggests that the sixth transmembrane segment evolved into a re-entrant loop. This evidence suggests that the voltage-sensor domain and the channel domain have a common origin. The classification of the pLIC family within the VIC superfamily sheds light onto the topological origins of this family and its evolution, which will facilitate experimental verification and further research into this superfamily by the scientific community. [ABSTRACT FROM AUTHOR]

Islet beta cells (β-cells) produce insulin in response to high blood glucose levels, which is essential for preserving glucose homeostasis. Voltage-gated ion channels in β-cells, including Na+, K+, and Ca2+ channels, aid in the release of insulin. The epithelial sodium channel alpha subunit (α-ENaC), a voltage-independent sodium ion channel, is also expressed in human pancreatic endocrine cells. However, there is no reported study on the function of ENaC in the β-cells. In the current study, we found that α-ENaC was expressed in human pancreatic glandule and pancreatic islet β-cells. In the pancreas of db/db mice and high-fat diet-induced mice, and in mouse islet β-cells (MIN6 cells) treated with palmitate, α-ENaC expression was increased. When α-ENaC was overexpressed in MIN6 cells, insulin content and glucose-induced insulin secretion were significantly reduced. On the other hand, palmitate injured islet β-cells and suppressed insulin synthesis and secretion, but increased α-ENaC expression in MIN6 cells. However, α-ENaC knockout (Scnn1a−/−) in MIN6 cells attenuated β-cell disorder induced by palmitate. Furthermore, α-ENaC regulated the ubiquitylation and degradation of sirtuin 2 in β-cells. α-ENaC also modulated β-cell function in correlation with the inositol-requiring enzyme 1 alpha/X-box binding protein 1 (IRE1α/XBP1) and protein kinase RNA-like endoplasmic reticulum kinase/C/EBP homologous protein (PERK/CHOP) endoplasmic reticulum stress pathways. These results suggest that α-ENaC may play a novel role in insulin synthesis and secretion in the β-cells, and the upregulation of α-ENaC promotes islet β-cell dysfunction. In conclusion, α-ENaC may be a key regulator involved in islet β-cell damage and a potential therapeutic target for type 2 diabetes mellitus. [ABSTRACT FROM AUTHOR]

Voltage‐gated ion channels prevalent in neurons play important roles in generating action potential and information transmission by responding to transmembrane potential. Fabricating bio‐inspired ionic transistors with ions as charge carriers will be crucial for realizing neuro‐inspired devices and brain‐liking computing. Here, we reported a two‐dimensional nanofluidic ionic transistor based on a MXene membrane with sub‐1 nm interlayer channels. By applying a gating voltage on the MXene nanofluidic, a transmembrane potential will be generated to active the ionic transistor, which is similar to the transmembrane potential of neuron cells and can be effectively regulated by changing membrane parameters, e.g. thickness, composition, and interlayer spacing. For the symmetric MXene nanofluidic, a high on/off ratio of ~2000 can be achieved by forming an ionic depletion or accumulation zone, contingent on the sign of the gating potential. An asymmetric PET/MXene‐composited nanofluidic transitioned the ionic transistor from ambipolar to unipolar, resulting in a more sensitive gate voltage characteristic with a low subthreshold swing of 560 mV/decade. Furthermore, ionic logic gate circuits, including the "NOT", "NAND", and "NOR" gate, were implemented for neuromorphic signal processing successfully, which provides a promising pathway towards highly parallel, low energy consumption, and ion‐based brain‐like computing. [ABSTRACT FROM AUTHOR]

Chemotherapy-induced peripheral neuropathy (CIPN) is the most common off-target adverse effects caused by various chemotherapeutic agents, such as cisplatin, oxaliplatin, paclitaxel, vincristine and bortezomib. CIPN is characterized by a substantial loss of primary afferent sensory axonal fibers leading to sensory disturbances in patients. An estimated of 19-85% of patients developed CIPN during the course of chemotherapy. The lack of preventive measures and limited treatment options often require a dose reduction or even early termination of life-saving chemotherapy, impacting treatment efficacy and patient survival. In this Review, we summarized the current understanding on the pathogenesis of CIPN. One prominent change induced by chemotherapeutic agents involves the disruption of neuronal cytoskeletal architecture and axonal transport dynamics largely influenced by the interference of microtubule stability in peripheral neurons. Due to an ineffective blood-nerve barrier in our peripheral nervous system, exposure to some chemotherapeutic agents causes mitochondrial swelling in peripheral nerves, which lead to the opening of mitochondrial permeability transition pore and cytochrome c release resulting in degeneration of primary afferent sensory fibers. The exacerbated nociceptive signaling and pain transmission in CIPN patients is often linked the increased neuronal excitability largely due to the elevated expression of various ion channels in the dorsal root ganglion neurons. Another important contributing factor of CIPN is the neuroinflammation caused by an increased infiltration of immune cells and production of inflammatory cytokines. In the central nervous system, chemotherapeutic agents also induce neuronal hyperexcitability in the spinal dorsal horn and anterior cingulate cortex leading to the development of central sensitization that causes CIPN. Emerging evidence suggests that the change in the composition and diversity of gut microbiota (dysbiosis) could have direct impact on the development and progression of CIPN. Collectively, all these aspects contribute to the pathogenesis of CIPN. Recent advances in RNA-sequencing offer solid platform for in silico drug screening which enable the identification of novel therapeutic agents or repurpose existing drugs to alleviate CIPN, holding immense promises for enhancing the quality of life for cancer patients who undergo chemotherapy and improve their overall treatment outcomes. [ABSTRACT FROM AUTHOR]

Mammalian Ca2+‐dependent Slo K+ channels can stably associate with auxiliary γ subunits which fundamentally alter their behavior. By a so far unknown mechanism, the four γ subunits reduce the need for voltage‐dependent activation and, thereby, allow Slo to open independently of an action potential. Here, using cryo‐EM, we reveal how the transmembrane helix of γ1/LRRC26 binds and presumably stabilizes the activated voltage‐sensor domain of Slo1. The activation is further enhanced by an intracellular polybasic stretch which locally changes the charge gradient across the membrane. Our data provide a possible explanation for Slo1 regulation by the four γ subunits and also their different activation efficiencies. This suggests a novel activation mechanism of voltage‐gated ion channels by auxiliary subunits. [ABSTRACT FROM AUTHOR]

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by social and communication deficits and repetitive behaviors. The genetic heterogeneity of ASD presents a challenge to the development of an effective treatment targeting the underlying molecular defects. ASD gating charge mutations in the KCNQ/KV7 potassium channel cause gating pore currents (Igp) and impair action potential (AP) firing of dopaminergic neurons in brain slices. Here, we investigated ASD gating charge mutations of the voltage-gated SCN2A/NaV1.2 brain sodium channel, which ranked high among the ion channel genes with mutations in individuals with ASD. Our results show that ASD mutations in the gating charges R2 in Domain-II (R853Q), and R1 (R1626Q) and R2 (R1629H) in Domain-IV of NaV1.2 caused Igp in the resting state of ~0.1% of the amplitude of central pore current. The R1626Q mutant also caused significant changes in the voltage dependence of fast inactivation, and the R1629H mutant conducted proton-selective Igp. These potentially pathogenic Igp were exacerbated by the absence of the extracellular Mg2+ and Ca2+. In silico simulation of the effects of these mutations in a conductance-based single-compartment cortical neuron model suggests that the inward Igp reduces the time to peak for the first AP in a train, increases AP rates during a train of stimuli, and reduces the interstimulus interval between consecutive APs, consistent with increased neural excitability and altered input/output relationships. Understanding this common pathophysiological mechanism among different voltage-gated ion channels at the circuit level will give insights into the underlying mechanisms of ASD. [ABSTRACT FROM AUTHOR]

Ion channels mediate voltage fluxes or action potentials that are central to the functioning of excitable cells such as neurons. The KCNB family of voltage-gated potassium channels (Kv) consists of two members (KCNB1 and KCNB2) encoded by KCNB1 and KCNB2 , respectively. These channels are major contributors to delayed rectifier potassium currents arising from the neuronal soma which modulate overall excitability of neurons. In this study, we identified several mono-allelic pathogenic missense variants in KCNB2 , in individuals with a neurodevelopmental syndrome with epilepsy and autism in some individuals. Recurrent dysmorphisms included a broad forehead, synophrys, and digital anomalies. Additionally, we selected three variants where genetic transmission has not been assessed, from two epilepsy studies, for inclusion in our experiments. We characterized channel properties of these variants by expressing them in oocytes of Xenopus laevis and conducting cut-open oocyte voltage clamp electrophysiology. Our datasets indicate no significant change in absolute conductance and conductance-voltage relationships of most disease variants as compared to wild type (WT), when expressed either alone or co-expressed with WT-KCNB2. However, variants c.1141A>G (p.Thr381Ala) and c.641C>T (p.Thr214Met) show complete abrogation of currents when expressed alone with the former exhibiting a left shift in activation midpoint when expressed alone or with WT-KCNB2. The variants we studied, nevertheless, show collective features of increased inactivation shifted to hyperpolarized potentials. We suggest that the effects of the variants on channel inactivation result in hyper-excitability of neurons, which contributes to disease manifestations. [Display omitted] Channelopathies arise due to perturbations in ion channel function. In this study, we identify 10 variants in KCNB2 in individuals with neurodevelopmental disorders. Our data suggest that most KCNB2 variants show reduced potassium conductance due to either reduced functional expression or increased channel inactivation. [ABSTRACT FROM AUTHOR]

Inorganic polyphosphate (polyP) is widely recognized for playing important roles and processes involved in energy and phosphate storage, regulation of gene expression, and calcium signaling. The less well-known role of polyP is as a direct mediator of ion transport across biological membranes. Here, we will briefly summarize current knowledge of the molecular mechanisms of how polyP can be involved in membrane ion transport. We discuss three types of mechanisms that might involve polyP: (1) formation of non-protein channel complex that includes calcium, polyP, and polyhydroxybutyrate (PHB); (2) modulation of the channel activity of PHBlated protein channels; and (3) direct effects of polyP on the function of the voltage-gated ion channels in the process that do not involve PHB. [ABSTRACT FROM AUTHOR]

Abstract Drug studies targeting neuronal ion channels are crucial to understand neuronal function and develop therapies for neurological diseases. The traditional method to study neuronal ion‐channel activities heavily relies on the whole‐cell patch clamp as the industry standard. However, this technique is both technically challenging and labour‐intensive, while involving the complexity of keeping cells alive with low throughput. Therefore, the shortcomings are limiting the efficiency of ion‐channel‐related neuroscience research and drug testing. Here, this work reports a new system of integrating neuron membranes with organic microelectrode arrays (OMEAs) for ion‐channel‐related drug studies. This work demonstrates that the supported lipid bilayers (SLBs) derived from both neuron‐like (neuroblastoma) cells and primary neurons are integrated with OMEAs for the first time. The increased expression of voltage‐gated calcium (CaV) ion channels on differentiated SH‐SY5Y SLBs compared to non‐differentiated ones is sensed electrically. Also, dose‐response of the CaV ion‐channel blocking effect on primary cortical neuronal SLBs from rats is monitored. The dose range causing ion channel blocking is comparable to literature. This system overcomes the major challenges from traditional methods (e.g., patch clamp) and showcases an easy‐to‐test, rapid, ultra‐sensitive, cell‐free, and high‐throughput platform to monitor dose‐dependent ion‐channel blocking effects on native neuronal membranes.

Chronic pain affects a significant portion of military veterans and active duty personnel, and current pharmacological approaches to pain management come with negative side effects. Non-drug treatments like audio analgesia have shown promise in relieving pain without these side effects. One potential therapeutic target for chronic pain is the Pannexin 1 (Panx1) channel-forming protein, which plays a role in the release of Adenosine triphosphate (ATP) and the development of inflammatory pain. However, there are challenges in translating findings from animal models to human conditions, and more research is needed to adapt animal models to the human condition and ensure high-quality studies. [Extracted from the article]

Abstract Muscle spindles encode mechanosensory information by mechanisms that remain only partially understood. Their complexity is expressed in mounting evidence of various molecular mechanisms that play essential roles in muscle mechanics, mechanotransduction and intrinsic modulation of muscle spindle firing behaviour. Biophysical modelling provides a tractable approach to achieve more comprehensive mechanistic understanding of such complex systems that would be difficult/impossible by more traditional, reductionist means. Our objective here was to construct the first integrative biophysical model of muscle spindle firing. We leveraged current knowledge of muscle spindle neuroanatomy and in vivo electrophysiology to develop and validate a biophysical model that reproduces key in vivo muscle spindle encoding characteristics. Crucially, to our knowledge, this is the first computational model of mammalian muscle spindle that integrates the asymmetric distribution of known voltage‐gated ion channels (VGCs) with neuronal architecture to generate realistic firing profiles, both of which seem likely to be of great biophysical importance. Results predict that particular features of neuronal architecture regulate specific characteristics of Ia encoding. Computational simulations also predict that the asymmetric distribution and ratios of VGCs is a complementary and, in some instances, orthogonal means to regulate Ia encoding. These results generate testable hypotheses and highlight the integral role of peripheral neuronal structure and ion channel composition and distribution in somatosensory signalling.

Myasthenia gravis (MG) is a neuromuscular disease that results in compromised transmission of electrical signals at the neuromuscular junction (NMJ) from motor neurons to skeletal muscle fibers. As a result, patients with MG have reduced skeletal muscle function and present with symptoms of severe muscle weakness and fatigue. ClC-1 is a skeletal muscle specific chloride (Cl−) ion channel that plays important roles in regulating neuromuscular transmission and muscle fiber excitability during intense exercise. Here, we show that partial inhibition of ClC-1 with an orally bioavailable small molecule (NMD670) can restore muscle function in rat models of MG and in patients with MG. In severely affected MG rats, ClC-1 inhibition enhanced neuromuscular transmission, restored muscle function, and improved mobility after both single and prolonged administrations of NMD670. On this basis, NMD670 was progressed through nonclinical safety pharmacology and toxicology studies, leading to approval for testing in clinical studies. After successfully completing phase 1 single ascending dose in healthy volunteers, NMD670 was tested in patients with MG in a randomized, placebo-controlled, single-dose, three-way crossover clinical trial. The clinical trial evaluated safety, pharmacokinetics, and pharmacodynamics of NMD670 in 12 patients with mild MG. NMD670 had a favorable safety profile and led to clinically relevant improvements in the quantitative myasthenia gravis (QMG) total score. This translational study spanning from single muscle fiber recordings to patients provides proof of mechanism for ClC-1 inhibition as a potential therapeutic approach in MG and supports further development of NMD670. Editor's summary: Myasthenia gravis (MG) is caused by an autoimmune response against postsynaptic components of the neuromuscular junction, leading to impaired communication between motor neurons and muscle fibers. Here, Skov et al. show that inhibition of the ClC-1 chloride channel with an orally bioavailable small molecule (NMD670) augmented muscle excitability in response to motor commands and thereby improved muscle function in rat models of MG. Data from a small randomized clinical trial demonstrate that treatment with NMD670 was well tolerated in patients with MG and improved a quantitative disease severity score. These findings support further clinical development of ClC-1 inhibitors for MG. —Daniela Neuhofer [ABSTRACT FROM AUTHOR]

The voltage-gated ion channels, also known as ionic transistors, play substantial roles in biological systems and ion-ion selective separation. However, implementing the ultrafast switchable capabilities and polarity switching of ionic transistors remains a challenge. Here, we report a nanofluidic ionic transistor based on carbon nanotubes, which exhibits an on/off ratio of 104 at operational gate voltage as low as 1 V. By controlling the morphology of carbon nanotubes, both unipolar and ambipolar ionic transistors are realized, and their on/off ratio can be further improved by introducing an Al2O3 dielectric layer. Meanwhile, this ionic transistor enables the polarity switching between p-type and n-type by controlled surface properties of carbon nanotubes. The implementation of constructing ionic circuits based on ionic transistors is demonstrated, which enables the creation of NOT, NAND, and NOR logic gates. The ionic transistors are expected to have profound implications for low-energy consumption computing devices and brain-machine interfacing. [ABSTRACT FROM AUTHOR]

The widespread adoption of genetically modified (GM) crops has escalated concerns about their safety and ethical implications, underscoring the need for efficient GM crop detection methods. Conventional detection methods, such as polymerase chain reaction, can be costly, lab-bound, and time-consuming. To overcome these challenges, we have developed RapiSense, a cost-effective, portable, and sensitive biosensor platform. This sensor generates a measurable voltage shift (0.1–1 V) in the system's current-voltage characteristics, triggered by an increase in membrane's negative charge upon hybridization of DNA/RNA targets with a specific DNA probe. Probes designed to identify the herbicide resistance gene hygromycin phosphotransferase show a detection range from ∼1 nM to ∼10 μM and can discriminate between complementary, non-specific, and mismatched nucleotide targets. The incorporation of a small membrane sensor to detect fragmented RNA samples substantially improve the platform's sensitivity. In this study, RapiSense has been effectively used to detect specific DNA and fragmented RNA in transgenic variants of Arabidopsis, sweet potato, and rice, showcasing its potential for rapid, on-site GM crop screening. • Accelerated GM plant detection with anion exchange membrane-based nucleic acid sensor. • Improved sensitivity with small membrane sensor integration to detect fragmented RNA. • The RapiSense prototype device is easy-to-operate, portable, and time-efficient. [ABSTRACT FROM AUTHOR]

The most promising anticonvulsant phytocompounds were explored in this work using docking, molecular dynamic (MD) simulation, and Molecular Mechanics-Poisson–Boltzmann Surface Area (MM-PBSA) approaches. A total of 70 phytochemicals were screened against α-amino-3-hydroxyl-5-methyl-4-isoxazole propionic acid (AMPA), N-methyl-d-aspartate (NMDA), voltage-gated sodium ion channels (VGSC), and carbonic anhydrase enzyme II (CA II) receptors, and the docking results were compared to the reference drug phenytoin. Amentoflavone displayed the highest affinity for AMPA and VGSC receptors, with docking scores of − 10.4 and − 10.1 kcal/mol, respectively. Oliganthin H-NMDA and epigallocatechin-3-gallate-CA II complexes showed docking scores of − 10.9 and − 6.9 kcal/mol, respectively. All four complexes depicted a high dock score compared to the phenytoin complex at the binding site of the corresponding proteins. The MD simulation investigated the stabilities and favorable conformation of apoproteins and ligand/reference-bound complexes. The results revealed that proteins AMPA, VGSC, and CA II were more efficiently stabilized by lead phytochemicals than phenytoin binding. Additionally, principal component analysis and MM-PBSA results suggested that these lead phytocompounds have good compactness and strong binding free energy. Further, physicochemical and pharmacokinetic studies revealed that these final lead phytochemicals would be suitable for oral intake, have sufficient intestinal permeability, and have the ability to cross the blood–brain barrier (BBB). Comprehensively, this study predicted amentoflavone as the best lead phytochemical out of the 70 anticonvulsant phytocompounds that can be used to treat epilepsy. [ABSTRACT FROM AUTHOR]

Electrical stimulation is a fundamental tool in studying neural circuits, treating neurological diseases, and advancing regenerative medicine. Injectable, free-standing piezoelectric particle systems have emerged as non-genetic and wireless alternatives for electrode-based tethered stimulation systems. However, achieving cell-specific and high-frequency piezoelectric neural stimulation remains challenging due to high-intensity thresholds, non-specific diffusion, and internalization of particles. Here, we develop cell-sized 20 μm-diameter silica-based piezoelectric magnetic Janus microparticles (PEMPs), enabling clinically-relevant high-frequency neural stimulation of primary neurons under low-intensity focused ultrasound. Owing to its functionally anisotropic design, half of the PEMP acts as a piezoelectric electrode via conjugated barium titanate nanoparticles to induce electrical stimulation, while the nickel-gold nanofilm-coated magnetic half provides spatial and orientational control on neural stimulation via external uniform rotating magnetic fields. Furthermore, surface functionalization with targeting antibodies enables cell-specific binding/targeting and stimulation of dopaminergic neurons. Taking advantage of such functionalities, the PEMP design offers unique features towards wireless neural stimulation for minimally invasive treatment of neurological diseases. Wireless and localized stimulation of neural cells remains challenging. Here, the authors propose piezoelectric magnetic Janus microparticles that can target and stimulate neurons under low-intensity ultrasound through voltage-gated ion channels. [ABSTRACT FROM AUTHOR]