Search Results (217)

The development of antiepileptic drugs remains a serious challenge for both academia and industry. Ionotropic glutamate receptors and voltage-gated sodium channels are among the primary targets of antiepileptic agents. Recent studies have revealed a unique property of phenytoin: unlike other sodium-channel blockers, it inhibits calcium-impermeable AMPA receptors at micromolar concentrations. In this study, we explored the structure–activity relationships of eight phenytoin derivatives. The effects of the compounds on neuronal voltage-gated Na⁺ channels and neuronal AMPA receptor channels were examined using the patch-clamp technique. For the Na⁺ channels, we analyzed tonic block, shifts of steady-state inactivation, and frequency-dependent block. For the AMPA receptors, we investigated kinetics, agonist dependence, and trapping effects. NH groups at positions 1 and 3, the carbonyl groups at positions 2 and 4, and the phenyl group at position 5 are important, since their replacement causes a decrease in activity. Replacement of oxygen with sulfur at position 2 results in a significant increase in activity on both types of channels. For the AMPA receptor, this increase is attributable to a more stable drug–channel complex. The enhanced action on sodium channels is due to an increase in tonic block, whereas the effects on inactivated and open channels remain unchanged. These results suggest a new possibility for tuning the activities of phenytoin derivatives against both primary targets to obtain anticonvulsants with novel properties. Full article

Background/Objectives: Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive neuromodulatory approach with potential therapeutic value for cognitive impairment in Alzheimer’s disease (AD). Ferroptosis-related oxidative injury has been implicated in AD-associated neuronal dysfunction, but whether rTMS-induced functional improvement is accompanied by changes in ferroptosis-related oxidative injury remains unclear. This study evaluated the effects of high-frequency rTMS on cognitive function, hippocampal neuronal excitability, and ferroptosis-related oxidative injury in amyloid precursor protein/presenilin-1 (APP/PS1) mice, using Ferrostatin-1 (Fer-1) as a pharmacological comparator. Methods: Six-month-old female mice were used, including age-matched C57BL/6J controls and APP/PS1 mice assigned to the AD + Sham, AD + rTMS, and AD + Fer-1 groups (n = 6 per group). After 14 days of intervention, cognitive performance was assessed using behavioral tests. Whole-cell patch-clamp recordings were performed in hippocampal dentate gyrus granule neurons to evaluate neuronal excitability and voltage-gated sodium (Na⁺) and potassium (K⁺) channel properties. Biochemical assays and transmission electron microscopy were used to assess oxidative, iron-related, and mitochondrial changes, and mitochondrial ultrastructure was examined in an independent cohort (n = 3 per group) using transmission electron microscopy. Results: Compared with AD + Sham mice, high-frequency rTMS improved cognitive performance, increased evoked action potential firing, lowered the elevated action potential threshold, partially restored voltage-gated Na⁺ and K⁺ current amplitudes, and accelerated recovery of Na⁺ currents from inactivation. Fer-1 produced partially overlapping, but not identical, effects across behavioral, electrophysiological, biochemical, and ultrastructural outcomes. Both interventions increased hippocampal glutathione (GSH) levels, reduced malondialdehyde (MDA) and total iron levels, partially restored superoxide dismutase (SOD) activity, and improved mitochondrial ultrastructure and reduced the prevalence of mitochondrial profiles with small cross-sectional areas. Conclusions: High-frequency rTMS improved cognitive and hippocampal neuronal outcomes in female APP/PS1 mice. These improvements were accompanied by biochemical and mitochondrial changes compatible with attenuation of ferroptosis-related injury. However, the findings do not establish ferroptosis inhibition as either necessary or sufficient for the effects of rTMS. Full article

Chronic synovial inflammation is a hallmark of osteoarthritis progression and is tightly regulated by synovial macrophages. Recently, voltage-gated sodium channels (NaV) have emerged as potent modulators of macrophage-driven inflammation, positioning them as novel therapeutic targets. Among selective NaV channel blockers, neosaxitoxin exerts remarkable anesthetic and immunomodulatory effects; however, its effects on joint inflammation upon intra-articular delivery remain unexplored. Using an equine model of bilateral carpal osteoarthritis, this study evaluated the immunomodulatory and tissue-preserving effects of intra-articular neosaxitoxin. Sixteen horses were randomized into two experimental groups (n = 8/each): Neosaxitoxin in one joint and triamcinolone (+control) in the contralateral joint; or neosaxitoxin in one joint and saline (−control) in the contralateral joint. Clinical parameters, synovial fluid cytology and cytokine profiles, and histological changes in synovium and cartilage were assessed over 30 days. Neosaxitoxin reduced synovial inflammation, evidenced by decreased synovial effusion and surface temperature, along with improved joint flexion. Furthermore, synovial fluid from neosaxitoxin-treated joints exhibited lower counts of erythrocytes, neutrophils, total protein, and key pro-inflammatory mediators (IL-1β and IL-6) compared to saline-treated controls. Histologically, neosaxitoxin-treated joints exhibited modest synovial inflammatory cell infiltration and minor cartilage abnormalities. In contrast, control joints exhibited synovial hyperplasia, fibrovascular proliferation, and cartilage degeneration. Our data suggests that intra-articular neosaxitoxin better preserved joint homeostasis by limiting synovial inflammation and cartilage damage. These results warrant further investigation on Neosaxitoxin as a candidate treatment for inflammatory arthropathies. Full article

Full-length ACTH molecule and ACTH-related hexapeptide H-PKKRRP-OH are demonstrated by the patch-clamp method to decrease the Na_V1.8 channel activation gating system effective charge in the nociceptive neuron membrane, while ACTH-related tetrapeptide Ac-KKRR-NH₂ has no effect. ACTH(1–24), a fully functional ACTH mimetic, and H-PKKRRP-OH show analgesic effects in the formalin test in vivo. All peptides contain the cationic KKRR motif, but only H-PKKRRP-OH and ACTH(1–24) relieve acute pain, targeting the Na_V1.8 channel as a receptor. This seemingly controversial result is explained by application of conformational analysis and blind docking. Though conformational analysis indicates that both H-PKKRRP-OH and Ac-KKRR-NH₂ contain the cationic functional groups at the earlier suggested characteristic distance of 9–12 Å, Ac-KKRR-NH₂ does not interact with the S4_I voltage sensor of the Na_V1.8 channel activation gating system. The docking demonstrates that an extensive network of ligand–receptor ionic and hydrogen bonds involving D151, E157, R218, and R221 VSD_I residues, essential for the analgesic tripeptide Ac-KKK-NH₂ binding, is formed upon the H-PKKRRP-OH binding. Particularly important are the ionic bonds between the H-PKKRRP-OH C-terminal carboxylate anion and the S4_I R218 and R221 guanidinium groups. The described mechanism of Na_V1.8 channel modulation is fundamentally different from the effect of channel blockers. Full article

Little is known about how nicotinic signalling in human astrocytes may contribute to the functional neurotoxicity of compounds related to tobacco alkaloids and neonicotinoid pesticides. We generated a single-cell Ca²⁺-imaging assay in induced pluripotent stem cell (iPSC)-derived astrocytes, and profiled functional expressions of some neurotoxicologically relevant receptors. Responses to pharmacological tool compounds indicated the expression of nicotinic, muscarinic, purinergic, glutamatergic receptors and voltage-gated Na⁺/Ca²⁺ channels. Closer investigation of the nicotinic system, e.g., using the alpha7 nicotinic acetylcholine receptor (nAChR)-selective positive allosteric modulator PNU-120596 and alpha7-preferring agonist (AR-R17779) demonstrated that Ca²⁺ signals elicited by nicotine and neonicotinoids are dominated by alpha7 nAChRs and depend on the downstream activation of L-type Ca²⁺ channels and tetrodotoxin-sensitive Na⁺ channels. Crosstalk of nAChR activation/desensitization was not observed for the inflammatory response elicited by TNF or for activation of glutamatergic or purinergic signalling. However, pre-stimulation of nAChR by neonicotinoids significantly blunted the response to the neurotransmitter acetylcholine. Comparative experiments in the human neuronal cultures (LUHMES cells) revealed similar potency ranges and pharmacological fingerprints for several neonicotinoids and their human-relevant metabolites descyanothiacloprid and desnitroimidacloprid. The pesticide metabolites showed a high potency, compared with their respective parent compounds. After this basic system characterization, the hitherto data-poor pesticides cycloxaprid and flupyradifurone were comparatively profiled in astrocytic and neuronal test systems. They showed the typical features of alpha7 nAChR agonists. The disruption of cholinergic signalling in astrocytes suggests that neonicotinoids affect not only neurons in human brains. Therefore, future neurotoxicity screening approaches may need to consider astrocyte toxicity. Full article

Voltage-gated ion channels (VGICs) are traditionally associated with electrically excitable cells; however, increasing evidence indicates that they are also expressed in non-excitable cells, including vascular endothelial cells. This review aims to summarize the current knowledge on the expression, regulation, and functional role of VGICs in the vascular endothelium, and to highlight their potential contribution to endothelial signaling. We examined the molecular structure, biophysical properties, and functional roles of voltage-gated Na⁺ (Na_V), Ca²⁺ (Ca_V), and K⁺ (K_V) channels in vascular endothelial cells. Particular attention was given to studies investigating VGIC activity in native endothelium and to emerging mechanisms regulating their activation. Endothelial cells express multiple VGIC subtypes at low densities, which are insufficient to generate action potentials but can modulate membrane potential (V_M) and Ca²⁺-dependent signaling. The dynamic regulation of the endothelial V_M, through the interplay between hyperpolarizing and depolarizing conductances, emerges as a key determinant of VGIC availability and activation. VGICs contribute to essential endothelial functions, including angiogenesis, vasomotor responses, blood–brain barrier permeability, and inflammation. Dysregulated VGIC expression and/or activity may be implicated in several pathological conditions, such as atherosclerosis, calcific aortic stenosis, and tumor vascularization. VGICs represent an unexpected but functionally relevant component of endothelial signaling. Elucidating their role in native vascular beds and disease contexts may uncover novel mechanisms of endothelial regulation and identify new therapeutic targets in cardiovascular and cancer biology. Full article

Voltage-gated sodium channels are central to electrical excitability, and Nav1.7 is a major therapeutic target implicated in pain disorders and sensory signaling. Within the channel pore, permeating Na⁺ ions experience dynamically fluctuating hydration and coordination environments that may influence local ion–protein interactions. Identifying chemically distinct coordination states from molecular dynamics (MD) simulations is an important prerequisite for future higher-level electronic structure investigations. In this study, we present a reproducible workflow for identifying and classifying Na⁺ hydration–coordination microstates in the Nav1.7 pore using explicit-solvent molecular dynamics simulations. A geometrically defined pore region was used to quantify pore hydration and Na⁺ inner-shell coordination based on a 3.2 Å Na–O distance criterion. Na⁺ configurations were classified according to ligand identity into water-only (W), mixed protein–water (PW), and protein-only (P) microstates. Analysis of a 2 ns proof-of-principle simulation revealed a persistently hydrated pore environment, with Na⁺ coordination dominated by water-rich states and a smaller but distinct population of protein-contact configurations. These observations demonstrate that local coordination environments are chemically heterogeneous and cannot be fully described by hydration number alone. Representative structures from each microstate class were extracted to provide candidate configurations for future quantum mechanical, Quantum Mechanics/Molecular Mechanics (QM/MM), or density functional theory investigations of ion–ligand interactions in confined pore environments. The present work establishes a transparent and reproducible microstate-selection framework and does not report quantum mechanical energies, free-energy landscapes, or converged microstate populations. More broadly, the workflow provides a practical strategy for reducing complex MD ensembles into chemically interpretable coordination states suitable for subsequent higher-level analysis. Full article

Telmisartan (TEL) is a non-peptide, orally administered antihypertensive agent primarily known as angiotensin II type 1 (AT1) blocker. In this review, we provide a detailed overview of how TEL modulates voltage-gated Na⁺ current (I_Na) and affects action potential (AP) firing behavior. TEL exerts differential stimulatory effects on the peak and late components of I_Na when subjected to brief depolarizing pulses across a range of cell types, such as mHippoE-14 hippocampal neuron, cultured dorsal root ganglion neurons, and HL-1 atrial cardiomyocytes. TEL can augment the non-inactivating (persistent) I_Na elicited by ascending long ramp pulse in mHippoE-14 cells. By using a parvalbumin-expressing interneuron-based modeled cell combined with bifurcation analysis, it is possible to predict how applied current influences subthreshold oscillations and the generation of somatic spiking in the presence of TEL. According to the Hodgkin-Huxley model, mimicking the action of TEL—characterized by an increased peak amplitude of I_Na and a slowed inactivation time course—leads to the emergence of periodic oscillations in membrane potential. Using a Markovian process, a separate model can also be mathematically constructed, showing that changes in certain rate constants can simulate the effect of TEL on I_Na in cardiac cells. The molecular docking prediction between TEL and the Na_V1.7 channel was made by expected formation of hydrophobic interactions as well as hydrogen bonding. In addition to its antagonistic action at the AT1 receptor and its agonistic activation of peroxisome proliferator-activator-γ, TEL may also directly enhance I_Na, thereby modulating AP firing in a variety of excitable cells. Current evidence supports TEL’s modulatory impact on Na_V channel activity and cellular excitability, while also acknowledging that the mechanism—whether direct or indirect—remains under investigation. Full article

This study was performed to elucidate the mechanism underpinning the nodal swelling induced by equinatoxin II (EqtII), a cation-selective pore-forming toxin derived from the sea anemone Actinia equina. Experiments were conducted using frog myelinated nerve fibers as a model system. Application of EqtII led to an approximately two-fold increase in the nodal volume of myelinated axons, but only when extracellular Ca²⁺ was present. Replacing extracellular Cl⁻ with isethionate had no measurable effect on this response, whereas substitution of NaCl with either sucrose or LiCl, an established Na⁺/Ca²⁺ exchanger (NCX) inhibitor, abolished the swelling. The persistence of the effect in the presence of tetrodotoxin indicates that voltage-gated Na⁺ channels are not involved in the underlying mechanism. Our data suggest that Ca²⁺ influx through EqtII-induced membrane pores raises intracellular Ca²⁺ levels, thereby stimulating the NCX in its forward-operating mode. This process promotes Ca²⁺ extrusion in exchange for Na⁺ entry. The resulting accumulation of intracellular Na⁺ increases osmotic pressure within the axon, leading to water influx and nodal swelling. Full article

Human endometrial mesenchymal stem/stromal cells (eMSCs) are widely used in laboratories and clinical applications to study various aspects of tissue engineering and regenerative medicine. Three-dimensional (3D) cultivated MSCs have a higher therapeutic efficacy compared to 2D culture. Ion channels are involved in maintaining many physiological cell functions, including proliferation, differentiation, apoptosis, and migration. This study describes the functional expression of voltage-gated sodium channels (NaV) in eMSCs and the role of these channels in cell migration. Using RT-PCR analysis and immunofluorescent microscopy, we identified the expression of almost all pore-forming alpha (NaV 1.1, 1.2, 1.4–1.9) and channel-modulating beta-NaV subunits (except beta2) in eMSCs. In the whole-cell patch-clamp configuration, channels activated by membrane depolarization of eMSC were detected. The channels were blocked by the selective NaV antagonist TTX in nanomolar concentrations. The NaV agonist veratridine at a concentration of less than 40 μM inhibited voltage-gated sodium currents, while 100 μM and above prevented channel inactivation. The wound healing assay showed that both TTX (10 μM) and veratridine (100 μM) reduced the migration properties (the wound healing rate) of eMSCs cultivated in 2D conditions compared to the control. An opposite effect by both agents was shown on the motility of eMSCs cultivated in 3D conditions, increasing the cell spreading rate from spheroids. Our data suggest that NaV channels are expressed in human eMSCs and play an important role in the regulation of stem cell migration; this regulatory mechanism significantly depends on the culture conditions of MSCs. Full article

Dravet syndrome (DS) is a severe, catastrophic childhood epilepsy predominantly caused by loss-of-function mutations in the SCN1A gene, which encodes the voltage-gated sodium channel Na_v1.1. In this study, we evaluated the therapeutic potential of 5-(Benzofuran-2-yl)-3-(2-chloro-4-fluorobenzyl)-1,3,4-oxadiazol-2(3H)-one (GM-90663), a novel small molecule designed to address the complex pathophysiology of DS. Using scn1lab knockout (KO) zebrafish larvae—a robust vertebrate model for DS—we demonstrated that GM-90663 significantly alleviates seizure-like behavioral movements and rescues deficit in cognitive-like functions. Whole-cell patch-clamp recordings in hippocampal slices revealed that GM-90663 modulates voltage-gated Na⁺ channel kinetics; specifically, it suppresses slow ramp-induced currents, thereby effectively attenuating neuronal hyperexcitability. Furthermore, neurochemical profiling indicated that GM-90663 treatment leads to a marked increase in endogenous serotonin (5-HT) levels in both wild-type and KO larvae. Molecular docking simulations and subsequent in vitro enzymatic assays confirmed that this elevation in serotonin is mediated through the potent inhibition of monoamine oxidase (MAO) activity. Collectively, our findings suggest that GM-90663 exerts its anti-seizure effects through a synergistic dual mechanism—stabilizing sodium channel conductance and elevating serotonergic activity—positioning it as a promising multi-target candidate for the treatment of DS. Full article

We propose a terahertz (THz) antenna-coupled wire-channel field-effect transistor—modified EdgeFET (m-EdgeFET), formed by combining single-gate FinFET and dual-side-gate EdgeFET concepts, which is used for THz detection. The proposed hybrid design was implemented on AlGaN/GaN high-electron-mobility transistor (HEMT) structures, demonstrating distinct response characteristics under 150 GHz and 300 GHz radiation at room temperature. The responsivity dependence on the channel length was determined, revealing that the peak responsivity reached up to 6.5 V/W at a gate voltage of −3 V, i.e., at a gate bias that is an order lower in magnitude than that required for EdgeFET to reach the maximum response. Meanwhile, the gate leakage current decreased by an order of magnitude (to about 1 nA) compared to a FinFET with similar geometry. The proposed geometry was shown to operate in two regimes: source-drain coupling (SD) and gate coupling (GG) of THz radiation with the transistor wire channel. The results confirm that the m-EdgeFET design is suitable for electrically controlled and fast THz detection. Full article

This review provides a comprehensive overview of the modulatory actions of plant-derived constituents on membrane ion channels in various cell types. Among their diverse bioactivities, ion channel regulation—governing membrane excitability, signal transduction, and cellular homeostasis—has emerged as a critical mechanistic basis for their pharmacological effects. Twenty-four representative phytoconstituents are discussed and classified into five major categories based on their structural features: alkaloids, terpenoids, lignans and acetogenins, polyphenols, and other aromatic and conjugated compounds. Across these categories, the reviewed compounds exhibit distinct and often highly specific effects on the amplitude and gating kinetics of multiple ionic currents, including voltage-gated Na⁺ currents (I_Na), delayed-rectifier K⁺ currents (I_K(DR)), M-type K⁺ currents (I_K(M)), hyperpolarization-activated cation currents (I_h), erg-mediated K⁺ currents (I_K(erg)), inwardly rectifying K⁺ currents, and Ca²⁺-activated K⁺ currents (I_K(Ca)). Alkaloids predominantly suppress voltage-gated K⁺ currents, with notable exceptions such as aconitine, which alters the properties of both I_Na and I_K(DR), thereby contributing to its proarrhythmic toxicity. Terpenoids, including cannabidiol, croton diterpenoids, lutein, thymol, and triptolide, exert multifaceted effects on I_K(M), I_h, inwardly rectifying K⁺ currents, and Ca²⁺-activated K⁺ channels. Lignans and acetogenins, such as gomisin A, honokiol, sesamin, and squamocin, primarily modulate I_Na, I_h, and I_K(Ca), with several compounds demonstrating strong links between ion-channel modulation and anti-neoplastic or neuroprotective actions. Polyphenolic compounds, including curcumin, eugenol, resveratrol, gastrodigenin, gastrodin, and pterostilbene, display diverse ion-channel targeting profiles, influencing multiple Na⁺ and K⁺ channel subtypes. Other aromatic or conjugated compounds, such as isoplumbagin, plumbagin, and verteporfin, regulate I_K(erg) and I_K(Ca), potentially contributing to both therapeutic efficacy and adverse effects. Collectively, the compound-specific modulation of current amplitude and gating kinetics offers valuable mechanistic insight into the pharmacological and toxicological significance of plant-derived natural products, highlighting the functional role of ion channel evaluation in guiding their therapeutic development and ensuring safety assessment. Full article

Scorpion neurotoxins are small peptides that target ion channels and offer opportunities for novel therapeutic discovery. This study analyzed the functional effects of the venom and toxins from the Costa Rican endemic scorpion, Tityus championi. Initially, crude venom was tested on different isoforms of voltage-gated sodium channels. Our findings revealed that the venom contains toxins that affect mammalian Na_V1.6 and Na_V1.7, as well as the cockroach BgNa_V1 channel. Increased currents through Na_V1.6 and BgNa_V1 channels were associated with bigger window currents and inhibition of inactivation. Decreased Na_V1.7 currents were associated with smaller conductance. Crude venom and TCh3 toxin inhibited action potential generation in invertebrate neurons expressing Na_V1.7-like channels. In these neurons, Tch2 and Tch4 toxins shifted voltage sensitivity to more negative potentials, ultimately widening the window current but decreasing channel availability. Conversely, Tch3 behaved as an inhibitory toxin, closing window currents and decreasing channel availability. Structural modeling showed that Tch3 adopts an αββ fold and binds the S3–S4 loop of Domain II in human Na_V1.7. These data show the diverse effects of scorpion venoms on channels and neurons, characterize its principal toxins, and show that Tch3 has therapeutic potential for pain relief. Full article

Peptides from scorpion venom, mainly in species such as Olivierus martensii (formerly Olivierus martensii Karsch, often designated BMK) (BmK) and Tityus serrulatus from the Buthidae family, show real promise as painkillers that skip opioids altogether. They work by hitting specific ion channels and dialing down inflammation. This review gathers information on their molecular setups: disulfide-bridged types and those without, weighing in at 3 to 10 kilodaltons (kDa). Structural features include motifs stabilized by cysteines. In pain signaling, they block voltage-gated sodium channels (NaV) such as NaV1.7 and NaV1.8; take the BmK analgesic–antitumor peptide (BmK-AGAP) for example. Additionally, scorpion venom heat-resistant peptide (SVHRP) reduces microglia activity. Tests on rodents using formalin injections, acetic acid writhing, and chronic constriction injury (CCI) setups reveal pain relief that depends on dose and stacks up to morphine. Pairings like AGAP with lidocaine decrease the effective dose by half. In terms of safety, therapeutic levels have low-toxicity with a median lethal dose (LD50) over 20 mg/kg. Issues crop up with immune responses, unintended targets, and differences in venom batches. Clinical information remains thin, so gaps persist. Engineered versions could change the game for neuropathic pain, inflammatory conditions, and cancer-related discomfort. Standardization plus Phase I studies would help move this forward. Full article